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The Journal of Biological Chemistry Aug 2023Radiotherapy is one of the mainstay treatments for hepatocellular carcinoma (HCC). However, a substantial number of patients with HCC develop radioresistance and...
Radiotherapy is one of the mainstay treatments for hepatocellular carcinoma (HCC). However, a substantial number of patients with HCC develop radioresistance and eventually suffer from tumor progression or relapse, which is a major impediment to the use of radiotherapy. Therefore, elucidating the mechanisms underlying radioresistance and identifying novel therapeutic targets to improve patient prognosis are important in HCC management. In this study, using in vitro and in vivo models, laser microirradiation and live cell imaging methods, and coimmunoprecipitation assays, we report that a DNA repair enhancer, human positive cofactor 4 (PC4), promotes nonhomologous end joining-based DNA repair and renders HCC cells resistant to radiation. Mechanistically, PC4 interacts with poly (ADP-ribose) polymerase 1 and directs Ku complex PARylation, resulting in the successful recruitment of the Ku complex to damaged chromatin and increasing the efficiency of nonhomologous end joining repair. Clinically, PC4 is highly expressed in tumor tissues and is correlated with poor prognosis in patients with HCC. Taken together, our data suggest that PC4 is a DNA repair driver that can be targeted to radiosensitize HCC cells.
Topics: Humans; Carcinoma, Hepatocellular; DNA Damage; DNA End-Joining Repair; DNA Repair; Ku Autoantigen; Liver Neoplasms; Neoplasm Recurrence, Local; Poly ADP Ribosylation; Radiation Tolerance
PubMed: 37437887
DOI: 10.1016/j.jbc.2023.105032 -
International Journal of Biological... Dec 2023Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Radiotherapy, one of the standard treatments for GBM patients, could induce GBM radioresistance via...
Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Radiotherapy, one of the standard treatments for GBM patients, could induce GBM radioresistance via rewiring cellular metabolism. However, the precise mechanism attributing to GBM radioresistance or targeting strategies to overcome GBM radioresistance are lacking. Here, we demonstrate that SLC25A22, a mitochondrial bi-directional glutamate transporter, is upregulated and showed uni-directionality from mitochondria to cytosol in radioresistant GBM cells, resulting in accumulating cytosolic glutamate. However, mitochondrial glutaminolysis-mediated TCA cycle metabolites and OCR are maintained constantly. The accumulated cytosolic glutamate enhances the glutathione (GSH) production and proline synthesis in radioresistant GBM cells. Increased GSH protects cells against ionizing radiation (IR)-induced reactive oxygen species (ROS) whereas increased proline, a rate-limiting substrate for collagen biosynthesis, induces extracellular matrix (ECM) remodeling, leading to GBM invasive phenotypes. Finally, we discover that genetic inhibition of SLC25A22 using miR-184 mimic decreases GBM radioresistance and aggressiveness both in vitro and in vivo. Collectively, our study suggests that SLC25A22 upregulation confers GBM radioresistance by rewiring glutamate metabolism, and SLC25A22 could be a significant therapeutic target to overcome GBM radioresistance.
Topics: Humans; Glioblastoma; Glutamic Acid; Radiation Tolerance; Cell Line, Tumor; Brain Neoplasms; Mitochondria; Proline; Mitochondrial Membrane Transport Proteins
PubMed: 37866557
DOI: 10.1016/j.ijbiomac.2023.127511 -
Advanced Materials (Deerfield Beach,... Sep 2023The perovskite compound CsPbBr has recently been discovered as a promising room-temperature semiconductor radiation detector, offering an inexpensive and...
The perovskite compound CsPbBr has recently been discovered as a promising room-temperature semiconductor radiation detector, offering an inexpensive and easy-to-manufacture alternative to the current benchmark material Cd Zn Te (CZT). The performance of CsPbBr sensors is evaluated under harsh conditions, such as high radiation doses often found in industrial settings and extreme radiation in space. Results show minimal degradation in detector performance after exposure to 1 Mrad of Co-60 gamma radiation, with no significant change to energy resolution or hole mobility and lifetime. Additionally, many of the devices are still functional after being exposed to a 10 Mrad dose over 3 days, and those that do not survive can still be refabricated into working detectors. These results suggest that the failure mode in these devices is likely related to the interface between the electrode and material and their reaction, or the electrode itself and not the material itself. Overall, the study suggests that CsPbBr has high potential as a reliable and efficient radiation detector in various applications, including those involving extreme fluxes and energies of gamma-ray radiation.
PubMed: 37285797
DOI: 10.1002/adma.202303244 -
Radiotherapy and Oncology : Journal of... Aug 2023Mouse and non-human primate models showed that serum miRNAs may be used to predict the biological impact of radiation doses. We hypothesized that these results can be...
PURPOSE
Mouse and non-human primate models showed that serum miRNAs may be used to predict the biological impact of radiation doses. We hypothesized that these results can be translated to humans treated with total body irradiation (TBI), and that miRNAs may be used as clinically feasible biodosimeters.
METHODS
To test this hypothesis, serial serum samples were obtained from 25 patients (pediatric and adults) who underwent allogeneic stem-cell transplantation and profiled for miRNA expression using next-generation sequencing. miRNAs with diagnostic potential were quantified with qPCR and used to build logistic regression models with lasso penalty to reduce overfitting, identifying samples drawn from patients who underwent total body irradiation to a potentially lethal dose.
RESULTS
Differential expression results were consistent with previous studies in mice and non-human primates. miRNAs with detectable expression in this and two prior animal sets allowed for distinction of the irradiated from non-irradiated samples in mice, macaques and humans, validating the miRNAs as radiation-responsive through evolutionarily conserved transcriptional regulation mechanisms. Finally, we created a model based on the expression of miR-150-5p, miR-30b-5p and miR-320c normalized to two references and adjusted for patient age with an AUC of 0.9 (95%CI:0.83-0.97) for identifying samples drawn after irradiation; a separate model differentiating between high and low radiation dose achieved AUC of 0.85 (95%CI: 0.74-0.96).
CONCLUSIONS
We conclude that serum miRNAs reflect radiation exposure and dose for humans undergoing TBI and may be used as functional biodosimeters for precise identification of people exposed to clinically significant radiation doses.
Topics: Adult; Humans; Mice; Animals; Child; MicroRNAs; Radiation Exposure; Whole-Body Irradiation; Dose-Response Relationship, Radiation; Biomarkers
PubMed: 37301262
DOI: 10.1016/j.radonc.2023.109731 -
Journal of Translational Medicine Nov 2023Investigating the impact of centromere protein N (CENP-N) on radiosensitivity of nasopharyngeal carcinoma (NPC) cells.
OBJECTIVE
Investigating the impact of centromere protein N (CENP-N) on radiosensitivity of nasopharyngeal carcinoma (NPC) cells.
METHODS
Using immunohistochemistry and immunofluorescence to detect CENP-N expression in tissues from 35 patients with radiosensitive or radioresistant NPC. Assessing the effect of combined CENP-N knockdown and radiotherapy on various cellular processes by CCK-8, colony formation, flow cytometry, and Western blotting. Establishing a NPC xenograft model. When the tumor volume reached 100 mm, a irradiation dose of 6 Gy was given, and the effects of the combined treatment were evaluated in vivo using immunofluorescence and Western blotting techniques.
RESULTS
The level of CENP-N was significantly reduced in radiosensitive tissues of NPC (p < 0.05). Knockdown of CENP-N enhanced NPC radiosensitivity, resulting in sensitizing enhancement ratios (SER) of 1.44 (5-8 F) and 1.16 (CNE-2Z). The combined treatment showed significantly higher levels of proliferation suppression, apoptosis, and G2/M phase arrest (p < 0.01) compared to either CENP-N knockdown alone or radiotherapy alone. The combined treatment group showed the highest increase in Bax and γH2AX protein levels, whereas the protein Cyclin D1 exhibited the greatest decrease (p < 0.01). However, the above changes were reversed after treatment with AKT activator SC79. In vivo, the mean volume and weight of tumors in the radiotherapy group were 182 ± 54 mm and 0.16 ± 0.03 g. The mean tumor volume and weight in the combined treatment group were 84 ± 42 mm and 0.04 ± 0.01 g.
CONCLUSION
Knockdown of CENP-N can enhance NPC radiosensitivity by inhibiting AKT/mTOR.
Topics: Humans; Nasopharyngeal Carcinoma; Proto-Oncogene Proteins c-akt; Nasopharyngeal Neoplasms; Cell Line, Tumor; Radiation Tolerance; TOR Serine-Threonine Kinases; Cell Proliferation; Apoptosis
PubMed: 37940975
DOI: 10.1186/s12967-023-04654-x -
Clinical and Translational Radiation... Mar 2024Radiotherapy is the dominant treatment modality for painful spine and non-spine bone metastases (NSBM). Historically, this was achieved with conventional low dose...
Radiotherapy is the dominant treatment modality for painful spine and non-spine bone metastases (NSBM). Historically, this was achieved with conventional low dose external beam radiotherapy, however, stereotactic body radiotherapy (SBRT) is increasingly applied for these indications. Meta-analyses and randomized clinical trials have demonstrated improved pain response and more durable tumor control with SBRT for spine metastases. However, in the setting of NSBM, there is limited evidence supporting global adoption and large scale randomized clinical trials are in need. SBRT is technically demanding requiring careful consideration of organ at risk tolerance, and strict adherence to technical requirements including immobilization, simulation, contouring and image-guidance procedures. Additional considerations include follow up practices after SBRT, with appropriate imaging playing a critical role in response assessment. Finally, there is renewed research into promising new technologies that may further refine the use of SBRT in both spinal and NSBM in the years to come.
PubMed: 38226025
DOI: 10.1016/j.ctro.2023.100716 -
Biochemical and Biophysical Research... Sep 2023The therapeutic effects and application of radiotherapy are restricted to some extent due to low radiosensitivity of tumor tissues and adverse effects by excess dosage....
The therapeutic effects and application of radiotherapy are restricted to some extent due to low radiosensitivity of tumor tissues and adverse effects by excess dosage. Current radiosensitizers are confronted with problems in clinical translation because of complicated manufacture technique and high cost. In this research, we have synthesized a radiosensitizer with advantages in low cost and mass production, which could be applied to CT imaging and enhanced radiotherapy in breast cancer, namely Bi-DTPA. It not only enhanced tumor CT imaging which resulted in better therapeutic accuracy, but also realized radiotherapy sensitization by producing massive ROS and inhibit tumor proliferation, providing a sound perspective in the clinical translation of the radiosensitizer.
Topics: Humans; Radiation-Sensitizing Agents; Radiation Tolerance; Neoplasms; Pentetic Acid; Tomography, X-Ray Computed
PubMed: 37302294
DOI: 10.1016/j.bbrc.2023.05.065 -
IScience Oct 2023Multi-principal element alloys (MPEAs) have gained extensive interest for structural applications owing to their excellent strength, fracture toughness, wear resistance,... (Review)
Review
Multi-principal element alloys (MPEAs) have gained extensive interest for structural applications owing to their excellent strength, fracture toughness, wear resistance, creep resistance, and fatigue resistance. In this review, recent progress in the computational design of MPEAs for structural applications is outlined. This includes the scientific advancements achieved through computational methods in the field of structural MPEAs, how new methodologies have emerged due to the needs of complex alloy systems, and adaptations to the existing tools to address emerging problems in the field. We discuss advances in atomistic simulation methods, including structure generation algorithms, element-resolved local lattice distortion, chemical short-range order, local slip resistance, and radiation tolerance, along with experimental comparisons. A detailed discussion on interatomic potentials is included, with a focus on various machine learning-based fitting methods. The application of data science and machine learning for identifying and discovering MPEAs with desirable mechanical performance is summarized and presented.
PubMed: 37727734
DOI: 10.1016/j.isci.2023.107751 -
Advanced Science (Weinheim,... May 2024Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis...
Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.
Topics: Colorectal Neoplasms; Mice; Animals; Humans; Mitochondria; Liposomes; Metformin; Radiation Tolerance; Cell Line, Tumor; Disease Models, Animal; Activating Transcription Factor 4
PubMed: 38520732
DOI: 10.1002/advs.202400845 -
Japanese Journal of Radiology Nov 2023Metformin is considered as radiation modulator in both tumors and healthy tissues. Radiomics has the potential to decode biological mechanisms of radiotherapy response....
PURPOSE
Metformin is considered as radiation modulator in both tumors and healthy tissues. Radiomics has the potential to decode biological mechanisms of radiotherapy response. The aim of this study was to apply radiomics analysis in metformin-induced radiosensitivity and finding radioproteomics associations of computed tomography (CT) imaging features and proteins involved in metformin radiosensitivity signaling pathways.
MATERIALS AND METHODS
A total of 32 female BALB/c mice were used in this study and were subjected to injection of breast cancer cells. When tumors reached a mean volume of 150 mm, mice were randomly divided into the four groups including Control, Metformin, Radiation, and Radiation + Metformin. Western blot analysis was performed after treatment to measure expression of proteins including AMPK-alpha, phospho-AMPK-alpha (Thr172), mTOR, phospho-mTOR (Ser2448), phospho-4EBP1 (Thr37/46), phospho-ACC (Ser79), and β-actin. CT imaging was performed before treatment and at the end of treatment in all groups. Radiomics features extracted from segmented tumors were selected using Elastic-net regression and were assessed in terms of correlation with expression of the proteins.
RESULTS
It was observed that proteins including phospho-mTOR, phospho-4EBP1, and mTOR had positive correlations with changes in tumor volumes in days 28, 24, 20, 16, and 12, while tumor volume changes at these days had negative correlations with AMPK-alpha, phospho-AMPK-alpha, and phospho-ACC proteins. Furthermore, median feature had a positive correlation with AMPK-alpha, phospho-ACC, and phospho-AMPK-alpha proteins. Also, Cluster shade feature had positive correlations with mTOR and p-mTOR. On the other hand, LGLZE feature had negative correlations with AMPK-alpha and phospho-AMPK-alpha.
CONCLUSION
Radiomics features can decode proteins that involved in response to metformin and radiation, although further studies are warranted to investigate the optimal way to integrate radiomics into biological experiments.
Topics: Female; Mice; Animals; Metformin; AMP-Activated Protein Kinases; TOR Serine-Threonine Kinases; Radiation Tolerance; Neoplasms
PubMed: 37204669
DOI: 10.1007/s11604-023-01445-8