Single Irradiation Research Articles

Light-Triggered Nitric Oxide Nanogenerator with High l-Arginine Loading for Synergistic Photodynamic/Gas/Photothermal Therapy.

The development of nanomedicines that combine photothermal therapy (PTT) with photodynamic therapy (PDT) is considered promising for cancer treatment, but still faces the challenge of enhancing tumoricidal efficiency. Fortunately, apart from the well-acknowledged effect on direct tumor cell-killing, nitric oxide (NO) is also considered to be effective for the enhancement of both PTT and PDT. However, both the low loading efficiency of NO precursor and the short half-life time and diffusion distance of NO hamper the synergistic therapeutic efficacy of NO. Taking the aforementioned factors into account, a mitochondria-targeted nitric oxide nanogenerator, EArgFe@Ce6, is constructed to achieve high loading of the NO donor l-Arginine (l-Arg) for synergistic photodynamic/gas/photothermal therapy upon single 660nm light irradiation. The coordination of epigallocatechin gallate (EGCG) and ferric ions (Fe3+ ) provides EArgFe@Ce6 supreme photothermal capability to perform low-temperature PTT (mPTT). EGCG endows EArgFe@Ce6 with mitochondria-targeting capability and meanwhile favors hypoxia alleviation for enhanced PDT. The PDT-produced massive reactive oxygen species (ROS) further catalyzes l-Arg to generate a considerable amount of NO to perform gas therapy and sensitize both mPTT and PDT. In vitro and in vivo studies demonstrate that the synergistic photodynamic/gas/photothermal therapy triggered by single 660nm light irradiation is highly effective for tumor treatments.

Hollow MnO2-Based Nanoprobes for Enhanced Photothermal/Photodynamic /Chemodynamic Co-Therapy of Hepatocellular Carcinoma

The effect of monotherapy in cancer is frequently influenced by the tumor's unique hypoxic microenvironment, insufficient drug concentration at the treatment site, and tumour cells' increased drug tolerance. In this work, we expect to design a novel therapeutic nanoprobe with the ability to solve these problems and improve the efficacy of antitumor therapy. We have prepared a hollow manganese dioxide nanoprobes loaded with photosensitive drug IR780 for the photothermal/photodynamic/chemodynamic co-therapy of liver cancer. The nanoprobe demonstrates efficient thermal transformation ability under a single laser irradiation, and under the synergistic influence of photo heat, accelerates the Fenton/ Fenton-like reaction efficiency based on Mn2+ ions to produce more ·OH under the synergistic effect of photo heat. Moreover, the oxygen released under the degradation of manganese dioxide further promotes the ability of photosensitive drugs to produce singlet oxygen (ROS). The nanoprobe has been found to efficiently destroy tumour cells in vivo and in vitro experiments when used in combination with photothermal/photodynamic/ chemodynamic modes of treatment under laser irradiation. In all, this research shows that a therapeutic strategy based on this nanoprobe could be a viable alternative for cancer treatment in the near future.

Age-related morphofunctional changes of thyroid mast cells under low-intensity laser irradiation (an experimental study)

Purpose: to study the dynamics of morphofunctional parameters of thyroid mast cells under low-intensity laser irradiation depending on age. Material and methods. The experiment was conducted on 96 white male laboratory rats of the Wistar breed. Animals were divided into four groups: 1 – control young, 2 – control old, 3 – young, low-intensity laser irradiation, 4 – old, low-intensity laser irradiation. A single laser irradiation session in continuous mode (wavelength – 970 nm, power – 1 W, exposure – 60 s) was made in the projection of thyroid gland. The animals were removed from the experiment 1 hour and 1, 3 and 7 days after exposure to laser light. Thyroid preparations were fixed in the formalin; histological sections were prepared and stained with toluidine blue; the morphometric analysis was performed to determine the number of thyroid mast cells and their varieties depending on the granular saturation level and degranulation degree.Results. The reaction of thyroid mast cells of experimental animals to laser exposure had some specific features: in young animals there was the increase in the number of cells and in their synthetic activity with the increase in granular saturation level and with the decrease in degranulation level which indicates an increased migration of cells into the thyroid gland and a pronounced adaptive reaction of the entire population of mast cells of the body. In old animals, exposure to laser light caused degranulation activity of thyroid mast cells with decrease in the level of granular saturation. No changes in the number of cells indicates that the reaction is limited within the organ contours.Conclusion. The results obtained expand our understanding of specific reactions of mast cells to laser exposure and confirm the need for individual correction of low-level laser therapy depending on age.

Design of high gain base station antenna array for mm-wave cellular communication systems

Millimeter wave (mm-Wave) wireless communication systems require high gain antennas to overcome path loss effects and thereby enhance system coverage. This paper presents the design and analysis of an antenna array for high gain performance of future mm-wave 5G communication systems. The proposed antenna is based on planar microstrip technology and fabricated on 0.254 mm thick dielectric substrate (Rogers-5880) having a relative permittivity of 2.2 and loss tangent of 0.0009. The single radiating element used to construct the antenna array is a microstrip patch that has a configuration resembling a two-pronged fork. The single radiator has a realized gain of 7.6 dBi. To achieve the gain required by 5G base stations, a 64-element array antenna design is proposed which has a bore side gain of 21.2 dBi at 37.2 GHz. The 8 × 8, 8 × 16, and 8 × 32 antenna array designs described here were simulated and optimized using CST Microwave Studio, which is a 3D full-wave electromagnetic solver. The overall characteristics of the array in terms of reflection-coefficient and radiation patterns makes the proposed design suitable for mm-Wave 5G and other communication systems.

Прооксидантно-антиоксидантні процеси в крові та печінці мишоподібних гризунів (Myodes Glareolus та Apodemus Flavicollis) за разового опромінення

The effect of total single X-ray irradiation (1.5 Gy) on the course of free radical processes (FRP) in the blood and liver of red fistula (Myodes glareolus) and yellow-throated mouse (Apodemus flavicollis) was studied. It is shown that physicochemical regulation of FRP in the blood of murine rodents under total X-ray irradiation (1.5 Gy) in the early stages is carried out mainly due to catalase and reduced glutathione (GSH). This is evidenced by the stoichiometry of the CL reaction and symbat changes in the prooxidant-antioxidant ratio (PAR) and basic kinetic parameters of the CL reaction (Imax, Ifin) and antibat changes to PAR - catalase and GSH.

Radiation reaction effects in relativistic plasmas: The electrostatic limit.

We study the evolution of electrostatic plasma waves, using the relativistic Vlasov equationextended by the Landau-Lifshitz radiation reaction, accounting for the back-reaction due to the emission of single particle Larmor radiation. In particular, the Langmuir wave damping is calculated as a function of wave number, initial temperature, and initial electric field amplitude. Moreover, the background distribution function loses energy in the process, and we calculate the cooling rate as a function of initial temperature and initial wave amplitude. Finally, we investigate how the relative magnitude of wave damping and background cooling varies with the initial parameters. In particular, it is found that the relative contribution to the energy loss associated with background cooling decreases slowly with the initial wave amplitude.

Lifetime Evaluation of Left Ventricular Structure and Function in Male C57BL/6J Mice after Gamma and Space-Type Radiation Exposure.

The lifetime effects of space irradiation (IR) on left ventricular (LV) function are unknown. The cardiac effects induced by space-type IR, specifically 5-ion simplified galactic cosmic ray simulation (simGCRsim), are yet to be discovered. Three-month-old, age-matched, male C57BL/6J mice were irradiated with 137Cs gamma (γ; 100, 200 cGy) and simGCRsim (50 and 100 cGy). LV function was assessed via transthoracic echocardiography at 14 and 28 days (early), and at 365, 440, and 660 (late) days post IR. We measured the endothelial function marker brain natriuretic peptide in plasma at three late timepoints. We assessed the mRNA expression of the genes involved in cardiac remodeling, fibrosis, inflammation, and calcium handling in LVs harvested at 660 days post IR. All IR groups had impaired global LV systolic function at 14, 28, and 365 days. At 660 days, 50 cGy simGCRsim-IR mice exhibited preserved LV systolic function with altered LV size and mass. At this timepoint, the simGCRsim-IR mice had elevated levels of cardiac fibrosis, inflammation, and hypertrophy markers Tgfβ1, Mcp1, Mmp9, and βmhc, suggesting that space-type IR may induce the cardiac remodeling processes that are commonly associated with diastolic dysfunction. IR groups showing statistical significance were modeled to calculate the Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER). The observed dose-response shape did not indicate a lower threshold at these IR doses. A single full-body IR at doses of 100-200 cGy for γ-IR, and 50-100 cGy for simGCRsim-IR decreases the global LV systolic function in WT mice as early as 14 and 28 days after exposure, and at 660 days post IR. Interestingly, there is an intermediate time point (365 days) where the impairment in LV function is observed. These findings do not exclude the possibility of increased acute or degenerative cardiovascular disease risks at lower doses of space-type IR, and/or when combined with other space travel-associated stressors such as microgravity.

Study on surface thermal oxidation of silicon carbide irradiated by pulsed laser using reactive molecular dynamics.

Pulsed lasers are a powerful tool for fabricating silicon carbide (SiC) that has a hard and brittle nature, but oxidation is usually unavoidable. This study presents an exploration of the oxidation mechanism of 4H-SiC in oxygen and water under different temperatures via reactive force field molecular dynamics. Single pulse irradiation experiments were conducted to study the oxygen content of the laser-affected zone through energy dispersive x-ray spectrometry. The results show that laser-induced thermal oxidation is a complex dynamic process with the interactions among H, C, O, and Si atoms. The oxidation zone includes an oxide layer, a graphite layer, and a C-rich layer. With an increase in oxygen concentration, the amorphous oxide layer changes from silicon oxide to silicon dioxide. In addition, the formation of carbon clusters at the interface between SiOx and C-rich layers promotes the desorption of the oxide layer. The mechanism revealed in this study provides theoretical guidance for high-quality processing of 4H-SiC at atomic and close-to-atomic scales.

Defect evolution under intense electronic energy deposition in uranium dioxide

The coupled effects of nuclear and electronic energy losses were investigated in uranium dioxide (UO2). Single and sequential ion irradiations were carried out with 92 MeV Xe ions and 0.9 MeV I ions. Raman spectroscopy and X-ray diffraction analyses were combined with the inelastic thermal spike (iTS) model to investigate the effect of electronic ionizations on the ballistic damage. It appears that the high-energy ions induce a significant change in the defect distribution with an amplitude that depends on the level of pre-existing disorder. This modification essentially results in an acceleration of the transformation from the dislocation loops to the dislocation lines, a process that is accompanied by a stress relaxation. Surprisingly, with the fluence increase of 92 MeV Xe ions, the stress starts to increase again, highlighting a possible synergetic effect between the pre-existing defects and those generated by the 92 MeV Xe ions irradiation.

The interaction of ionizing radiation and silicone medical implants: Evaluation of the effects on radiotherapy dose distribution and alteration in the physical properties of the silicone

Silicone prostheses are implanted inside the human body for medical aesthetics and reconstructive reasons. The presence of a silicone prosthesis around the radiotherapy volume may alter radiotherapy dose distribution and cause overdose and underdose areas in the target volumes and organs at risk. The interaction of silicone with radiation may be two-sided since high dose radiation may cause alteration of the physical and chemical properties of silicone which further contributes to changes in the dose distribution. The aim of this study was to evaluate the changes in radiation dose distribution caused by silicone and the effects of irradiation on silicone elastomer prostheses.A special set-up was prepared in the water phantom to obtain depth dose and profile data for non-irradiated silicone blocks prior to the irradiation schedule. Entrance and exit doses between silicone and water medium were measured using thermoluminescence dosimetry (TLD). Hardness tests on silicone blocks were performed by using Tronic Shore A Durometer device and density tests were performed by using Scaltec density determination instrument. Irradiation of the silicone was performed using a linear accelerator with 6 MV and 10 MV photon energies, 2 Gy daily fractions in 5 weeks were delivered to a total dose of 50 Gy. After the completion of 5 weeks schedule depth doses, profile measurements, entrance-exit doses and density-hardness tests were repeated.The non-irradiated silicone blocks affected the depth dose distribution in the water phantom to a maximum dose reduction of 1.5% for 6 MV and 1.6% for 10 MV. After the 5 weeks of irradiation, depth dose reduction increased to 2.5% for 6 MV and 2.0% for 10 MV. Silicone blocks affected the dose profile as well: maximum dose difference was 2.7% for 6 MV and 2.4% for 10 MV for non-irradiated silicone, 2.6% for 6 MV, and 2% for 10 MV after 50 Gy. However, these changes in depth dose and profile data in non-irradiated and irradiated silicone were not significant. There was up to an 8% dose decrease in exit doses beyond the silicone with the use of a single direct irradiation field, which is expected to be reduced with multi-field radiotherapy. The physical properties of the non-irradiated and irradiated silicone measured by hardness and density tests were similar. The only physical difference we noted was the discoloration of silicone to a yellowish color. According to our results silicone elastomer prostheses did not have significant effects on dose distribution after 50 Gy irradiation, and radiation doses used for radiotherapy did not alter the physical properties of silicone blocks except for discoloration.

Toward Highly Efficient Multimode Superconducting Quantum Memory

Microwave quantum memory promises advanced capabilities for noisy intermediate-scale superconducting quantum computers. Existing approaches to microwave quantum memory lack complete combination of high efficiency, long storage time, noiselessness and multi-qubit capacity. Here we report an efficient microwave broadband multimode quantum memory. The memory stores two spectral modes of single photon level microwave radiation in on-chip system of eight coplanar superconducting resonators. Single mode storage shows a power efficiency of up to $60\pm 3\%$ at single photon energy and more than $73\pm 3\%$ at higher intensity. The demonstrated efficiency is an order of magnitude larger than the previously reported multimode microwave quantum memory. The noiseless character of the storage is confirmed by coherent state quantum process tomography. The demonstrated results pave the way to further increase in efficiency and hence building a practical multimode microwave memory for superconducting quantum circuits.

Genome-wide analyses of lung cancer after single high-dose radiation at five time points (2, 6, 12, 24, and 48h).

Background: An increasing number of clinicians are experimenting with high-dose radiation. This study focuses on the genomic effects of high-dose single-shot radiotherapy and aims to provide a dynamic map for non-small cell lung cancer (NSCLC). Methods: We used whole-transcriptome sequencing to understand the evolution at molecular levels in A549 and H1299 exposed to 10 Gy X-rays at different times (2, 6, 12, 24, and 48h) in comparison with the no radiation group. Ingenuity pathway analysis, ceRNA analysis, enrichment analysis, and cell cycle experiments are performed for molecular analyses and function analyses. Results: Whole-transcriptome sequencing of NSCLC showed a significant dynamic change after radiotherapy within 48h. MiR-219-1-3p and miR-221-3p, miR-503-5p, hsa-miR-455-5p, hsa-miR-29-3p, and hsa-miR-339-5p were in the core of the ceRNA related to time change. GO and KEGG analyses of the top 30 mRNA included DNA repair, autophagy, apoptosis, and ferroptosis pathways. Regulation of the cell cycle-related transcription factor E2F1 might have a key role in the early stage of radiotherapy (2.6h) and in the later stage of autophagy (24 and 48h). Functions involving different genes/proteins over multiple periods implied a dose of 10Gy was related to the kidney and liver pathway. Radiation-induced cell cycle arrest at the G2/M phase was evident at 24h. We also observed the increased expression of CCNB1 at 24h in PCR and WB experiments. Conclusion: Our transcriptomic and experimental analyses showed a dynamic change after radiation therapy in 48h and highlighted the key molecules and pathways in NSCLC after high-dose single-shot radiotherapy.

Transfersome Encapsulated with the R-carvedilol Enantiomer for Skin Cancer Chemoprevention.

The R-carvedilol enantiomer, present in the racemic mixture of the chiral drug carvedilol, does not bind to the β-adrenergic receptors, but exhibits skin cancer preventive activity. For skin delivery, R-carvedilol-loaded transfersomes were prepared using various ratios of drug, lipids, and surfactants, and characterized for particle size, zeta potential, encapsulation efficiency, stability, and morphology. Transfersomes were compared for in vitro drug release and ex vivo skin penetration and retention. Skin irritation was evaluated by viability assay on murine epidermal cells and reconstructed human skin culture. Single-dose and repeated-dose dermal toxicity was determined in SKH-1 hairless mice. Efficacy was evaluated in SKH-1 mice exposed to single or multiple ultraviolet (UV) radiations. Transfersomes released the drug at a slower rate, but significantly increased skin drug permeation and retention compared with the free drug. The transfersome with a drug-lipid-surfactant ratio of 1:3:0.5 (T-RCAR-3) demonstrated the highest skin drug retention and was selected for further studies. T-RCAR-3 at 100 µM did not induce skin irritation in vitro and in vivo. Topical treatment with T-RCAR-3 at 10 µM effectively attenuated acute UV-induced skin inflammation and chronic UV-induced skin carcinogenesis. This study demonstrates feasibility of using R-carvedilol transfersome for preventing UV-induced skin inflammation and cancer.

Abstract GS5-07: Estradiol represses anti-tumoral immune response to promote progression of triple-negative breast cancer brain metastases

Abstract Background: Younger women with breast cancer have increased risk of development of brain metastases irrespective of the tumor subtype. We have shown that pre-menopausal levels of 17-β-Estradiol (E2) contributes to the promotion of brain metastases by influencing the tumor microenvironment. E2 promotes brain metastasis (BM) of estrogen receptor negative (ER¯) BC cells by inducing neuroinflammatory ER+ astrocytes in the brain niche to secrete pro-metastatic factors critical for early brain colonization. Ovarieoctomy (OVX) in combination with the aromatase inhibitor (Letrozole) prevented brain colonization of triple negative (TNBC) (ER-PR-HER2-) human xenografts (MDA231BR/NSG) and murine models (E0711/C57Bl6, 4T1/BALBc) through paracrine activation of EGFR and TRKB, pathways involved in increased invasion and early tumor initiation. Yet, the extent to which E2-depletion therapies can decrease progression of established BM in combination with current standard of care for brain metastasis remains unknown. Goal: Current standard of care (SOC) for patients with TNBC brain metastasis includes irradiation (SRS, whole brain) and immunotherapy (PD-1/PDL-1 inhibitors). The goal of this study was to assess how E2-depletion therapies affects brain immune function in the context of SOC for brain metastatic progression of TNBC. Results: To assess whether E2-depletion could decrease BM progression in a model that mimics standard of care for BM, TNBC E0771-GFP-luc cells were injected intracardially in syngeneic ovariectomized (OVX)-female C57Bl6 mice supplemented with pre-menopausal levels of E2. Seven days after injection (when cancer cells have colonized), mice received a single 15Gy dose brain irradiation and were randomized to continue receiving E2, E2 withdrawal (E2WD) or E2WD plus the aromatase-inhibitor letrozole (E2WD+LET). Brain metastatic burden significantly decreased in E2WD and E2WD+Letrozole treated mice as compared to E2-treated mice. Injection of E0711 cells in immunocompromised NSG mice or in the absence of brain irradiation abolished this effect, suggesting that E2-depletion therapies decrease BM progression through boosting radiation-induced anti-tumor immunity. Accordingly, there were no differences in BM progression in E2, E2WD or E2WD+let treated mice in a xenograft model (F2-7 TNBC cells) in NSG mice, even in the presence of brain irradiation. Immune-profiling of brains from OVX+E2, OVX and OVX+Let C57BL6 mice carrying BMs showed dynamic changes in immune populations at early and late stages of brain metastatic colonization. At early stages post brain colonization (3 days post ic injection) E2-treated mice showed a decreased fraction of CD11b+CD45Int CD206+ microglia/CNS macrophages as compared to OVX+LET-treated mice, without significant changes in the fraction of infiltrated lymphocytes, suggesting E2 represses early immunosurveillance through repression of microglia/CNS macrophage activation. At later stages of brain colonization (7 days post ic injection), E2-treated mice showed an increased fraction of proinflammatory microglia and decreased fraction of T and B cells as compared to OVX or OVX+let treated mice. While E2-depletion increased the recruitment of T cells to the brain niche, the fraction of CD279 (PD1+) brain T cells was similar among groups. Ongoing studies assess the efficacy of E2-depletion therapies in combination with brain radiation and PD-1 inhibitors to decrease metastatic burden and improve survival in preclinical models. Conclusion: Our results support the hypothesis that estradiol promotes brain metastatic progression by stimulating an immunosuppressive brain microenvironment. As such, FDA-approved E2-depletion therapies (aromatase inhibitors and selective-estrogen modulators) could be used in combination with brain irradiation and PD-1 inhibitors to promote a more effective anti-tumoral immune response. Citation Format: Diana Cittelly, Maria J. Contreras-Zarate, Karen ALvarez-Eraso, Vesna Tesic, Nicole Tsuji, Leanna Chafee, Sana Karam, D. Ryan Ormond, Peter Kabos. Estradiol represses anti-tumoral immune response to promote progression of triple-negative breast cancer brain metastases [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-07.

Creation of NV centers over a millimeter-sized region by intense single-shot ultrashort laser irradiation

Recently, ultrashort laser processing has attracted attention for creating nitrogen-vacancy (NV) centers because this method can create single NV centers in spatially-controlled positions, which is an advantage for quantum information devices. On the other hand, creating high-density NV centers in a wide region is also important for quantum sensing because the sensitivity is directly enhanced by increasing the number of NV centers. A recent study demonstrated the creation of high-density NV centers by irradiating femtosecond laser pulses, but the created region was limited to micrometer size, and this technique required many laser pulses to avoid graphitization of diamond. Here, we demonstrate the creation of NV centers in a wide region using only an intense single femtosecond laser pulse irradiation. We irradiated a diamond sample with a femtosecond laser with a focal spot size of 41 µm and a laser fluence of up to 54 J/cm2, which is much higher than the typical graphitization threshold in multi-pulse processing. We found that single-pulse irradiation created NV centers without post-annealing for a laser fluence higher than 1.8 J/cm2, and the region containing NV centers expanded with increasing laser fluence. The diameter of the area was larger than the focal spot size and reached over 100 µm at a fluence of 54 J/cm2. Furthermore, we demonstrated the NV centers’ creation in a millimeter-sized region by a single-shot defocused laser pulse over 1100 µm with a fluence of 33 J/cm2. The demonstrated technique will bring interest in the fundamentals and applications of fabricating ultrahigh-sensitivity quantum sensors.

Proton Therapy, Magnetic Nanoparticles and Hyperthermia as Combined Treatment for Pancreatic BxPC3 Tumor Cells.

We present an investigation of the effects on BxPC3 pancreatic cancer cells of proton therapy combined with hyperthermia, assisted by magnetic fluid hyperthermia performed with the use of magnetic nanoparticles. The cells' response to the combined treatment has been evaluated by means of the clonogenic survival assay and the estimation of DNA Double Strand Breaks (DSBs). The Reactive Oxygen Species (ROS) production, the tumor cell invasion and the cell cycle variations have also been studied. The experimental results have shown that the combination of proton therapy, MNPs administration and hyperthermia gives a clonogenic survival that is much smaller than the single irradiation treatment at all doses, thus suggesting a new effective combined therapy for the pancreatic tumor. Importantly, the effect of the therapies used here is synergistic. Moreover, after proton irradiation, the hyperthermia treatment was able to increase the number of DSBs, even though just at 6 h after the treatment. Noticeably, the magnetic nanoparticles' presence induces radiosensitization effects, and hyperthermia increases the production of ROS, which contributes to cytotoxic cellular effects and to a wide variety of lesions including DNA damage. The present study indicates a new way for clinical translation of combined therapies, also in the vision of an increasing number of hospitals that will use the proton therapy technique in the near future for different kinds of radio-resistant cancers.

Alliance A032002 (ART): Phase II randomized trial of atezolizumab versus atezolizumab and radiation therapy for platinum-ineligible/refractory metastatic urothelial cancer.

TPS589 Background: In patients (pts) with metastatic unresectable urothelial cancer, platinum-based chemotherapy remains the standard of care for first-line treatment followed by switch maintenance avelumab if disease control is achieved with chemotherapy. Outside of this setting, single agent immunotherapy is often used in pts that have recurrence after platinum-based chemotherapy or are platinum ineligible. Atezolizumab is a PD-L1 inhibitor currently approved for pts that have urothelial cancers expressing positive PD-L1 or pts ineligible for receiving platinum-based chemotherapy. Tumor-targeted radiotherapy can generate immune-stimulating effects without immune suppression as was previously thought. Moreover, it has become clear that radiotherapy can induce profound effects on tumor cells and the tumor microenvironment that can enhance or trigger an anticancer immune response. While numerous trials have investigated the abscopal effect, this trial will have specific parameters regarding drug type, radiation dose and administration. Methods: A032002 is a phase 2 trial addressing pts that are platinum ineligible or refractory to platinum-based chemotherapy. 144 pts will be randomized to receive either atezolizumab or atezolizumab and single site radiation therapy. The atezolizumab regimen is 1200 mg every 3 weeks. Administration of radiotherapy will occur to one non-target site (8 Gy x 3) for pts randomized to the atezolizumab + radiotherapy arm. All pts will undergo centralized PD-L1 testing (SP142 monoclonal primary antibody), which can be performed on archival tissue; a new biopsy is only required if no archival tissue is available. Key eligibility criteria include age ≥ 18 years, ECOG performance status 0-2, histologically confirmed metastatic urothelial cancer, having at least one measurable site per RECIST 1.1 to monitor for abscopal response, one site targetable for radiation, and tissue available for PD-L1 testing. The primary endpoint is tumor response within 6 months of randomization. Tumor response is defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using RECIST 1.1 criteria. For a one-sided log rank test with a type 1 error rateof 0.10, the study has 90% power to detect a 20% increase in response rate. Key secondary endpoints include tumor response using iRECIST, progression-free survival and overall survival. Quality of life assessments include EORTC QLQ-C30, QLQ-BLM30 and PROMIS-Fatigue. Tissue, urine and blood samples will be collected and biobanked for future correlative science. Enrollment to ART began in December 2021. The study is available for participation at all US NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882. Clinical trial information: NCT04936230 .

Single High-Dose Irradiation-Induced iRhom2 Upregulation Promotes Macrophage Antitumor Activity Through cGAS/STING Signaling

The clinical application of stereotactic body radiation therapy (SBRT) allows a high dose of radiation to be safely delivered to extracranial targets within the body; however, a high dose per fraction (hypofractionation) has opened the radiation oncology field to new questions on a variety of dose-fractionation schedules, especially the immunomodulatory effects of radiation therapy, which can change after various dose-fractionation schedules. We investigated the immunomodulatory effects of different fractionation schedules. We established a subcutaneous tumor model in wild-type C57BL/6J mice and STING (stimulator of interferon genes)-deficient mice. We then compared the tumor control efficacy of 3 different fractionation schedules: 2 Gy×8, 4.5 Gy×3, and 10 Gy×1, which are similar biologically effective doses. We found the fractionation schedule of 10 Gy×1 had a significantly higher antitumor effect, suggesting that a single high dose induced enhanced antitumor immunity compared with conventional fractionation (2 Gy×8) and moderate hypofractionation (4.5 Gy×3). However, in STING-deficient mice, differential tumor control was not observed among the 3 dose-fractionation schedules, suggesting that cGAS (cyclic GMP-AMP synthase)/STING signaling is involved in the antitumor immune effects of single high-dose schedules. Mechanistically, we found that conventional fractionation induced apoptosis; by comparison, a single high dose was more attuned to induced necroptosis, leading to the release of intracellular irradiation-induced double-stranded DNA (dsDNA) due to the loss of plasma membrane integrity, which then activated the dsDNA sensing signaling cGAS/STING in the recruited macrophage. Furthermore, iRhom2, a member of the conserved family of inhibitory rhomboid-like pseudoproteases, was upregulated in infiltrated macrophages in the single high-dose irradiation microenvironment. Therefore, iRhom2 positively regulates STING and directly promotes tumor necrosis factor α secretion. This exacerbates necroptosis of irradiated tumor cells, leading to continuous dsDNA release and enhancement of cGAS/STING signaling antitumor immunity in a positive feedback loop. iRhom2 amplifies antitumor signaling in a positive feedback loop mediated by cGAS/STING signaling and tumor necrosis factor-driven necroptosis after single high-dose radiation.

Formation and Evolution of Micro/Nano Periodic Ripples on 2205 Stainless Steel Machined by Femtosecond Laser

The preparation of micro/nano periodic surface structures using femtosecond laser machining technology has been the academic frontier and hotspot in recent years. The formation and evolution of micro/nano periodic ripples were investigated on 2205 stainless steel machined by femtosecond laser. Using single spot irradiation with fixed laser fluences and various pulse numbers, typical ripples, including nano HSFLs (‖), nano LSFLs (⟂), nano HSFLs (⟂) and micro grooves (‖), were generated one after another in one test. The morphologies of the ripples were analyzed, and the underlying mechanisms were discussed. It was found that the nano holes/pits presented at all stages could have played a key role in the formation and evolution of micro/nano periodic ripples. A new kind of microstructure, named the pea pod-like structure here, was discovered, and it was suggested that the formation and evolution of the micro/nano periodic ripples could be well explained by the pea pod-like structure model.

Longitudinal Patient-Reported Voice Quality in Early-Stage Glottic Cancer.

Patient-reported voice quality is an important outcome during counseling in early-stage glottic cancer. However, there is a paucity of adequate longitudinal studies concerning voice outcomes. This study aimed to investigate longitudinal trajectories for patient-reported voice quality and associated risk factors for treatment modalities such as transoral CO2 laser microsurgery, single vocal cord irradiation, and local radiotherapy. A longitudinal observational cohort study. Tertiary cancer center. Patients treated for Tcis-T1b, N0M0 glottic cancer were included in this study (N = 294). The Voice Handicap Index was obtained at baseline and during follow-up (N = 1944). Mixed-effects models were used for investigating the different trajectories for patient-reported voice quality. The mean follow-up duration was 43.4 (SD 21.5) months. Patients received transoral CO2 laser microsurgery (57.8%), single vocal cord irradiation (24.5%), or local radiotherapy (17.5%). A steeper improvement during the first year after treatment for single vocal cord irradiation (-15.7) and local radiotherapy (-12.4) was seen, compared with a more stable trajectory for laser surgery (-6.1). All treatment modalities showed equivalent outcomes during long-term follow-up. Associated risk factors for different longitudinal trajectories were age, tumor stage, and comorbidity. Longitudinal patient-reported voice quality after treatment for early-stage glottic cancer is heterogeneous and nonlinear. Most improvement is seen during the first year of follow-up and differs between treatment modalities. No clinically significant differences in long-term trajectories were found. Insight into longitudinal trajectories can enhance individual patient counseling and provide the foundation for an individualized dynamic prediction model.