The association between non-HDL cholesterol and high-grade pancreatic neuroendocrine neoplasms.

PURPOSE: High-density lipoprotein cholesterol (HDL-c) plays an important role in tumorigenesis in several endocrine-related cancers. Few studies have shown the effect of non-HDL-c in malignant tumors. The present study aimed to identify the association between non-HDL-c and high-grade pancreatic neuroendocrine neoplasms (PNENs). METHODS: A total of 197 PNEN patients who underwent surgery were analyzed retrospectively. Clinical and histopathological features, such as patients' age and sex, tumor location and size, tumor grade, the level of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and fasting plasma-glucose levels were obtained. Non-HDL-c was calculated as total cholesterol - HDL-c. The relationships between those features and high-grade PNENs were identified using logistic regression analysis. RESULTS: Among the 197 patients with PNENs, a lower HDL-c level was more common seen in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.05). The non-HDL-c/HDL-c ratio was greater in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.01). Similarly, a greater proportion of patients with a non-HDL-c/HDL-c ratio larger than 5 was found in patients with poorly differentiated PNENs than in those with well-differentiation PNENs (P < 0.01). Multivariate logistic analysis showed that the non-HDL-c/HDL-c ratio was positively associated with poorly differentiated PNENs (odds ratio (OR) = 1.45, 95% conference interval (CI):1.13-1.87). Similarly, the risk of poorly differentiated PNENs increased significantly in patients with a non-HDL-c/HDL-c greater than 5 (OR = 14.13, 95%CI: 2.98-66.89). The risk of high-grade PNENs increased in patients with a high non-HDL-c/HDL-c ratio (OR = 1.27, 95% CI: 1.04-1.55), and the risk also increased markedly when the ratio was greater than 5 (OR = 5.00, 95%CI: 1.28-19.49). CONCLUSIONS: A high ratio of non-HDL-c/HDL-c was associated with high-grade PNENs or poorly differentiated PNENs.

Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Cognitive Impairment and Intestinal Microecological Dysfunction Induced by High-Fat Diet in Rats.

Consuming a high-fat diet (HFD) is widely recognized to cause obesity and result in chronic brain inflammation that impairs cognitive function. Repetitive transcranial magnetic stimulation (rTMS) has shown effectiveness in both weight loss and cognitive improvement, although the exact mechanism is still unknown. Our study examined the effects of rTMS on the brain and intestinal microecological dysfunction. rTMS successfully reduced cognitive decline caused by an HFD in behavioral assessments involving the Y maze and novel object recognition. This was accompanied by an increase in the number of new neurons and the transcription level of genes related to synaptic plasticity (spindlin 1, synaptophysin, and postsynaptic protein-95) in the hippocampus. It was reached that rTMS decreased the release of high mobility group box 1, activation of microglia, and inflammation in the brains of HFD rats. rTMS also reduced hypothalamic hypocretin levels and improved peripheral blood lipid metabolism. In addition, rTMS recovered the HFD-induced gut microbiome imbalances, metabolic disorders, and, in particular, reduced levels of the microvirus. Our research emphasized that rTMS enhanced cognitive abilities, resulting in positive impacts on brain inflammation, neurodegeneration, and the microbiota in the gut, indicating the potential connection between the brain and gut, proposing that rTMS could be a new approach to addressing cognitive deficits linked to obesity.

Real-world setting comparison of bridging therapy versus direct mechanical thrombectomy for acute ischemic stroke: A meta-analysis.

BACKGROUND AND PURPOSE: Intravenous Thrombolysis (IVT) prior to Mechanical Thrombectomy (MT) for Acute Ischaemic Stroke (AIS) due to Large-Vessel Occlusion (LVO) remains controversial. Therefore, the authors performed a meta-analysis of the available real-world evidence focusing on the efficacy and safety of Bridging Therapy (BT) compared with direct MT in patients with AIS due to LVO. METHODS: Four databases were searched until 01 February 2023. Retrospective and prospective studies from nationwide or health organization registry databases that compared the clinical outcomes of BT and direct MT were included. Odds Ratios (ORs) and 95 % Confidence Intervals (CIs) for efficacy and safety outcomes were pooled using a random-effects model. RESULTS: Of the 12 studies, 86,695 patients were included. In patients with AIS due to LVO, BT group was associated with higher odds of achieving excellent functional outcome (modified Rankin Scale score 0-1) at 90 days (OR = 1.48, 95 % CI 1.25-1.75), favorable discharge disposition (to the home with or without services) (OR = 1.33, 95 % CI 1.29-1.38), and decreased mortality at 90 days (OR = 0.62, 95 % CI 0.56-0.70), as compared with the direct MT group. In addition, the risk of symptomatic intracranial hemorrhage did not increase significantly in the BT group. CONCLUSION: The present meta-analysis indicates that BT was associated with favorable outcomes in patients with AIS due to LVO. These findings support the current practice in a real-world setting and strengthen their validity. For patients eligible for both IVT and MT, BT remains the standard treatment until more data are available.

Impact of active pharmaceutical ingredient variables and oleaginous base on the in vitro drug release from ophthalmic ointments: An investigation using dexamethasone as a model drug.

The present study systematically investigates the impact of active pharmaceutical ingredient (API) variables and oleaginous base characteristics on the in vitro release (IVR) performance of ophthalmic ointments, utilizing dexamethasone as a model drug. The interplay between selected attributes (i.e., particle size distribution, crystallinity, and polymorphic form for API, and rheological factors for compendial-grade white petrolatum) and IVR performance was investigated. APIs from different vendors exhibited variations in crystallinity and polymorphism. Ointments containing amorphous dexamethasone presented higher release amounts/rates compared to crystalline counterparts, emphasizing the role of physical state in release kinetics. Variations in particle size of this lipophilic API (5.4 - 21.2 µm) did not appear to impact IVR performance significantly. In contrast, white petrolatum's rheological attributes, which varied substantially within USP-grade petrolatum, were found to critically affect the drug release rate and extent of the ointment. The study's comprehensive analysis establishes a coherent connection between the quality attributes of both API and petrolatum and IVR, delineating their intricate interdependent effects on ophthalmic ointment performance. These findings provide reference to formulation design, quality control, and regulatory considerations within the pharmaceutical industry, fostering a robust foundational understanding of commonly overlooked quality attributes in ophthalmic ointments.

Pb nanospheres encapsulated in metal-organic frameworks-derived porous carbon as anode for high-performance sodium-ion batteries.

Alloying-type anode materials are considered promising candidates for sodium-ion batteries (SIBs) due to their high theoretical capacities. However, their application is limited by the severe capacity decay stemming from dramatic volume changes during Na+ insertion/extraction processes. Here, Pb nanospheres encapsulated in a carbon skeleton (Pb@C) were successfully synthesized via a facile metal-organic frameworks (MOFs)-derived method and used as anodes for SIBs. The nanosized Pb particles are uniformly incorporated into the porous carbon framework, effectively mitigating volume changes and enhancing Na+ ion transport during discharging/charging. Benefiting from this unique architecture, a reversible capacity of 334.2 mAh g-1 at 2 A g-1 is achieved after 6000 cycles corresponding to an impressive 88.2 % capacity retention and a minimal capacity loss of 0.00748 % per cycle. Furthermore, a high-performance full sodium-ion battery of Pb@C//NVPF was constructed, demonstrating a high energy density of 291 Wh kg-1 and power density of 175 W kg-1. This facile MOFs-derived method offers insights into the design of high-capacity alloy-type anode materials using Pb sources, opening up new possibilities for innovative approaches to Pb recycling and pollution prevention.

Coupling High Hardness and Zn Affinity in Amorphous-Crystalline Diamond for Stable Zn Metal Anodes.

The highly reversible plating/stripping of Zn is plagued by dendrite growth and side reactions on metallic Zn anodes, retarding the commercial application of aqueous Zn-ion batteries. Herein, a distinctive nano dual-phase diamond (NDPD) comprised of an amorphous-crystalline heterostructure is developed to regulate Zn deposition and mechanically block dendrite growth. The rich amorphous-crystalline heterointerfaces in the NDPD endow modified Zn anodes with enhanced Zn affinity and result in homogeneous nucleation. In addition, the unparalleled hardness of the NDPD effectively overcomes the high growth stress of dendrites and mechanically impedes their proliferation. Moreover, the hydrophobic surfaces of the NDPD facilitate the desolvation of hydrate Zn2+ and prevent water-mediated side reactions. Consequently, the Zn@NDPD presents an ultrastable lifespan exceeding 3200 h at 5 mA cm-2 and 1 mAh cm-2. The practical application potential of Zn@NDPD is further demonstrated in full cells. This work exhibits the great significance of a chemical-mechanical synergistic anode modification strategy in constructing high-performance aqueous Zn-ion batteries.

Parametric Analysis of Free Vibration of Functionally Graded Porous Sandwich Rectangular Plates Resting on Elastic Foundation.

Based on the three-dimensional elasticity theory, the free vibration of functionally graded porous (FGP) sandwich rectangular plates is studied, and a unified solution for free vibration of the plates is proposed in this study. The arbitrary boundary conditions of FGP sandwich rectangular plates are simulated by using the Rayleigh-Ritz method combined with artificial spring theory. The calculation performances of the unified solution for FGP sandwich rectangular plates such as convergence speed and computational efficiency are compared extensively under different displacement functions. In addition, three kinds of elastic foundation (Winkler/Pasternak/Kerr foundations) and three porosity distributions are considered. Some benchmark results and accurate values for the free vibration of FGP sandwich rectangular plates resting on elastic foundations are given. Finally, the effects of diverse structural parameters, elastic foundations with different parameters, and boundary conditions on the free vibration of the FGP sandwich rectangular plates are analyzed.

The Safety and Efficacy of Remimazolam Compared to Dexmedetomidine for Awake Tracheal Intubation by Flexible Bronchoscopy: A Randomized, Double-Blind, Controlled Trial.

Background: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that has the potential to be an alternative for procedural sedation due to its rapid sedation and recovery, no accumulation effect, stable hemodynamics, minimal respiratory depression, anterograde amnesia effect, and specific antagonist. Here, we aimed to compare the safety and efficacy of remimazolam with dexmedetomidine for awake tracheal intubation by flexible bronchoscopy (ATI-FB). Methods: Ninety patients scheduled for ATI-FB were randomly divided into three groups, each consisting of 30 cases: dexmedetomidine 0.6 µg/kg + sufentanil (group DS), remimazolam 0.073 mg/kg + sufentanil (group R1S), or remimazolam 0.093 mg/kg + sufentanil (group R2S). The primary outcome was the success rate of sedation. Secondary outcomes were MOAA/S scores, hemodynamic and respiratory parameters, intubation conditions, intubation time, tracheal intubation amnesia, and adverse events. Results: The success rates of sedation in groups R2S and DS were higher than that in group R1S (93.3%, 86.7%, respectively, vs 58.6%; P = 0.002), and intubation conditions were better than those in group R1S (P < 0.05). Group R2S had shorter intubation times than groups R1S and DS (P = 0.003), and a higher incidence of tracheal intubation amnesia than group DS (P = 0.006). No patient in the three groups developed hypoxemia or hypotension, and there were no significant differences in oligopnea, PetCO2, or bradycardia (P > 0.05). Conclusion: In conclusion, both DS and R2S had higher success rates of sedation, better intubation conditions, and minor respiratory depression, but R2S, with its shorter intubation time, higher incidence of anterograde amnesia, and ability to be antagonized by specific antagonists, may be a good alternative sedation regimen for patients undergoing ATI-FB.

Characteristics of early gastric tumors with different differentiation and predictors of long-term outcomes after endoscopic submucosal dissection.

BACKGROUND: Gastric cancer is a common malignant tumor of the digestive tract, and endoscopic submucosal dissection (ESD) is the preferred treatment for early-stage gastric cancer. The analysis of the epidemiological characteristics of gastric mucosal tumors with different differentiation degrees and the influencing factors of long-term ESD efficacy may have certain significance for revealing the development of gastric cancer and ESD. AIM: To analyze the features of gastric mucosal tumors at different differentiation levels, and to explore the prognostic factors of ESD. METHODS: We retrospectively studied 301 lesions in 285 patients at The Second Affiliated Hospital of Xi'an Jiaotong University from 2014 to 2021, according to the latest Japanese guidelines (sixth edition), and divided them into low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and differentiated and undifferentiated early carcinoma. They are followed up by endoscopy, chest and abdominal computed tomography at 3, 6 and 12 months after ESD. We compared clinicopathologic characteristics, ESD efficacy, and complications with different degrees of differentiation, and analyzed the related factors associated with ESD. RESULTS: HGIN and differentiated carcinoma patients were significantly older compared with LGIN patients (P < 0.001) and accounted for more 0-IIc (P < 0.001), atrophic gastritis was common (P < 0.001), and irregular microvascular patterns (IMVPs) and demarcation lines (DLs) were more obvious (P < 0.001). There was more infiltration in the undifferentiated carcinoma tissue (P < 0.001), more abnormal folds and poorer mucosal peristalsis (P < 0.001), and more obvious IMVPs, irregular microsurface patterns and DLs (P < 0.05) than in the LGIN and HGIN tissues. The disease-free survival rates at 2, 5, and 8 years after ESD were 95.0%, 90.1%, and 86.9%, respectively. Undifferentiated lesions (HR 5.066), white moss (HR 7.187), incomplete resection (HR 3.658), and multiple primary cancers (HR 2.462) were significantly associated with poor prognosis. CONCLUSION: Differentiations of gastric mucosal tumors have different epidemiological and endoscopic characteristics, which are closely related to the safety and efficacy of ESD.

Ultrasound enhanced siRNA delivery using cationic liposome-microbubble complexes for the treatment of squamous cell carcinoma.

Rationale: Microbubble (MB) contrast agents combined with ultrasound targeted microbubble cavitation (UTMC) are a promising platform for site-specific therapeutic oligonucleotide delivery. We investigated UTMC-mediated delivery of siRNA directed against epidermal growth factor receptor (EGFR), to squamous cell carcinoma (SCC) via a novel MB-liposome complex (LPX). Methods: LPXs were constructed by conjugation of cationic liposomes to the surface of C4F10 gas-filled lipid MBs using biotin/avidin chemistry, then loaded with siRNA via electrostatic interaction. Luciferase-expressing SCC-VII cells (SCC-VII-Luc) were cultured in Petri dishes. The Petri dishes were filled with media in which LPXs loaded with siRNA against firefly luciferase (Luc siRNA) were suspended. Ultrasound (US) (1 MHz, 100-µs pulse, 10% duty cycle) was delivered to the dishes for 10 sec at varying acoustic pressures and luciferase assay was performed 24 hr later. In vivo siRNA delivery was studied in SCC-VII tumor-bearing mice intravenously infused with a 0.5 mL saline suspension of EGFR siRNA LPX (7×108 LPX, ~30 µg siRNA) for 20 min during concurrent US (1 MHz, 0.5 MPa spatial peak temporal peak negative pressure, five 100-µs pulses every 1 ms; each pulse train repeated every 2 sec to allow reperfusion of LPX into the tumor). Mice were sacrificed 2 days post treatment and tumor EGFR expression was measured (Western blot). Other mice (n=23) received either EGFR siRNA-loaded LPX + UTMC or negative control (NC) siRNA-loaded LPX + UTMC on days 0 and 3, or no treatment ("sham"). Tumor volume was serially measured by high-resolution 3D US imaging. Results: Luc siRNA LPX + UTMC caused significant luciferase knockdown vs. no treatment control, p<0.05) in SCC-VII-Luc cells at acoustic pressures 0.25 MPa to 0.9 MPa, while no significant silencing effect was seen at lower pressure (0.125 MPa). In vivo, EGFR siRNA LPX + UTMC reduced tumor EGFR expression by ~30% and significantly inhibited tumor growth by day 9 (~40% decrease in tumor volume vs. NC siRNA LPX + UTMC, p<0.05). Conclusions: Luc siRNA LPXs + UTMC achieved functional delivery of Luc siRNA to SCC-VII-Luc cells in vitro. EGFR siRNA LPX + UTMC inhibited tumor growth and suppressed EGFR expression in vivo, suggesting that this platform holds promise for non-invasive, image-guided targeted delivery of therapeutic siRNA for cancer treatment.

Mixed-size spot scanning with a compact large momentum acceptance superconducting (LMA-SC) gantry beamline for proton therapy.

Objective. Lowering treatment costs and improving treatment quality are two primary goals for next-generation proton therapy (PT) facilities. This work will design a compact large momentum acceptance superconducting (LMA-SC) gantry beamline to reduce the footprint and expense of the PT facilities, with a novel mixed-size spot scanning method to improve the sparing of organs at risk (OAR).Approach. For the LMA-SC gantry beamline, the movable energy slit is placed in the middle of the last achromatic bending section, and the beam momentum spread of delivered spots can be easily changed during the treatment. Simultaneously, changing the collimator size can provide spots with various lateral spot sizes. Based on the provided large-size and small-size spot models, the treatment planning with mixed spot scanning is optimized: the interior of the target is irradiated with large-size spots (to cover the uniform-dose interior efficiently), while the peripheral of the target is irradiated with small-size spots (to shape the sharp dose falloff at the peripheral accurately).Main results. The treatment plan with mixed-size spot scanning was evaluated and compared with small and large-size spot scanning for thirteen clinical prostate cases. The mixed-size spot plan had superior target dose homogeneities, better protection of OAR, and better plan robustness than the large-size spot plan. Compared to the small-size spot plan, the mixed-size spot plan had comparable plan quality, better plan robustness, and reduced plan delivery time from 65.9 to 40.0 s.Significance. The compact LMA-SC gantry beamline is proposed with mixed-size spot scanning, with demonstrated footprint reduction and improved plan quality compared to the conventional spot scanning method.

Identifying Predictors for Hypoplastic Aortic Arch (HAA) in Pediatric Patients with Complex Coarctation of the Aorta (CoA).

OBJECTIVE: HAA is a significant risk factor in complex CoA patients. We conducted a retrospective study to explore the relationship between HAA and other cardiovascular factors. METHODS: We analyzed 103 patients diagnosed with complex CoA using CT angiography and echocardiography. Aortic diameter was measured at six levels, and severe coarctation was defined as coarctation site to diaphragmatic level ratio (CDR) < 50%. Correlations between non-HAA and HAA groups were assessed. Univariate and multivariate logistic regression identified HAA risk factors. RESULTS: Among 103 children with complex CoA, 55 were in the non-HAA group and 48 in the HAA group. The incidence of PDA (56.3% vs. 32.7%, p < 0.05), severe coarctation (CDR < 50%, 81.3% vs. 34.5%, p < 0.01), and collateral arteries (39.6% vs. 0, p < 0.01) were higher in the HAA group than one in the non-HAA group. The aortic arch size was positively correlated with age and negatively correlated with severe coarctation, VSD, collateral arteries, and left heart dysfunction. Logistic regression results showed that collateral arteries were risk factors for the whole aortic arch (proximal arch OR = 11.458; p < 0.01, distal arch OR = 4.211; p < 0.05, and isthmus OR = 11.744; p < 0.01), severe coarctation (OR = 6.653; p < 0.01), and left heart dysfunction (OR = 5.149; p < 0.01) associated with isthmus hypoplasia. CONCLUSION: This study highlights the prevalence of HAA in complex CoA patients and its associations with various cardiovascular factors. These insights improve diagnosis and treatment approaches.

Cobalt-Catalyzed Carbon-Heteroatom Transfer Enables Regioselective Tricomponent 1,4-Carboamination.

Tricomponent cobalt(salen)-catalyzed carbofunctionalization of unsaturated substrates by radical-polar crossover has the potential to streamline access to broad classes of heteroatom-functionalized synthetic targets, yet the reaction platform has remained elusive, despite the well-developed analogous hydrofunctionalizations mediated by high-valent alkylcobalt intermediates. We report herein the development of a cobalt(salen) catalytic system that enables carbofunctionalization. The reaction entails a tricomponent decarboxylative 1,4-carboamination of dienes and provides a direct route to aromatic allylic amines by obviating preformed allylation reagents and protection of oxidation-sensitive aromatic amines. The catalytic system merges acridine photocatalysis with cobalt(salen)-catalyzed regioselective 1,4-carbofunctionalization that facilitates the crossover of the radical and polar phases of the tricomponent coupling process, revealing critical roles of the reactants, as well as ligand effects and the nature of the formal high-valent alkylcobalt species on the chemo- and regioselectivity.

The long rod-shaped Sr2 MgSi2 O7 :Eu2+ ,Dy3+ with ultrahigh afterglow performance.

The afterglow properties of long afterglow luminescent materials are greatly affected by their defects, which are distributed on the grain surface. Increasing the exposed surface area is an important method to improve the afterglow performance. In this research, long rod-shaped long afterglow materials Sr2 MgSi2 O7 :Eu2+ ,Dy3+ were prepared using the hydrothermal-coprecipitation method. When the reaction time reached 96 h, the length of the afterglow materials could grow to 2 mm, and the sintering temperature was just 1150°C. The emission spectra of all obtained samples upon excitation at 397 nm had a maximum of 465 nm, which belonged to the representative transition of Eu2+ . The initial brightness was 1.35 cd/m2 . The afterglow time could reach 19 h, giving a good afterglow performance. The research on this kind of material has essential significance in the exploration of luminescence mechanisms and their applications.

Human vulnerability assessment based on bullet motion and cavity expansion model with tissue identification.

In human vulnerability assessment, the wound characteristics are derived from a single soft media penetration experiment, and there is a lack of mathematical model or algorithm to accurately describe the bullet motion (consider bullet rolling) and temporary cavity variation during bullet penetration into different soft media. This paper derives a bullet motion and cavity expansion-contraction model for bullet penetration into soft tissue; Established a dynamic wound reconstruction model based on neural networks that considers tissue differences. Assessment of damage to tissues using the Abbreviated Injury Scale; Developed software for assessing human vulnerability based on dynamic wound reconstruction. Research results show that the bullet motion model and the cavity expansion-contraction model can predict the characteristic volume of the wound and the temporary cavity profile changes during bullet penetration more accurately; the maximum temporary cavity diameters of the muscle wound, the cardiac wound, and the muscle-cardiac-muscle coupling wound are 183.6, 158.06, and 174.74 mm respectively, and using the cavity in a single target as the basis for human injury assessment will introduce errors. The process of bullet penetration into soft tissue can be accurately described based on a predictive model that considers tissue differences. This paper provides the model that improves the accuracy of human injury assessment compared to existing penetration models.

Derived the bullet motion model and temporary cavity expansion- contraction model when the projectile penetrates a soft medium.Derived a dynamic wound reconstruction model based on feed-forward neural networks that considers tissue variation.Developed a wound visualization program that is more consistent with experimental phenomena.Analysis of the differences in wound channels when projectile penetrating different tissues shows that using the results of penetrating a single medium as the basis for assessment introduces errors.

Feasibility study of multiple-energy Bragg peak proton FLASH on a superconducting gantry with large momentum acceptance.

BACKGROUND: While the Bragg peak proton beam (BP) is capable of superior target conformity and organs-at-risk sparing than the transmission proton beam (TB), its efficacy in FLASH-RT is hindered by both a slow energy switching process and the beam current. A universal range shifter (URS) can pull back the high-energy proton beam while preserving the beam current. Meanwhile, a superconducting gantry with large momentum acceptance (LMA-SC gantry) enables fast energy switching. PURPOSE: This study explores the feasibility of multiple-energy BP FLASH-RT on the LMA-SC gantry. METHOD AND MATERIALS: A simultaneous dose and spot map optimization algorithm was developed for BP FLASH-RT treatment planning to improve the dose delivery efficiency. The URS was designed to be 0-27 cm thick, with 1 cm per step. BP plans using the URS were optimized using single-field optimization (SFO) and multiple-field optimization (MFO) for ten prostate cancer patients and ten lung cancer patients. The plan delivery parameters, dose, and dose rate metrics of BP plans were compared to those of TB plans using the parameters of the LMA-SC gantry. RESULTS: Compared to TB plans, BP plans significantly reduced MUs by 42.7% (P < 0.001) with SFO and 33.3% (P < 0.001) with MFO for prostate cases. For lung cases, the reduction in MUs was 56.8% (P < 0.001) with SFO and 36.4% (P < 0.001) with MFO. BP plans also outperformed TB plans by reducing mean normal tissue doses. BP-SFO plans achieved a reduction of 56.7% (P < 0.001) for prostate cases and 57.7% (P < 0.001) for lung cases, while BP-MFO plans achieved a reduction of 54.2% (P < 0.001) for the prostate case and 40.0% (P < 0.001) for lung cases. For both TB and BP plans, normal tissues in prostate and lung cases received 100.0% FLASH dose rate coverage (>40 Gy/s). CONCLUSIONS: By utilizing the URS and the LMA-SC gantry, it is possible to perform multiple-energy BP FLASH-RT, resulting in better normal tissue sparing, as compared to TB plans.

Micro-to-Nano Oncolytic Microbial System Shifts from Tumor Killing to Tumor Draining Lymph Nodes Remolding for Enhanced Immunotherapy.

Because the tumor-draining lymph nodes (TDLNs) microenvironment is commonly immunosuppressive, oncolytic microbe-induced tumor antigens aren't sufficiently cross-primed tumor specific T cells through antigen-presenting cells (e.g., dendritic cells (DCs)) in TDLNs. Herein, this work develops the micro-to-nano oncolytic microbial therapeutics based on pyranose oxidase (P2 O) overexpressed Escherichia coli (EcP) which are simultaneously encapsulated by PEGylated mannose and low-concentrated photosensitizer nanoparticles (NPs). Following administration, P2 O from this system generates toxic hydrogen peroxide for tumor regression and leads to the release of tumor antigens. The "microscale" EcP is triggered, following exposure to the laser irradiation, to secrete the "nanoscale" bacterial outer membrane vesicles (OMVs). The enhanced TDLNs delivery via OMVs significantly regulates the TDLNs immunomicroenvironment, promoting the maturation of DCs to potentiate tumor antigen-specific T cells immune response. The micro-to-nano oncolytic microbe is leveraged to exert tumor killing and remold TDLNs for initiating potent activation of DCs, providing promising strategies to facilitate microbial cancer vaccination.

Allograft inflammatory factor-1 enhances inflammation and oxidative stress via the NF-κB pathway of bladder urothelium in diabetic rat model.

OBJECTIVES: To explore the role of allograft inflammatory factor-1 (AIF-1) both in diabetic rat bladder urothelium and in high-glucose-treated human urothelial cell line (SV-HUC-1). METHODS: Inflammation and oxidative stress (OS) promote diabetic cystopathy (DCP), but the mechanisms are not fully understood. The expression level of AIF-1 in diabetic rat bladder urothelium and in the SV-HUC-1 cells treated with high glucose was detected using tissue immunofluorescence, immunohistochemistry and western blot assays. AIF-1 was knocked down and NF-κB was suppressed with the specific inhibitor BAY 11-7082 in high-glucose-treated SV-HUC-1 cells. RESULTS: High-glucose condition induced AIF-1 upregulation in vivo and in vitro. The up-regulated AIF-1 induced the production of inflammatory factors IL-6 and TNF-α and elevation of ROS. Informatics analysis suggested that NF-κB pathway is implicated in DCP. Through knockdown of AIF-1, we confirmed that AIF-1 simulated NF-κB pathway by enhancing the phosphorylation of IκB (p-IκB) and promoting the translocation of NF-κB p65 from cytoplasm into nucleus. Additionally, High-glucose-induced inflammation in SV-HUC-1 cells was attenuated by the addition of NF-κB inhibitor. CONCLUSIONS: This study provides novel information to understand the molecular regulation mechanisms of AIF-1 in DCP.

Development of a human glioblastoma model using humanized DRAG mice for immunotherapy.

Glioblastoma (GBM) is the most common and lethal primary brain tumor. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. We successfully generated humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model by transplantation of human DR4+ hematopoietic stem cells (hHSCs), and effectively grafted GBM patient-derived tumorsphere cells to form xenografted tumors intracranially. The engrafted tumors recapitulated the pathological features and the immune cell composition of human GBM. Administration of anti-human PD-1 antibodies in these tumor-bearing humanized DRAG mice decreased the major tumor-infiltrating immunosuppressive cell populations, including CD4+PD-1+ and CD8+PD-1+ T cells, CD11b+CD14+HLA-DR+ macrophages, CD11b+CD14+HLA-DR-CD15- and CD11b+CD14-CD15+ myeloid-derived suppressor cells, indicating the humanized DRAG mice as a useful model to test the efficacy of GBM immunotherapy. Taken together, these results suggest that the humanized DRAG mouse model is a reliable preclinical platform for studying brain cancer immunotherapy and beyond.