scholarly journals Impact of Hypoxia on Carbon Ion Therapy in Glioblastoma Cells: Modulation by LET and Hypoxia-Dependent Genes

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2019 ◽  
Author(s):  
Samuel Valable ◽  
Aurélie N. Gérault ◽  
Gaëlle Lambert ◽  
Marine M. Leblond ◽  
Clément Anfray ◽  
...  
Keyword(s):  
Tumor Hypoxia ◽  
Physical Factors ◽  
X Rays ◽  
Erk Activation ◽  
Carbon Ion ◽  
Hypoxic Environment ◽  
Ion Therapy ◽  
High Let ◽  
A Cell

Tumor hypoxia is known to limit the efficacy of ionizing radiations, a concept called oxygen enhancement ratio (OER). OER depends on physical factors such as pO2 and linear energy transfer (LET). Biological pathways, such as the hypoxia-inducible transcription factors (HIF), might also modulate the influence of LET on OER. Glioblastoma (GB) is resistant to low-LET radiation (X-rays), due in part to the hypoxic environment in this brain tumor. Here, we aim to evaluate in vitro whether high-LET particles, especially carbon ion radiotherapy (CIRT), can overcome the contribution of hypoxia to radioresistance, and whether HIF-dependent genes, such as erythropoietin (EPO), influence GB sensitivity to CIRT. Hypoxia-induced radioresistance was studied in two human GB cells (U251, GL15) exposed to X-rays or to carbon ion beams with various LET (28, 50, 100 keV/µm), and in genetically-modified GB cells with downregulated EPO signaling. Cell survival, radiobiological parameters, cell cycle, and ERK activation were assessed under those conditions. The results demonstrate that, although CIRT is more efficient than X-rays in GB cells, hypoxia can limit CIRT efficacy in a cell-type manner that may involve differences in ERK activation. Using high-LET carbon beams, or targeting hypoxia-dependent genes such as EPO might reduce the effects of hypoxia.

scholarly journals 64Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6159
Author(s):  
Ankita Nachankar ◽  
Takahiro Oike ◽  
Hirofumi Hanaoka ◽  
Ayaka Kanai ◽  
Hiro Sato ◽  
...  
Keyword(s):  
Antioxidant Capacity ◽  
Predictive Biomarkers ◽  
Carbon Ion Radiotherapy ◽  
Therapeutic Window ◽  
Antioxidant Systems ◽  
Related Factor ◽  
X Rays ◽  
Carbon Ion ◽  
New Findings

Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.

scholarly journals Differential effects of high versus low linear energy transfer (LET) radiation on type-I interferon (IFNβ) and TREX1 responses

2021 ◽  
Author(s):  
Devin Miles ◽  
Ning Cao ◽  
George Sandison ◽  
Robert D Stewart ◽  
Greg Moffitt ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Bragg Peak ◽  
Type I Interferon ◽  
Absorbed Dose ◽  
Fast Neutrons ◽  
Type I ◽  
X Rays ◽  
High Let ◽  
Unit Dose

Purpose: Cancer cells produce innate immune signals following radiation damage, with STING pathway signaling as a critical mediator. High linear energy transfer (LET) radiations create larger numbers of DNA double-strand breaks (DSBs) per unit dose than low-LET radiations and may therefore be more immunogenic. We studied the dose response characteristics of pro-immunogenic type-I interferon, interferon-beta (IFNβ), and its reported suppressor signal, three-prime repair exonuclease 1 (TREX1), in vitro with low-LET x-rays and high-LET fast neutrons. Methods: Merkel cell carcinoma cells (MCC) were irradiated by graded doses of x-rays (1-24 Gy) or fast neutrons (1-8 Gy). IFNβ was measured as a function of dose via ELISA assay, and exonuclease TREX1 expression via immunofluorescence microscopy. The Monte Carlo damage simulation (MCDS) was used to model fast neutron relative biological effectiveness for DSB induction (RBEDSB) and compared to laboratory measurements of the RBE for IFNβ production (RBEIFNβ) and TREX1 upregulation (RBETREX1). RBEIFNβ models were also applied to radiation transport simulations to quantify the potential secretion of IFNβ in representative clinical beams. Results: Peak IFNβ secretion occurred at 5.7 Gy for fast neutrons and at 14.0 Gy for x-rays, i.e., an effective RBEIFNβ of 2.5 ± 0.2. The amplitude (peak value) of secreted IFNβ signal did not significantly differ between x-rays and fast neutrons (P > 0.05). TREX1 signal increased linearly with absorbed dose, with a four-fold higher upregulation per unit dose for fast neutrons relative to x-rays (RBETREX1 of 4.0 ± 0.1). Monte Carlo modeling of IFNβ suggests Bragg peak-to-entrance ratios of IFNβ production of 40, 100, and 120 for proton, alpha, and carbon ion beams, respectively, a factor of 10-20-fold higher compared to their corresponding physical dose peak-to-entrance ratios. The spatial width of the Bragg peak for IFNβ production is also a factor of two smaller. Conclusion: High-LET fast neutrons initiate a larger IFNβ response per unit absorbed dose than low-LET x-rays (i.e., RBEIFNβ value of 2.5). The RBE value for IFNβ is quite similar to data reported in the literature for DSB induction and cellular, post-irradiation micronucleation formation for neutrons and x-rays. The increased IFNβ release after high-LET radiation may be a contributing factor in stimulating a systemic anti-tumor, adaptive immune response (abscopal effect). However, our results indicate that TREX1 anti-inflammatory signaling in vitro for MCC cells is larger per unit dose for fast neutrons than for x-rays (RBETREX1 of 4.0). Given these competing effects, additional studies are needed to clarify whether or not high-LET radiations are therapeutically advantageous over low-LET radiation for pro-inflammatory immune signaling in other cell lines in vitro and for in vivo cancer models.

scholarly journals Dependence and independence of survival parameters on linear energy transfer in cells and tissues

2016 ◽  
Vol 57 (6) ◽  
pp. 596-606 ◽  
Author(s):  
Koichi Ando ◽  
Dudley T. Goodhead
Keyword(s):  
Energy Transfer ◽  
Linear Energy Transfer ◽  
Quadratic Model ◽  
X Rays ◽  
Linear Quadratic ◽  
Linear Quadratic Model ◽  
Mammalian Cell Lines ◽  
High Let Radiation ◽  
High Let

Abstract Carbon-ion radiotherapy has been used to treat more than 9000 cancer patients in the world since 1994. Spreading of the Bragg peak is necessary for carbon-ion radiotherapy, and is designed based on the linear–quadratic model that is commonly used for photon therapy. Our recent analysis using in vitro cell kills and in vivo mouse tissue reaction indicates that radiation quality affects mainly the alpha terms, but much less the beta terms, which raises the question of whether this is true in other biological systems. Survival parameters alpha and beta for 45 in vitro mammalian cell lines were obtained by colony formation after irradiation with carbon ions, fast neutrons and X-rays. Relationships between survival parameters and linear energy transfer (LET) below 100 keV/μm were obtained for 4 mammalian cell lines. Mouse skin reaction and tumor growth delay were measured after fractionated irradiation. The Fe-plot provided survival parameters of the tissue reactions. A clear separation between X-rays and high-LET radiation was observed for alpha values, but not for beta values. Alpha values/terms increased with increasing LET in any cells and tissues studied, while beta did not show a systematic change. We have found a puzzle or contradiction in common interpretations of the linear-quadratic model that causes us to question whether the model is appropriate for interpreting biological effectiveness of high-LET radiation up to 500 keV/μm, probably because of inconsistency in the concept of damage interaction. A repair saturation model proposed here was good enough to fit cell kill efficiency by radiation of wide-ranged LET. A model incorporating damage complexity and repair saturation would be suitable for heavy-ion radiotherapy.

Nitroreductase-Induced Aggregation of Gold Nanoparticles for “Off–On” Photoacoustic Imaging of Tumor Hypoxia

2021 ◽  
Vol 17 (11) ◽  
pp. 2186-2197
Author(s):  
Xin Li ◽  
Xueyang Fang ◽  
Shiying Li ◽  
Kwok-Ho Lui ◽  
Wai-Sum Lo ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Photoacoustic Imaging ◽  
Tumor Hypoxia ◽  
Hypoxic Conditions ◽  
Hypoxic Environment ◽  
Diagnostic Agents ◽  
Surface Ligand ◽  
Induced Aggregation

Hypoxia is an important phenomenon due to insufficient oxygen supply in tumor tissue, and nitroreductase (NTR) is a characteristic enzyme used for evaluating hypoxia level in tumors. In this work, we designed a smart gold nanoparticle (AuNPs), modified by 16-mercaptoundecanoic acid (MHDA) and hypoxia-responsive 11-(2-nitro-1H-imidazol-1-yl)undecane-1-thiol (NI) ligand, that responds to the hypoxic environment in tumor sites. With proper surface ligand composition, the responsive nanoprobe exhibited aggregation through the bioreduction of the nitro group on NI ligands under hypoxic conditions and the UV-vis absorption peak maximum would shift to 630 nm from 530 nm, which acts as an “off–on” contrast agent for tumor hypoxic photoacoustic (PA) imaging. In vitro and in vivo experiments revealed that AuNPs@MHDA/NO2 exhibited an enhanced PA signal in hypoxic conditions. This study demonstrates the potential of hypoxia-responsive AuNPs as novel and sensitive diagnostic agents, which lays a firm foundation for precise cancer treatment in the future.

High-LET radiotherapy for adenoid cystic carcinoma of the head and neck: 15 years’ experience with raster-scanned carbon ion therapy

2016 ◽  
Vol 118 (2) ◽  
pp. 272-280 ◽  
Author(s):  
Alexandra D. Jensen ◽  
Melanie Poulakis ◽  
Anna V. Nikoghosyan ◽  
Thomas Welzel ◽  
Matthias Uhl ◽  
...  
Keyword(s):  
Adenoid Cystic Carcinoma ◽  
Head And Neck ◽  
Carbon Ion Therapy ◽  
Carbon Ion ◽  
Adenoid Cystic ◽  
Ion Therapy ◽  
High Let

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

Using FRET to Measure the Time it Takes for a Cell to Destroy a Virus

2019 ◽  
Author(s):  
Candace E. Benjamin ◽  
Zhuo Chen ◽  
Olivia Brohlin ◽  
Hamilton Lee ◽  
Stefanie Boyd ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Rhodamine B ◽  
Virus Like Particle ◽  
A Cell ◽  
Viral Nanoparticles ◽  
The Stability ◽  
Open Question ◽  
Viral Surface ◽  
Fret Pair

<div><div><div><p>The emergence of viral nanotechnology over the preceding two decades has created a number of intellectually captivating possible translational applications; however, the in vitro fate of the viral nanoparticles in cells remains an open question. Herein, we investigate the stability and lifetime of virus-like particle (VLP) Qβ - a representative and popular VLP for several applications - following cellular uptake. By exploiting the available functional handles on the viral surface, we have orthogonally installed the known FRET pair, FITC and Rhodamine B, to gain insight of the particle’s behavior in vitro. Based on these data, we believe VLPs undergo aggregation in addition to the anticipated proteolysis within a few hours of cellular uptake.</p></div></div></div>

Sign in / Sign up

Export Citation Format

Share Document