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International Journal of Molecular... May 2024The primary emphasis of photoimmunology is the impact of nonionizing radiation on the immune system. With the development of terahertz (THz) and sub-terahertz (sub-THz)...
The primary emphasis of photoimmunology is the impact of nonionizing radiation on the immune system. With the development of terahertz (THz) and sub-terahertz (sub-THz) technology, the biological effects of this emerging nonionizing radiation, particularly its influence on immune function, remain insufficiently explored but are progressively attracting attention. Here, we demonstrated that 0.1 sub-THz radiation can modulate the immune system and alleviate symptoms of arthritis in collagen-induced arthritis (CIA) mice through a nonthermal manner. The application of 0.1 sub-THz irradiation led to a decrease in proinflammatory factors within the joints and serum, reducing the levels of blood immune cells and the quantity of splenic CD4 T cells. Notably, 0.1 sub-THz irradiation restored depleted Treg cells in CIA mice and re-established the Th17/Treg equilibrium. These findings suggested that sub-THz irradiation plays a crucial role in systemic immunoregulation. Further exploration of its immune modulation mechanisms revealed the anti-inflammatory properties of 0.1 sub-THz on LPS-stimulated skin keratinocytes. Through the reduction in NF-κB signaling and NLRP3 inflammasome activation, 0.1 sub-THz irradiation effectively decreased the production of inflammatory factors and immune-active substances, including IL-1β and PGE, in HaCaT cells. Consequently, 0.1 sub-THz irradiation mitigated the inflammatory response and contributed to the maintenance of immune tolerance in CIA mice. This research provided significant new evidence supporting the systemic impacts of 0.1 sub-THz radiation, particularly on the immune system. It also enhanced the field of photoimmunology and offered valuable insights into the potential biomedical applications of 0.1 sub-THz radiation for treating autoimmune diseases.
Topics: Animals; Arthritis, Experimental; Mice; Terahertz Radiation; Anti-Inflammatory Agents; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; NF-kappa B; Mice, Inbred DBA; T-Lymphocytes, Regulatory; Humans; Signal Transduction; Keratinocytes
PubMed: 38892148
DOI: 10.3390/ijms25115963 -
Plants (Basel, Switzerland) May 2024The Valdivian region has a temperate rainy climate with differences in rainfall throughout the year. This heterogeneity results in periods of summer drought that expose...
The Valdivian region has a temperate rainy climate with differences in rainfall throughout the year. This heterogeneity results in periods of summer drought that expose the poikilohydric epiphytes to desiccation. With this research, we aim to answer different research questions related to phorophyte preference, response to desiccation, and response to radiation. How does the diversity of macrolichens vary at a local and microclimate scale in three tree species within an evergreen forest? What is the tolerance limit of macrolichens against prolonged desiccation, according to evaluation of the maximum efficiency of PSII (Fv/Fm) and pigment concentration? What is the tolerance limit against a potential increase in radiation? We found that macrolichen communities are determined by tree species, which regulate the suitability of the substrate by modifying the temperature and humidity conditions. In addition, our results show a rapid photosynthetic alteration in temporal exposure to desiccation, measured through Fv/Fm and pigment concentration. Our results showed that the most sensitive lichens to radiation and desiccation are not coincident. We confirm the low tolerance of macrolichen species to high radiation, reflected in the saturation profile obtained for the set studied. The lichen community in the evergreen forest showed high complexity and vulnerability, pointing to the importance of more research.
PubMed: 38891327
DOI: 10.3390/plants13111519 -
Radiation Oncology (London, England) Jun 2024Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at...
BACKGROUND AND PURPOSE
Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities.
MATERIALS AND METHODS
Radiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated.
RESULTS
For the index cases, which developed toxicities at low dose levels (mean, 50 Gy), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 Gy/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 Gy/s. LET-related metrics were not substantially different between the index and non-toxicity cases.
CONCLUSIONS
Our observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury.
Topics: Humans; Proton Therapy; Brain Neoplasms; Radiotherapy Dosage; Female; Male; Middle Aged; Adult; Radiation Injuries; Aged; Optic Nerve; Organs at Risk; Radiotherapy Planning, Computer-Assisted; Dose-Response Relationship, Radiation
PubMed: 38886727
DOI: 10.1186/s13014-024-02464-z -
Clinical and Experimental Medicine Jun 2024CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of... (Review)
Review
CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of persistent antigen, CD8 + T cells can differentiate into terminally exhausted CD8 + T cells and lose the ability of immune surveillance and disease clearance. New insights into the molecular mechanisms of T-cell exhaustion suggest that it is a potential way to improve the efficacy of immunotherapy by restoring the function of exhausted CD8 + T cells. Transforming growth factor-β (TGF-β) is an important executor of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Recent studies have shown that TGF-β is one of the drivers for the development of exhausted CD8 + T cells. In this review, we summarized the role and mechanisms of TGF-β in the formation of exhausted CD8 + T cells and discussed ways to target those to ultimately enhance the efficacy of immunotherapy.
Topics: Humans; Transforming Growth Factor beta; CD8-Positive T-Lymphocytes; Immunotherapy; Neoplasms; Animals
PubMed: 38884843
DOI: 10.1007/s10238-024-01394-0 -
Clinical and Translational Radiation... Jul 2024Aim of the present study is to characterize a deep learning-based auto-segmentation software (DL) for prostate cone beam computed tomography (CBCT) images and to...
PURPOSE
Aim of the present study is to characterize a deep learning-based auto-segmentation software (DL) for prostate cone beam computed tomography (CBCT) images and to evaluate its applicability in clinical adaptive radiation therapy routine.
MATERIALS AND METHODS
Ten patients, who received exclusive radiation therapy with definitive intent on the prostate gland and seminal vesicles, were selected. Femoral heads, bladder, rectum, prostate, and seminal vesicles were retrospectively contoured by four different expert radiation oncologists on patients CBCT, acquired during treatment. Consensus contours (CC) were generated starting from these data and compared with those created by DL with different algorithms, trained on CBCT (DL-CBCT) or computed tomography (DL-CT). Dice similarity coefficient (DSC), centre of mass (COM) shift and volume relative variation (VRV) were chosen as comparison metrics. Since no tolerance limit can be defined, results were also compared with the inter-operator variability (IOV), using the same metrics.
RESULTS
The best agreement between DL and CC was observed for femoral heads (DSC of 0.96 for both DL-CBCT and DL-CT). Performance worsened for low-contrast soft tissue organs: the worst results were found for seminal vesicles (DSC of 0.70 and 0.59 for DL-CBCT and DL-CT, respectively). The analysis shows that it is appropriate to use algorithms trained on the specific imaging modality. Furthermore, the statistical analysis showed that, for almost all considered structures, there is no significant difference between DL-CBCT and human operator in terms of IOV.
CONCLUSIONS
The accuracy of DL-CBCT is in accordance with CC; its use in clinical practice is justified by the comparison with the inter-operator variability.
PubMed: 38884004
DOI: 10.1016/j.ctro.2024.100796 -
Frontiers in Plant Science 2024Plantations located outside the species distribution area represent natural experiments to assess tree tolerance to climate variability. Climate change amplifies...
INTRODUCTION
Plantations located outside the species distribution area represent natural experiments to assess tree tolerance to climate variability. Climate change amplifies warming-related drought stress but also leads to more climate extremes.
METHODS
We studied plantations of the European larch (Larix decidua), a conifer native to central and eastern Europe, in northern Spain. We used climate, drought and tree-ring data from four larch plantations including wet (Valgañón, site V; Santurde, site S), intermediate (Ribavellosa, site R) and dry (Santa Marina, site M) sites. We aimed to benchmark the larch tolerance to climate and drought stress by analysing the relationships between radial growth increment (hereafter growth), climate data (temperature, precipitation, radiation) and a drought index.
RESULTS
Basal area increment (BAI) was the lowest in the driest site M (5.2 cm2 yr-1; period 1988-2022), followed by site R (7.5 cm2 yr-1), with the youngest and oldest and trees being planted in M (35 years) and R (150 years) sites. BAI peaked in the wettest sites (V; 10.4 cm2 yr-1; S, 10.8 cm2 yr-1). We detected a sharp BAI reduction (30% of the regional mean) in 2001 when springto-summer conditions were very dry. In the wettest V and S sites, larch growth positively responded to current March and June-July radiation, but negatively to March precipitation. In the R site, high April precipitation enhanced growth. In the driest M site, warm conditions in the late prior winter and current spring improved growth, but warm-sunny conditions in July and dry-sunny conditions in August reduced it. Larch growth positively responded to spring-summer wet conditions considering short (1-6 months) and long (9-24 months) time scales in dry (site M) and wet-intermediate (sites S and R) sites, respectively.
DISCUSSION
Larch growth is vulnerable to drought stress in dry slow-growing plantations, but also to extreme spring wet-cloudy events followed by dry-hot conditions in wet fast-growing plantations.
PubMed: 38882570
DOI: 10.3389/fpls.2024.1404347 -
Frontiers in Oncology 2024We tried to establish the normal tissue complication probability (NTCP) model of temporal lobe injury of recurrent nasopharyngeal carcinoma (NPC) patients after two...
PURPOSE
We tried to establish the normal tissue complication probability (NTCP) model of temporal lobe injury of recurrent nasopharyngeal carcinoma (NPC) patients after two courses of intensity modulated radiotherapy (IMRT) to provide more reliable dose-volume data reference to set the temporal lobe tolerance dose for recurrent NPC patients in the future.
METHODS AND MATERIALS
Recurrent NPC patients were randomly divided into training data set and validation data set in a ratio of 2:1, All the temporal lobes (TLs) were re-contoured as R/L structures and named separately in the MIM system. The dose distribution of the initial IMRT plan was deformed into the second course planning CT via MIM software to get the deformed dose. Equivalent dose of TLs in 2Gy fractions was calculated via linear quadratic model, using an α/β=3 for temporal lobes. NTCP model that correlated the irradiated volume of the temporal lobe and? the clinical variables were evaluated in a multivariate prediction model using AUC analysis.
RESULTS
From Jan. 2010 to Dec. 2020, 78 patients were enrolled into our study. Among which 26 (33.3%) developed TLI. The most important factors affecting TLI was the sum-dose d1.5cc of TL, while the possible clinical factors did not reach statistically significant differences in multivariate analysis. According to NTCP model, the TD5 and TD50 EQD2 dose of sum-dose d1.5cc were 65.26Gy (46.72-80.69Gy) and 125.25Gy (89.51-152.18Gy), respectively. For the accumulated EQD2 dose, the area under ROC shadow was 0.8702 (0.7577-0.9828) in model validation, p<0.001.
CONCLUSION
In this study, a NTCP model of temporal lobe injury after a second course of IMRT for recurrent nasopharyngeal carcinoma was established. TD5 and TD50 doses of temporal lobe injury after re-RT were obtained according to the model, and the model was verified by validation set data.
PubMed: 38873258
DOI: 10.3389/fonc.2024.1394111 -
Nature Communications Jun 2024Genetic testing is crucial for precision cancer medicine. However, detecting multiple same-site insertions or deletions (indels) is challenging. Here, we introduce CoHIT...
Genetic testing is crucial for precision cancer medicine. However, detecting multiple same-site insertions or deletions (indels) is challenging. Here, we introduce CoHIT (Cas12a-based One-for-all High-speed Isothermal Test), a one-pot CRISPR-based assay for indel detection. Leveraging an engineered AsCas12a protein variant with high mismatch tolerance and broad PAM scope, CoHIT can use a single crRNA to detect multiple NPM1 gene c.863_864 4-bp insertions in acute myeloid leukemia (AML). After optimizing multiple parameters, CoHIT achieves a detection limit of 0.01% and rapid results within 30 minutes, without wild-type cross-reactivity. It successfully identifies NPM1 mutations in 30 out of 108 AML patients and demonstrates potential in monitoring minimal residual disease (MRD) through continuous sample analysis from three patients. The CoHIT method is also competent for detecting indels of KIT, BRAF, and EGFR genes. Integration with lateral flow test strips and microfluidic chips highlights CoHIT's adaptability and multiplexing capability, promising significant advancements in clinical cancer diagnostics.
Topics: Humans; Leukemia, Myeloid, Acute; INDEL Mutation; CRISPR-Cas Systems; Nucleophosmin; Neoplasm, Residual; Nuclear Proteins; Proto-Oncogene Proteins B-raf; Genetic Testing; ErbB Receptors; Bacterial Proteins; Endodeoxyribonucleases; CRISPR-Associated Proteins
PubMed: 38866774
DOI: 10.1038/s41467-024-49414-7 -
Journal of Experimental & Clinical... Jun 2024Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and...
BACKGROUND
Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment.
METHODS
Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays.
RESULTS
BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t, ~8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade.
CONCLUSIONS
BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Animals; Female; Mice; Radiation Tolerance; Cell Line, Tumor; DNA End-Joining Repair; Protein Serine-Threonine Kinases; Xenograft Model Antitumor Assays; Cell Proliferation; Gene Expression Regulation, Neoplastic; Mice, SCID
PubMed: 38863037
DOI: 10.1186/s13046-024-03086-9 -
Radiotherapy and Oncology : Journal of... Jun 2024Use of stereotactic ablative radiotherapy (SABR) for central lung tumors can result in up to a 35% incidence of late pulmonary toxicity. We evaluated an automated...
INTRODUCTION
Use of stereotactic ablative radiotherapy (SABR) for central lung tumors can result in up to a 35% incidence of late pulmonary toxicity. We evaluated an automated scoring method to quantify post-SABR bronchial changes by using artificial intelligence (AI)-based airway segmentation.
MATERIALS AND METHODS
Central lung SABR patients treated at Amsterdam UMC (AUMC, internal reference dataset) and Peter MacCallum Cancer Centre (PMCC, external validation dataset) were identified. Patients were eligible if they had pre- and post-SABR CT scans with ≤ 1 mm resolution. The first step of the automated scoring method involved AI-based airway auto-segmentation using MEDPSeg, an end-to-end deep learning-based model. The Vascular Modeling Toolkit in 3D Slicer was then used to extract a centerline curve through the auto-segmented airway lumen, and cross-sectional measurements were computed along each bronchus for all CT scans. For AUMC patients, airway stenosis/occlusion was evaluated by both visual assessment and automated scoring. Only the automated method was applied to the PMCC dataset.
RESULTS
Study patients comprised 26 from AUMC, and 33 from PMCC. Visual scoring identified stenosis/occlusion in 8 AUMC patients (31 %), most frequently in the segmental bronchi. After airway auto-segmentation, minor manual edits were needed in 9 % of patients. Segmentation for a single scan averaged 83sec (range 73-136). Automated scoring nearly doubled detected airway stenosis/occlusion (n = 15, 58 %), and allowed for earlier detection in 5/8 patients who had also visually scored changes. Estimated rates were 48 % and 66 % at 1- and 2-years, respectively, for the internal dataset. The automated detection rate was 52 % in the external dataset, with 1- and 2-year risks of 56 % and 61 %, respectively.
CONCLUSION
An AI-based automated scoring method allows for detection of more bronchial stenosis/occlusion after lung SABR, and at an earlier time-point. This tool can facilitate studies to determine early airway changes and establish more reliable airway tolerance doses.
PubMed: 38857700
DOI: 10.1016/j.radonc.2024.110376