FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy.

DNA-damaging treatments such as radiotherapy (RT) have become promising to improve the efficacy of immune checkpoint inhibitors by enhancing tumor immunogenicity. However, accompanying treatment-related detrimental events in normal tissues have posed a major obstacle to radioimmunotherapy and present new challenges to the dose delivery mode of clinical RT. In the present study, ultrahigh dose rate FLASH X-ray irradiation was applied to counteract the intestinal toxicity in the radioimmunotherapy. In the context of programmed cell death ligand-1 (PD-L1) blockade, FLASH X-ray minimized mouse enteritis by alleviating CD8+ T cell-mediated deleterious immune response compared with conventional dose rate (CONV) irradiation. Mechanistically, FLASH irradiation was less efficient than CONV X-ray in eliciting cytoplasmic double-stranded DNA (dsDNA) and in activating cyclic GMP-AMP synthase (cGAS) in the intestinal crypts, resulting in the suppression of the cascade feedback consisting of CD8+ T cell chemotaxis and gasdermin E-mediated intestinal pyroptosis in the case of PD-L1 blocking. Meanwhile, FLASH X-ray was as competent as CONV RT in boosting the antitumor immune response initiated by cGAS activation and achieved equal tumor control in metastasis burdens when combined with anti-PD-L1 administration. Together, the present study revealed an encouraging protective effect of FLASH X-ray upon the normal tissue without compromising the systemic antitumor response when combined with immunological checkpoint inhibitors, providing the rationale for testing this combination as a clinical application in radioimmunotherapy.

High-energy high-dose microfocus X-ray computed tomography driven by high-average-current photo-injector.

High-energy, high-dose, microfocus X-ray computed tomography (HHM CT) is one of the most effective methods for high-resolution X-ray radiography inspection of high-density samples with fine structures. Minimizing the effective focal spot size of the X-ray source can significantly improve the spatial resolution and the quality of the sample images, which is critical and important for the performance of HHM CT. The objective of this study is to present a 9 MeV HHM CT prototype based on a high-average-current photo-injector in which X-rays with about 70µm focal spot size are produced via using tightly focused electron beams with 65/66µm beam size to hit an optimized tungsten target. In digital radiography (DR) experiment using this HHM CT, clear imaging of a standard 0.1 mm lead DR resolution phantom reveals a resolution of 6 lp/mm (line pairs per mm), while a 5 lp/mm resolution is obtained in CT mode using another resolution phantom made of 10 mm ferrum. Moreover, comparing with the common CT systems, a better turbine blade prototype image was obtained with this HHM CT system, which also indicates the promising application potentials of HHM CT in non-destructive inspection or testing for high-density fine-structure samples.

Hydrogel coils versus bare platinum coils for the endovascular treatment of intracranial aneurysms: a meta-analysis of randomized controlled trials.

BACKGROUND: Recent studies have shown conflicting results regarding the effect of hydrogel coils for treating intracranial aneurysm compared to bare platinum coils. We implemented a meta-analysis to assess the value of hydrogel coils in intracranial aneurysm treatment. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched for randomized controlled trials (RCTs) which had evaluated hydrogel coils versus bare platinum coils for intracranial aneurysms. RESULTS: We pooled 1526 patients from 4 RCTs with the mean follow-up time of more than 16 months. Hydrogel coils had reductions on mid-term recurrence (RR 0.78, 95% CI 0.65 to 0.94, P = 0.008) and residual aneurysm (RR 0.71, 95% CI 0.57 to 0.88, P = 0.002), but didn't show any significant differences in other favorable outcomes such as functional recovery, mortality and so on. In the subgroup analysis, we found that second-generation hydrogel coils might exhibit potential impacts on increasing mid-term complete occlusion (RR 1.26, 95% CI 1.07 to 1.48, P = 0.005) and decreasing residual aneurysm neck. (RR 0.54, 95% CI 0.34 to 0.86, P = 0.010). CONCLUSIONS: Hydrogel coils showed no significant efficacy on functional recovery but exhibited a lower rate of recurrences and residual aneurysms in patients with intracranial aneurysms.

Expression and clinical significance of non-phagocytic cell oxidase 2 and 4 after human traumatic brain injury.

The goal of this study was to examine NOX2 and NOX4 expression in clinical samples of patients with traumatic brain injury (TBI), and to explore the correlation of NOX2 and NOX4 expression with the severity of injury, duration of injury, and prognosis. Brain samples of 20 TBI patients within 1 cm of the contusion site were collected and grouped based on duration of injury, Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS), and immunofluorescence staining were performed to examine the expression levels of NOX2 and NOX4 in the neurons and astrocytes. We found that the expression level of NOX2 in neurons and positive rate of NOX2 expression in astrocytes peaked at 12-24 and 6-12 h after injury, respectively. The expression level of NOX4 in neurons peaked at 24-48 h, and the positive rate of NOX4 expression gradually increased with prolonged injury. We also found that the higher the GCS score, the lower the expression levels of NOX2 and NOX4 in neurons was, while higher the GCS score, the lower the positive rate of NOX4 expression in astrocytes was and the higher the GOS grade, the lower the positive rate of expression in astrocytes was. In conclusion, NOX2 and NOX4 expressions significantly increase at an early stage after TBI, and abnormal expressions of NOX2 and NOX4 are correlated to patient prognosis to certain extent.

Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model.

Melatonin has beneficial effects against early brain injury (EBI) by modulating cerebral oxidative stress after experimental subarachnoid hemorrhage (SAH); however, few investigations relate to the precise underlying molecular mechanisms. To date, the relation between melatonin and nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) pathway has not been studied in SAH models. This study was undertaken to evaluate the influence of melatonin on Nrf2-ARE pathway in rats after SAH. Adult male SD rats were divided into four groups: (i) control group (n=18); (ii) SAH group (n=18); (iii) SAH+vehicle group (n=18); and (iv) SAH+melatonin group (n=18). The rat SAH model was induced by injection of 0.3mL fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20s. In SAH+melatonin group, melatonin was administered i.p. at 150mg/kg at 2 and 24hr after the induction of SAH. Brain samples were extracted at 48hr after SAH. Treatment with melatonin markedly increased the expressions of Nrf2-ARE pathway-related agents, such as Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutathione S-transferase α-1. Administration of melatonin following SAH significantly ameliorated EBI, including brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and neurological deficits. In conclusion, post-SAH melatonin administration may attenuate EBI in this SAH model, possibly through activating Nrf2-ARE pathway and modulating cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.

First demonstration of the FLASH effect with ultrahigh dose rate high-energy X-rays.

PURPOSE: This study aimed to evaluate whether high-energy X-rays (HEXs) of the PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can produce ultrahigh dose rate (FLASH) X-rays and trigger the FLASH effect. MATERIALS AND METHODS: EBT3 radiochromic film and fast current transformer (FCT) devices were used to measure absolute dose and pulsed beam current of HEXs. Subcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional dose rate radiotherapy (CONV), respectively to observe the tumor control efficiency and normal tissue damage. RESULTS: The maximum dose rate of HEXs of PARTER was up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (p < 0.0001) and significant difference in survival curves (p < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a significant difference (p = 0.038) in survival among the three groups, with the risk of death decreased by 81% in the FLASH group compared to that in the CONV group. The survival time of healthy mice irradiated in the abdomen in the FLASH group was undoubtedly higher (62.5% of mice were still alive when we stopped observation) than that in the CONV group (7 days). CONCLUSION: This study confirmed that HEXs of the PARTER system can produce ultrahigh dose rate X-rays and trigger a FLASH effect, which provides a basis for future scientific research and clinical application of HEX in FLASH radiotherapy.

The safety and efficacy of intra-articular dual molecular weighted hyaluronic Acid in the treatment of knee osteoarthritis: the I.d.e.h.a. Study.

In clinical practice viscosupplementation with hyaluronic acid (HA) is common for the treatment of degenerative osteoarthritis (OA). Both molecular weight and concentration of HA have significant impact on its rheological properties, which in turn affects its therapeutic effects. The objective of this study is to evaluate the effectiveness of a double HA preparation for the treatment of knee osteoarthritis with respect to pain reduction, joint function improvement and concomitant medication consumption reduction. One thousand and fourteen patients (521 males and 693 females) with a mean age of 62.4 years old, suffering from OA of the knee, were enrolled into this study. All patients received two intra-articular injections one week apart and a third injection one month after the second one. Concomitant medication was recorded and evaluated at follow up visits. Evaluation was performed at baseline, day 30 and day 180, on several parameters: knee pain by visual analog scale (VAS) 0-10 cm, Lequesne Index, and consumption of concomitant medications including non-steroidal anti-inflammatory drugs, analgesics and chondoprotective supplementations. A statistically significant reduction in pain VAS score was recorded at D30 (38.01±17.68; P<0.01) before the third injection, and D180 (25.91±15.33; P<0.01) check-points comparing to baseline (67.12±15.99). Similarly, remarkable reduction in Lequesne Index was shown at D30 (5.91±4.01; P<0.01) in 1214 patients before the third injection, and D180 (3.59±3.45; P<0.01) (with 938 patients) when compared to the baseline (11.60±5.13). Patients also consumed less concomitant medications after the treatment course. The beneficial effects were maintained for up to six months. Intra-articular injection of a double HA preparation of low molecular weight and high molecular weight of different concentrations was well tolerated, and generated satisfactory results in terms of pain control, joint function improvement and concomitant medication reduction for the management of knee OA.

Potential contribution of matrix metalloproteinase-9 (mmp-9) to cerebral vasospasm after experimental subarachnoid hemorrhage in rats.

This study investigated the possible involvement of matrix metalloproteinase 9 (MMP-9) in cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in rats. The CVS model was established by injection of fresh autologous nonheparinized arterial blood into the cisterna magna. Experiment 1 aimed to investigate the timecourse of the MMP-9 expression in the basilar artery after SAH. In Experiment 2, we chose the maximum time point of vasospasm (Day 3) and assessed the effect of SB-3CT (a selective MMP- 9 inhibitor) on the regulation of cerebral vasospasm. The cross-sectional area of basilar artery was measured by H&E staining and the MMP-9 expression was assessed by immunohistochemistry analysis. The elevated expression of MMP-9 was detected in the basilar artery after SAH and peaked on day 3. After intracisternal administration of SB-3CT, the vasospasm was markedly attenuated after blood injection on day 3. Our results suggest that MMP-9 is increasingly expressed in a parallel time course to the development of cerebral vasospasm in this rat experimental model of SAH and that the administration of the specific MMP-9 inhibitor could prevent or reduce cerebral vasospasm caused by SAH.

Potential contribution of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 to blood-brain barrier disruption and brain edema after experimental subarachnoid hemorrhage.

The current research aimed to investigate the role of hypoxia-inducible factor-1α (HIF-1α), aquaporin-4 (AQP-4), and matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) dysfunction and cerebral edema formation in a rat subarachnoid hemorrhage (SAH) model. The SAH model was induced by injection of 0.3 ml fresh arterial, non-heparinized blood into the prechiasmatic cistern in 20 s. Anti-AQP-4 antibody, minocycline (an inhibitor of MMP-9), or 2-methoxyestradiol (an inhibitor of HIF-1α), was administered intravenously at 2 and 24 h after SAH. Brain samples were extracted at 48 h after SAH and examined for protein expressions, BBB impairment, and brain edema. Following SAH, remarkable edema and BBB extravasations were observed. Compared with the control group, the SAH animals have significantly upregulated expressions of HIF-1α, AQP-4, and MMP-9, in addition to decreased amounts of laminin and tight junction proteins. Brain edema was repressed after inhibition of AQP-4, MMP-9, or HIF-1α. Although BBB permeability was also ameliorated after inhibition of either HIF-1α or MMP-9, it was not modulated after inhibition of AQP-4. Inhibition of MMP-9 reversed the loss of laminin. Finally, inhibition of HIF-1α significantly suppressed the level of AQP-4 and MMP-9, which could induce the expression of laminin and tight junction proteins. Our results suggest that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular signaling pathway involving AQP-4 and MMP-9. Pharmacological intervention of this pathway in patients with SAH may provide a novel therapeutic strategy for early brain injury.