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Nature Communications Apr 2024Glioblastoma (GBM) is a highly lethal type of cancer. GBM recurrence following chemoradiation is typically attributed to the regrowth of invasive and resistant cells....
Glioblastoma (GBM) is a highly lethal type of cancer. GBM recurrence following chemoradiation is typically attributed to the regrowth of invasive and resistant cells. Therefore, there is a pressing need to gain a deeper understanding of the mechanisms underlying GBM resistance to chemoradiation and its ability to infiltrate. Using a combination of transcriptomic, proteomic, and phosphoproteomic analyses, longitudinal imaging, organotypic cultures, functional assays, animal studies, and clinical data analyses, we demonstrate that chemoradiation and brain vasculature induce cell transition to a functional state named VC-Resist (vessel co-opting and resistant cell state). This cell state is midway along the transcriptomic axis between proneural and mesenchymal GBM cells and is closer to the AC/MES1-like state. VC-Resist GBM cells are highly vessel co-opting, allowing significant infiltration into the surrounding brain tissue and homing to the perivascular niche, which in turn induces even more VC-Resist transition. The molecular and functional characteristics of this FGFR1-YAP1-dependent GBM cell state, including resistance to DNA damage, enrichment in the G2M phase, and induction of senescence/stemness pathways, contribute to its enhanced resistance to chemoradiation. These findings demonstrate how vessel co-option, perivascular niche, and GBM cell plasticity jointly drive resistance to therapy during GBM recurrence.
Topics: Glioblastoma; Humans; Animals; Brain Neoplasms; Cell Line, Tumor; Mice; Chemoradiotherapy; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Radiation Tolerance; YAP-Signaling Proteins; Brain; Proteomics
PubMed: 38684700
DOI: 10.1038/s41467-024-47985-z -
Acta Oncologica (Stockholm, Sweden) Apr 2024Doses to the coronary arteries in breast cancer (BC) radiotherapy (RT) have been suggested to be a risk predictor of long-term cardiac toxicity after BC treatment. We...
Doses to the right coronary artery and the left anterior descending coronary artery and death from ischemic heart disease after breast cancer radiotherapy: a case-control study in a population-based cohort.
BACKGROUND AND PURPOSE
Doses to the coronary arteries in breast cancer (BC) radiotherapy (RT) have been suggested to be a risk predictor of long-term cardiac toxicity after BC treatment. We investigated the dose-risk relationships between near maximum doses (Dmax) to the right coronary artery (RCA) and left anterior descending coronary artery (LAD) and ischemic heart disease (IHD) mortality after BC RT.
PATIENTS AND METHODS
In a cohort of 2,813 women diagnosed with BC between 1958 and 1992 with a follow-up of at least 10 years, we identified 134 cases of death due to IHD 10-19 years after BC diagnosis. For each case, one control was selected within the cohort matched for age at diagnosis. 3D-volume and 3D-dose reconstructions were obtained from individual RT charts. We estimated the Dmax to the RCA and the LAD and the mean heart dose (MHD). We performed conditional logistic regression analysis comparing piecewise spline transformation and simple linear modeling for best fit.
RESULTS
There was a linear dose-risk relationship for both the Dmax to the RCA (odds ratio [OR]/Gray [Gy] 1.03 [1.01-1.05]) and the LAD (OR/Gy 1.04 [1.02-1.06]) in a multivariable model. For MHD there was a linear dose-risk relationship (1,14 OR/Gy [1.08-1.19]. For all relationships, simple linear modelling was superior to spline transformations.
INTERPRETATION
Doses to both the RCA and LAD are independent risk predictors of long-term cardiotoxicity after RT for BC In addition to the LAD, the RCA should be regarded as an organ at risk in RT planning.
Topics: Humans; Female; Breast Neoplasms; Case-Control Studies; Middle Aged; Coronary Vessels; Myocardial Ischemia; Aged; Adult; Radiation Injuries; Radiotherapy Dosage; Dose-Response Relationship, Radiation; Organs at Risk; Follow-Up Studies; Cohort Studies
PubMed: 38682458
DOI: 10.2340/1651-226X.2024.19677 -
Journal of Synchrotron Radiation May 2024Improving the scalability of tissue imaging throughput with bright, coherent X-rays requires identifying and mitigating artifacts resulting from the interactions between...
Improving the scalability of tissue imaging throughput with bright, coherent X-rays requires identifying and mitigating artifacts resulting from the interactions between X-rays and matter. At synchrotron sources, long-term imaging of soft tissues in solution can result in gas bubble formation or cavitation, which dramatically compromises image quality and integrity of the samples. By combining in-line phase-contrast imaging with gas chromatography in real time, we were able to track the onset and evolution of high-energy X-ray-induced gas bubbles in ethanol-embedded soft tissue samples for tens of minutes (two to three times the typical scan times). We demonstrate quantitatively that vacuum degassing of the sample during preparation can significantly delay bubble formation, offering up to a twofold improvement in dose tolerance, depending on the tissue type. However, once nucleated, bubble growth is faster in degassed than undegassed samples, indicating their distinct metastable states at bubble onset. Gas chromatography analysis shows increased solvent vaporization concurrent with bubble formation, yet the quantities of dissolved gasses remain unchanged. By coupling features extracted from the radiographs with computational analysis of bubble characteristics, we uncover dose-controlled kinetics and nucleation site-specific growth. These hallmark signatures provide quantitative constraints on the driving mechanisms of bubble formation and growth. Overall, the observations highlight bubble formation as a critical yet often overlooked hurdle in upscaling X-ray imaging for biological tissues and soft materials and we offer an empirical foundation for their understanding and imaging protocol optimization. More importantly, our approaches establish a top-down scheme to decipher the complex, multiscale radiation-matter interactions in these applications.
Topics: X-Rays; Animals; Synchrotrons; Gases; Chromatography, Gas; Ethanol
PubMed: 38682274
DOI: 10.1107/S160057752400290X -
Frontiers in Bioscience (Landmark... Apr 2024Gliomas are characterized by aggressive behavior, leading to severe disability and high mortality. Ubiquitin-like modifier activating enzyme 2 (UBA2) is a subunit of the...
BACKGROUND
Gliomas are characterized by aggressive behavior, leading to severe disability and high mortality. Ubiquitin-like modifier activating enzyme 2 (UBA2) is a subunit of the E1-activating enzyme involved in the SUMOylation (SUMO, small ubiquitin-related modifier) of numerous proteins. Although the abnormality of is linked to the progression of various tumor types, the role of in glioma is still unknown.
METHODS
A bioinformatic analysis using several public databases was conducted to examine the expression level, clinicopathological correlations, and prognostic significance of UBA2 in glioma. The correlation between UBA2 expression and drug sensitivity in cancers was also explored. Multiple cellular experiments were conducted to validate the role of in glioma.
RESULTS
Analysis of multiple databases and cellular experiments revealed that UBA2 was overexpressed in glioma tissues and cell lines, respectively. UBA2 expression in gliomas correlated with World Health Organization (WHO) grade, gene status, deletion, histological type, and immune cell infiltration in glioma. UBA2 expression in carcinomas also correlated with drug sensitivity. Kaplan-Meier analysis revealed that high expression of UBA2 predicted poorer survival in glioma patients. A nomogram model containing UBA2 expression was constructed for clinical practice. Knockdown of was observed to suppress glioma cell progression and sensitize glioma cells to irradiation .
CONCLUSION
Overall, this research showed that might be involved not only in the development of glioma but also in the regulation of immunity, drug sensitivity, and radiosensitivity. Therefore, may be a potential target for therapy and a candidate biomarker for glioma diagnosis and prognosis.
Topics: Glioma; Biomarkers, Tumor; Cell Line, Tumor; Prognosis; Ubiquitin-Activating Enzymes; Immunotherapy; Radiation Tolerance; Disease Progression
PubMed: 38682183
DOI: 10.31083/j.fbl2904144 -
Micromachines Apr 2024The single-event effects (SEEs) of frequency divider circuits and the radiation tolerance of the hardened circuit are studied in this paper. Based on the experimental...
The single-event effects (SEEs) of frequency divider circuits and the radiation tolerance of the hardened circuit are studied in this paper. Based on the experimental results of SEEs in InP HBTs, a transient current model for sensitive transistors is established, taking into account the influence of factors such as laser energy, base-collector junction voltage, and radiation position. Moreover, the SEEs of the (2:1) static frequency divider circuit with the InP DHBT process are simulated under different laser energies by adding the transient current model at sensitive nodes. The effect of the time relationship between the pulsed laser and clock signal are discussed. Changes in differential output voltage and the degradation mechanism of unhardened circuits are analyzed, which are mainly attributed to the cross-coupling effect between the transistors in the differential pair. Furthermore, the inverted output is directly connected to the input, leading to a feedback loop and causing significant logic upsets. Finally, an effective hardened method is proposed to provide redundancy and mitigate the impacts of SEEs on the divider. The simulation results demonstrate a notable improvement in the radiation tolerance of the divider.
PubMed: 38675338
DOI: 10.3390/mi15040527 -
Microorganisms Apr 2024Studies investigating the taxonomic diversity and structure of soil bacteria in areas with enhanced radioactive backgrounds have been ongoing for three decades. An... (Review)
Review
Studies investigating the taxonomic diversity and structure of soil bacteria in areas with enhanced radioactive backgrounds have been ongoing for three decades. An analysis of data published from 1996 to 2024 reveals changes in the taxonomic structure of radioactively contaminated soils compared to the reference, showing that these changes are not exclusively dependent on contamination rates or pollutant compositions. High levels of radioactive exposure from external irradiation and a high radionuclide content lead to a decrease in the alpha diversity of soil bacterial communities, both in laboratory settings and environmental conditions. The effects of low or moderate exposure are not consistently pronounced or unidirectional. Functional differences among taxonomic groups that dominate in contaminated soil indicate a variety of adaptation strategies. Bacteria identified as multiple-stress tolerant; exhibiting tolerance to metals and antibiotics; producing antioxidant enzymes, low-molecular antioxidants, and radioprotectors; participating in redox reactions; and possessing thermophilic characteristics play a significant role. Changes in the taxonomic and functional structure, resulting from increased soil radionuclide content, are influenced by the combined effects of ionizing radiation, the chemical toxicity of radionuclides and co-contaminants, as well as the physical and chemical properties of the soil and the initial bacterial community composition. Currently, the quantification of the differential contributions of these factors based on the existing published studies presents a challenge.
PubMed: 38674676
DOI: 10.3390/microorganisms12040733 -
International Journal of Molecular... Apr 2024Cellular hypoxia, detectable in up to 80% of non-small cell lung carcinoma (NSCLC) tumors, is a known cause of radioresistance. High linear energy transfer (LET)...
Cellular hypoxia, detectable in up to 80% of non-small cell lung carcinoma (NSCLC) tumors, is a known cause of radioresistance. High linear energy transfer (LET) particle radiation might be effective in the treatment of hypoxic solid tumors, including NSCLC. Cellular hypoxia can activate nuclear factor κB (NF-κB), which can modulate radioresistance by influencing cancer cell survival. The effect of high-LET radiation on NF-κB activation in hypoxic NSCLC cells is unclear. Therefore, we compared the effect of low (X-rays)- and high (C)-LET radiation on NF-κB responsive genes' upregulation, as well as its target cytokines' synthesis in normoxic and hypoxic A549 NSCLC cells. The cells were incubated under normoxia (20% O) or hypoxia (1% O) for 48 h, followed by irradiation with 8 Gy X-rays or C ions, maintaining the oxygen conditions until fixation or lysis. Regulation of NF-κB responsive genes was evaluated by mRNA sequencing. Secretion of NF-κB target cytokines, IL-6 and IL-8, was quantified by ELISA. A greater fold change increase in expression of NF-κB target genes in A549 cells following exposure to C ions compared to X-rays was observed, regardless of oxygenation status. These genes regulate cell migration, cell cycle, and cell survival. A greater number of NF-κB target genes was activated under hypoxia, regardless of irradiation status. These genes regulate cell migration, survival, proliferation, and inflammation. X-ray exposure under hypoxia additionally upregulated NF-κB target genes modulating immunosurveillance and epithelial-mesenchymal transition (EMT). Increased IL-6 and IL-8 secretion under hypoxia confirmed NF-κB-mediated expression of pro-inflammatory genes. Therefore, radiotherapy, particularly with X-rays, may increase tumor invasiveness in surviving hypoxic A549 cells.
Topics: Humans; NF-kappa B; A549 Cells; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; X-Rays; Gene Expression Regulation, Neoplastic; Linear Energy Transfer; Cell Hypoxia; Carbon; Cell Survival; Radiation Tolerance; Interleukin-8
PubMed: 38674080
DOI: 10.3390/ijms25084495 -
Cancers Apr 2024Older adults with cancer often present with distinct complexities that complicate their care, yet the language used to discuss their management at multidisciplinary...
Older adults with cancer often present with distinct complexities that complicate their care, yet the language used to discuss their management at multidisciplinary cancer conferences (MCCs) remains poorly understood. A mixed methods study was conducted at a tertiary cancer centre in Toronto, Canada, where MCCs spanning five tumour sites were attended over six months. For presentations pertaining to a patient aged 75 or older, a standardized data collection form was used to record their demographic, cancer-related, and non-cancer-related information, as well as the presenter's specialty and training level. Descriptive statistics and thematic analysis were employed to explore MCC depictions of older patients ( = 75). Frailty status was explicitly mentioned in 20.0% of presentations, but discussions more frequently referenced comorbidity burden (50.7%), age (33.3%), and projected treatment tolerance (30.7%) as surrogate measures. None of the presentations included mentions of formal geriatric assessment (GA) or validated frailty tools; instead, presenters tended to feature select GA domains and subjective descriptions of appearance ("looks to be fit") or overall health ("relatively healthy"). In general, MCCs appeared to rely on age-focused language that may perpetuate ageism. Further work is needed to investigate how frailty and geriatric considerations can be objectively incorporated into discussions in geriatric oncology.
PubMed: 38672559
DOI: 10.3390/cancers16081477 -
Life Sciences in Space Research May 2024The cortical anthraquinone yellow-orange pigment parietin is a secondary lichen substance providing UV-shielding properties that is produced by several lichen species....
The cortical anthraquinone yellow-orange pigment parietin is a secondary lichen substance providing UV-shielding properties that is produced by several lichen species. In our work, the secondary metabolite has been extracted from air-dried thalli of Xanthoria parietina. The aims of this study were to characterize parietin absorbance through UV-VIS spectrophotometry and with IR spectroscopy and to evaluate its photodegradability under UV radiation through in situ reflectance IR spectroscopy to understand to what extent the substance may have a photoprotective role. This allows us to relate parietin photo-degradability to the lichen UV tolerance in its natural terrestrial habitat and in extreme environments relevant for astrobiology such as Mars. Extracted crystals were UV irradiated for 5.59 h under N flux. After the UV irradiation, we assessed relevant degradations in the 1614, 1227, 1202, 1160 and 755 cm bands. However, in light of Xanthoria parietina survivability in extreme conditions such as space- and Mars-simulated ones, we highlight parietin UV photo-resistance and its relevance for astrobiology as photo-protective substance and possible bio-hint.
Topics: Ultraviolet Rays; Exobiology; Lichens; Emodin; Photolysis; Spectrophotometry, Infrared
PubMed: 38670647
DOI: 10.1016/j.lssr.2024.03.004 -
Journal of Applied Clinical Medical... May 2024To establish the clinical applicability of deep-learning organ-at-risk autocontouring models (DL-AC) for brain radiotherapy. The dosimetric impact of contour editing,...
PURPOSE
To establish the clinical applicability of deep-learning organ-at-risk autocontouring models (DL-AC) for brain radiotherapy. The dosimetric impact of contour editing, prior to model training, on performance was evaluated for both CT and MRI-based models. The correlation between geometric and dosimetric measures was also investigated to establish whether dosimetric assessment is required for clinical validation.
METHOD
CT and MRI-based deep learning autosegmentation models were trained using edited and unedited clinical contours. Autosegmentations were dosimetrically compared to gold standard contours for a test cohort. D1%, D5%, D50%, and maximum dose were used as clinically relevant dosimetric measures. The statistical significance of dosimetric differences between the gold standard and autocontours was established using paired Student's t-tests. Clinically significant cases were identified via dosimetric headroom to the OAR tolerance. Pearson's Correlations were used to investigate the relationship between geometric measures and absolute percentage dose changes for each autosegmentation model.
RESULTS
Except for the right orbit, when delineated using MRI models, the dosimetric statistical analysis revealed no superior model in terms of the dosimetric accuracy between the CT DL-AC models or between the MRI DL-AC for any investigated brain OARs. The number of patients where the clinical significance threshold was exceeded was higher for the optic chiasm D1% than other OARs, for all autosegmentation models. A weak correlation was consistently observed between the outcomes of dosimetric and geometric evaluations.
CONCLUSIONS
Editing contours before training the DL-AC model had no significant impact on dosimetry. The geometric test metrics were inadequate to estimate the impact of contour inaccuracies on dose. Accordingly, dosimetric analysis is needed to evaluate the clinical applicability of DL-AC models in the brain.
Topics: Humans; Deep Learning; Organs at Risk; Magnetic Resonance Imaging; Radiotherapy Dosage; Tomography, X-Ray Computed; Brain Neoplasms; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Intensity-Modulated; Radiometry; Image Processing, Computer-Assisted
PubMed: 38664894
DOI: 10.1002/acm2.14345