Vertebrobasilar Artery Occlusion Treatment Outcomes Within 24 hours of Estimated Occlusion Time.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the efficacy and safety of endovascular treatment (EVT) in patients with acute vertebrobasilar artery occlusion (VBAO) within 24 hours of estimated occlusion time (EOT) and to evaluate the effect of early and late time window in a cohort of patients with VBAO treated with EVT. METHODS: Retrospective analysis was conducted on patients within 24 hours of the EOT in 65 stroke centers in China. Favorable outcome was defined as modified Rankin Scale ≤3 at 90 days. Patients were divided into the medical management (MM) group and the EVT group. Times were dichotomized into early (EOT ≤6 hours) and late (>6 hours) time windows. Multivariate logical regression models were used to evaluate the efficacy and safety of EVT and the effect of time windows on outcomes in EVT patients. RESULTS: Among 4124 patients, 2473 and 1651 patients were included in the early and late windows, respectively. 1702 patients received MM and 2422 were treated with EVT. EVT was associated with a higher rate of a favorable outcome at 90 days both in early (odds ratio [OR] 2.16, 95% CI 1.94-2.41) and late (OR 1.89, 95% CI 1.65-2.17) time windows. No differences were found regarding favorable outcome (OR 0.95, 95% CI 0.87-1.03) between VBAO patients treated with EVT within and beyond 6 hours. CONCLUSION: Patients with acute VBAO who received EVT within 24 hours were associated with improved favorable outcome compared with patients who received MM. EVT beyond 6 hours is feasible and safe with no increase in symptomatic intracranial hemorrhage.

Whether mTICI 3 or mTICI 2b is better in patients with vertebrobasilar artery occlusion undergoing endovascular treatment depends on pc-ASPECTS.

BACKGROUND: The clinical relevance of differentiating between mTICI (modified Thrombolysis In Cerebral Infarction) 2b and mTICI 3 in patients with vertebrobasilar artery occlusion (VBAO) remains unclear. This study aimed to investigate whether mTICI 3 improves functional outcomes compared with mTICI 2b in patients with VBAO and whether this improvement differs according to extent of ischemic damage. METHODS: This retrospective study enrolled patients with VBAO within 24 hours of the estimated occlusion time at 65 stroke centers in a nationwide registration in China. The primary outcome was favorable functional outcome (modified Rankin scale score 0-3) at 90 days. Patients were matched by final mTICI grade using propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Logistic regression and ordinal regression models were used to assess the impact of mTICI 2b versus mTICI 3 grading on prognosis, based on different extent of ischemia damage (posterior circulation Alberta Stroke Program Early CT Score-pc-ASPECTS of 9-10, 7-8, and 3-6) and treatment strategies (bridging therapy and direct endovascular therapy (EVT)). RESULTS: A total of 2075 patients with VBAO and successful reperfusion were included, 652 patients (31.4%) achieved mTICI 2b and 1423 patients (68.6%) achieved mTICI 3. After adjustment for confounders, achieving mTICI 3 following EVT in patients with VBAO and pc-ASPECTS 9-10 (OR 1.54, 95% CI 1.16 to 2.03) and pc-ASPECTS 7-8 (OR 1.80, 95% CI (1.26 to 2.56) were associated with favorable functional outcome compared with mTICI 2b, especially in those receiving direct EVT. However, in patients with pc-ASPECTS≤6, functional outcomes at 90 days did not differ between mTICI 3 and mTICI 2b (OR 1.12, 95% CI 0.67 to 1.88), irrespective of using bridging therapy or direct EVT. CONCLUSION: In patients with VBAO undergoing EVT with pc-ASPECTS>6, achieving mTICI 3 favors better outcomes compared with mTICI 2b, especially in those receiving direct EVT. However, in patients with pc-ASPECTS≤6, mTICI 3 did not improve functional outcomes compared with mTICI 2b. Interventionalists should carefully assess the risk-benefit of additional maneuvers once mTICI 2b reperfusion is restored in EVT for patients with VBAO and pc-ASPECTS≤6. Further studies are needed to guide treatment decisions in these cases.

Engineering AIEgens-Tethered Gold Nanoparticles with Enzymatic Dual Self-Assembly for Amplified Cancer-Specific Phototheranostics.

Accurate imaging and precise treatment are critical to controlling the progression of pancreatic cancer. However, current approaches for pancreatic cancer theranostics suffer from limitations in tumor specificity and invasive surgery. Herein, a pancreatic cancer-specific phototheranostic modulator (AuHQ) dominated by aggregation-induced emission (AIE) luminogens-tethered gold nanoparticles is meticulously designed to facilitate prominent fluorescence-photoacoustic bimodal imaging-guided photothermal immunotherapy. Once reaching the pancreatic tumor microenvironment (TME), the peptide Ala-Gly-Phe-Ser-Leu-Pro-Ala-Gly-Cys (AGFSLPAGC) linkage within AuHQ can be specifically cleaved by the overexpressed enzyme Cathepsin E (CTSE), triggering the dual self-assembly of AuNPs and AIE luminogens. The aggregation of AuNPs mediated by enzymatic cleavage results in potentiated photothermal therapy (PTT) under near-infrared (NIR) laser irradiation, induced immunogenic cell death (ICD), and enhanced photoacoustic imaging. Simultaneously, AIE luminogen aggregates formed by hydrophobic interaction can generate AIE fluorescence, enabling real-time and specific fluorescence imaging of pancreatic cancer. Furthermore, coadministration of an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor with AuHQ can address the limitations of PTT efficacy imposed by the immunosuppressive TME and leverage the synergistic potential to activate systemic antitumor immunity. Thus, this well-designed phototheranostic modulator AuHQ facilitates the intelligent enzymatic dual self-assembly of imaging and therapeutic agents, providing an efficient and precise approach for pancreatic cancer theranostics.

Well-Being and Cardiovascular Health: Insights From the UK Biobank Study.

BACKGROUND: Cardiovascular diseases (CVDs) are a leading global health concern. Emerging evidence suggests a potential protective role of well-being in reducing CVD risk. METHODS AND RESULTS: We conducted a cohort analysis using the UK Biobank data set, encompassing 121 317 participants. We assessed the well-being of participants using a well-being index derived from baseline questionnaires. Well-being categories were derived by latent class analysis using general happiness and satisfaction with family, friendships, health, and finance situations. The relationship between well-being and 4 major CVDs was analyzed using Cox proportional hazards models and Mendelian randomization. The study also examined the impacts of well-being on lifestyle factors and inflammatory markers, and its mediating role in the well-being-CVD relationship. Higher well-being was associated with a significantly reduced risk of various CVDs. Latent class analysis identified 4 distinct well-being groups (low, variable, moderate-to-high, and high satisfaction), with higher satisfaction levels generally associated with lower risk of CVDs. Mendelian randomization suggested potential causal relationships between well-being and reduced risk of CVDs. Participants with greater well-being demonstrated healthier behaviors and lower levels of inflammatory markers. Mediation analysis indicated that lifestyle and inflammatory markers partially mediated the relationship between well-being and CVDs. CONCLUSIONS: This study demonstrates a robust inverse association between well-being and the risks of CVDs, suggesting that enhancing well-being may be a viable strategy for CVD prevention. The role of lifestyle factors and inflammation as a mediator provides insight into possible biological pathways linking psychological states and cardiovascular health.

Biodegradable persistent ROS-generating nanosonosensitizers for enhanced synergistic cancer therapy by inducing cascaded oxidative stress.

Sonodynamic therapy (SDT) is gaining popularity in cancer treatment due to its superior controllability and high tissue permeability. Nonetheless, the efficacy of SDT is severely diminished by the transient generation of limited reactive oxygen species (ROS). Herein, we introduce an acid-activated nanosonosensitizer, CaO2@PCN, by the controllable coating of porphyrinic metal-organic frameworks (PCN-224) on CaO2 to induce cascaded oxidative stress in tumors. The PCN-224 doping can generate ROS during SDT to induce intracellular oxidative stress and abnormal calcium channels. Meanwhile, the ultrasound also promotes extracellular calcium influx. In addition, CaO2@PCN sequentially degrades in the tumor cell lysosomes, releasing Ca2+ and H2O2 to induce further abnormal calcium channels and elevate the levels of Ca2+. Insufficient catalase (CAT) in tumor cells promotes intracellular calcium overload, which can induce persistent ROS generation and mitochondrial dysfunction through ion interference therapy (IIT). More importantly, PCN-224 also protects CaO2 against significant degradation under neutral conditions. Hence, the well-designed CaO2@PCN produces synergistic SDT/IIT effects and persistent ROS against cancer. More notably, the acidity-responsive biodegradability endows CaO2@PCN with excellent biosafety and promising clinical potential.

New compatible pair of TCM: Paeoniae Radix Alba effectively alleviate Psoraleae Fructus-induced liver injury by suppressing NLRP3 inflammasome activation.

Objective: Drug-induced liver injury (DILI), a type of acute inflammation, has sparked significant concern owing to its unpredictability and severity. Psoraleae Fructus (PF), an edible Chinese herb widely used in traditional Chinese medicine (TCM), causes liver injury. Therefore, the elucidation of the mechanism underlying PF-induced liver injury and the search for more effective means of detoxification using herbal compatibility has become an urgent issue. This study evaluated the hepatoprotective effects of Paeoniae Radix Alba (PRA), a hepatoprotective Chinese medicine, on PF-induced liver injury and explored the underlying mechanisms. Methods: A rat model of lipopolysaccharide (LPS)-induced immune stress was established to evaluate the hepatotoxicity of PF and the detoxifying effect of PRA. Subsequently, inflammatory pathways were identified using network pharmacology. Finally, the molecular mechanism by which PRA alleviates PF-induced liver injury was validated using an inflammasome activation model in bone marrow-derived macrophages (BMDMs). Results: In vivo, hepatocytes in rats treated with LPS + PF exhibited massive inflammatory infiltration and apoptosis, and the expression of liver injury indicators and inflammatory factors was significantly upregulated, which was reversed by PRA pretreatment. Network pharmacology showed that PRA alleviated PF-induced liver injury and was associated with the NOD-like receptor signaling pathway. Moreover, PF directly induced inflammasome activation in LPS-primed BMDMs which in turn induced caspase-1 activation and the secretion of downstream effector cytokines such as IL-1ß. PRA pretreatment inhibited PF-induced activation of the NLRP3 inflammasome by mitigating the accumulation of mitochondrial reactive oxygen species (mtROS). Conclusions: The present study demonstrates that PRA alleviated PF induced-liver injury by inhibiting NLRP3 inflammasome activation. The results of this study are expected to inform the prevention and control of PF-induced hepatotoxicity in clinical practice.

mRNA-Lipid Nanoparticle-Mediated Restoration of PTPN14 Exhibits Antitumor Effects by Overcoming Anoikis Resistance in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) poses a challenging prognosis due to early metastasis driven by anoikis resistance. Identifying crucial regulators to overcome this resistance is vital for improving patient outcomes. In this study, a genome-wide CRISPR/Cas9 knockout screen in TNBC cells has identified tyrosine-protein phosphatase nonreceptor type 14 (PTPN14) as a key regulator of anoikis resistance. PTPN14 expression has shown a progressive decrease from normal breast tissue to metastatic tumors. Overexpressing PTPN14 has induced anoikis and inhibited cell proliferation in TNBC cells, while normal human breast cells are unaffected. Mechanistically, PTPN14 is identified as a key factor in dephosphorylating breast cancer antiestrogen resistance 3, a novel substrate, leading to the subsequent inhibition of PI3K/AKT and ERK signaling pathways. Local delivery of in vitro transcribed PTPN14 mRNA encapsulated by lipid nanoparticles in a TNBC mouse model has effectively inhibited tumor growth and metastasis, prolonging survival. The study underscores PTPN14 as a potential therapeutic target for metastatic TNBC, with the therapeutic strategy based on mRNA expression of PTPN14 demonstrating clinical application prospects in alleviating the burden of both primary tumors and metastatic disease.

Endovascular treatment effect in vertebrobasilar artery occlusion patients with posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) <6.

BACKGROUND: Endovascular treatment (EVT) has revolutionized the standard treatment of vertebrobasilar artery occlusion (VBAO) with moderate infarct core, but its effectiveness in patients with a low posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) is unclear. This study aimed to assess EVT effects in VBAO patients with pc-ASPECTS <6. METHODS: This retrospective study enrolled patients with VBAO within 24 hours of the estimated occlusion time at 65 stroke centers in a nationwide registration in China. The primary outcome was a favorable shift in the modified Rankin Scale (mRS) at 90 days. The secondary outcomes included a favorable outcome (mRS 0-3) and functional independence (mRS 0-2). Propensity score matching and inverse probability of treatment weighting were used to compare the outcomes of patients treated with EVT and those with best medical management. RESULTS: A total of 431 patients with VBAO and pc-ASPECTS <6 were included. EVT was associated with a favorable shift in the mRS score at 90 days (OR 1.72, 95% CI 1.19 to 2.5), a higher probability of a favorable outcome (OR 1.66, 95% CI 1.02 to 2.74), and improved functional independence (OR 1.76, 95% CI 1.06 to 2.96). EVT also significantly reduced the risk of 90-day mortality (OR 0.62, 95% CI 0.40 to 0.96), but increased the risk of symptomatic intracranial hemorrhage (OR 2.76, 95% CI 1.06 to 8.58). CONCLUSION: The results of this study suggest that EVT may be a safe and effective treatment option for patients with VBAO and pc-ASPECTS <6. Further studies are needed to investigate the effect of EVT in patients with pc-ASPECTS <6 and to identify patients who may benefit from EVT.

Clinical implementation and evaluation of deep learning-assisted automatic radiotherapy treatment planning for lung cancer.

PURPOSE: The purpose of the study is to investigate the clinical application of deep learning (DL)-assisted automatic radiotherapy planning for lung cancer. METHODS: A DL model was developed for predicting patient-specific doses, trained and validated on a dataset of 235 patients with diverse target volumes and prescriptions. The model was integrated into clinical workflow with DL-predicted objective functions. The automatic plans were retrospectively designed for additional 50 treated manual volumetric modulated arc therapy (VMAT) plans. A comparison was made between automatic and manual plans in terms of dosimetric indexes, monitor units (MUs) and planning time. Plan quality metric (PQM) encompassing these indexes was evaluated, with higher PQM values indicating superior plan quality. Qualitative evaluations of two plans were conducted by four reviewers. RESULTS: The PQM score was 40.7 ± 13.1 for manual plans and 40.8 ± 13.5 for automatic plans (P = 0.75). Compared to manual plans, the targets coverage and homogeneity of automatic plans demonstrated no significant difference. Manual plans exhibited better sparing for lung in V5 (difference: 1.8 ± 4.2 %, P = 0.02), whereas automatic plans showed enhanced sparing for heart in V30 (difference: 1.4 ± 4.7 %, P = 0.02) and for spinal cord in Dmax (difference: 0.7 ± 4.7 Gy, P = 0.04). The planning time and MUs of automatic plans were significantly reduced by 70.5 ± 20.0 min and 97.4 ± 82.1. Automatic plans were deemed acceptable in 88 % of the reviews (176/200). CONCLUSIONS: The DL-assisted approach for lung cancer notably decreased planning time and MUs, while demonstrating comparable or superior quality relative to manual plans. It has the potential to provide benefit to lung cancer patients.

The mechanism of low molecular weight fucoidan-incorporated nanofiber scaffolds inhibiting oral leukoplakia via SR-A/Wnt signal axis.

Oral leukoplakia (OLK) is the most common oral precancerous lesion, and 3%-17% of OLK patients progress to oral squamous cell carcinoma. OLK is susceptible to recurrence and has no effective treatment. However, conventional drugs have significant side effects and limitations. Therefore, it is important to identify drugs that target OLK. In this study, scavenger receptor A (SR-A) was found to be abnormally highly expressed in the oral mucosal epithelial cells of OLK patients, whereas molecular biology studies revealed that low molecular weight fucoidan (LMWF) promoted apoptosis of dysplastic oral keratinocytes (DOK) and inhibited the growth and migration of DOK, and the inhibitory effect of LMWF on OLK was achieved by regulating the SR-A/Wnt signaling axis and related genes. Based on the above results and the special situation of the oral environment, we constructed LMWF/poly(caprolactone-co-lactide) nanofiber membranes with different structures for the in-situ treatment of OLK using electrospinning technology. The results showed that the nanofiber membranes with a shell-core structure had the best physicochemical properties, biocompatibility, and therapeutic effect, which optimized the LMWF drug delivery and ensured the effective concentration of the drug at the target point, thus achieving precise treatment of local lesions in the oral cavity. This has potential application value in inhibiting the development of OLK.

Impact of 1.5†T Magnetic Field on Treatment Plan Quality in MR-Guided Radiotherapy: Typical Phantom Test Cases.

PURPOSE: This study aims to investigate the influence of the magnetic field on treatment plan quality using typical phantom test cases, which encompass a circle target test case, AAPM TG119 test cases (prostate, head-and-neck, C-shape, multi-target test cases), and a lung test case. MATERIALS AND METHODS: For the typical phantom test cases, two plans were formulated. The first plan underwent optimization in the presence of a 1.5 Tesla magnetic field (1.5 T plan). The second plan was re-optimized without a magnetic field (0 T plan), utilizing the same optimization conditions as the first plan. The two plans were compared based on various parameters, including con-formity index (CI), homogeneity index (HI), fit index (FI) and dose coverage of the planning target volume (PTV), dose delivered to organs at risk (OARs) and normal tissue (NT), monitor unit (MU). A plan-quality metric (PQM) scoring procedure was employed. For the 1.5 T plans, dose verifications were performed using an MR-compatible ArcCHECK phantom. RESULTS: A smaller dose influence of the magnetic field was found for the circle target, prostate, head-and-neck, and C-shape test cases, compared with the multi-target and lung test cases. In the multi-target test case, the significant dose influence was on the inferior PTV, followed by the superior PTV. There was a relatively large dose influence on the PTV and OARs for lung test case. No statistically significant differences in PQM and MUs were observed. For the 1.5 T plans, gamma passing rates were all higher than 95% with criteria of 2 mm/3% and 2 mm/2%. CONCLUSION: The presence of a 1.5 T magnetic field had a relatively large impact on dose parameters in the multi-target and lung test cases compared with other test cases. However, there were no significant influences on the plan-quality metric, MU and dose accuracy for all test cases.

Biodegradable Long-Circulating Nanoagonists Optimize Tumor-Tropism Chemo-Metalloimmunotherapy for Boosted Antitumor Immunity by Cascade cGAS-STING Pathway Activation.

The activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) has been recognized as one of the most promising immunotherapeutic strategies to induce innate antitumor immune responses. However, it is far from effective to just activate the cGAS-STING pathway, owing to abundant immunosuppressive cells that infiltrate the tumor microenvironment (TME) to impair antitumor immunity. Here, we present the smart design of biodegradable Mn-doped mesoporous silica (MM) nanoparticles with metal-organic framework (MOF) gating and hyaluronic acid (HA)-modified erythrocyte membrane (eM) camouflaging to coload cisplatin (CDDP) and SR-717 (a STING agonist) for long-circulating tumor-tropism synergistic chemo-metalloimmunotherapy by cascade cGAS-STING activation. Once internalized by tumor cells, the acidity/redox-responsive gated MOF rapidly disintegrates to release SR-717 and exposes the dual-responsive MM to decompose with CDDP release, thus inducing damage to double-stranded DNA (dsDNA) in cancer cells. As tumor-specific antigens, these dsDNA fragments released from tumor cells can trigger cGAS-STING activation and enhance dendritic cell (DC) maturation and cytotoxic T cell (CTL) infiltration, thus giving rise to excellent therapeutic effects for efficient tumor regression. Overall, this custom-designed biodegradable long-circulating nanoagonist represents a paradigm of nanotechnology in realizing the synergistic cooperation of chemotherapy and metalloimmunotherapy based on cascade cGAS-STING activation for future oncological applications.

Protective effects of Nogo-B deficiency in NAFLD mice and its multiomics analysis of gut microbiology and metabolism.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver ailment that can lead to serious conditions such as cirrhosis and hepatocellular carcinoma. Hepatic Nogo-B regulates glucose and lipid metabolism, and its inhibition has been shown to be protective against metabolic syndrome. Increasing evidence suggests that imbalances in the gut microbiota (GM) and lipid metabolism disorders are significant contributors to NAFLD progression. Nevertheless, it is not yet known whether Nogo-B can affect NAFLD by influencing the gut microbiota and metabolites. Hence, the aim of the present study was to characterize this process and explore its possible underlying mechanisms. METHODS: A NAFLD model was constructed by administering a high-fat diet (HFD) to Nogo-B-/- and WT mice from the same litter, and body weight was measured weekly in each group. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to assess blood glucose levels. At the end of the 12-week period, samples of serum, liver, and intestinal contents were collected and used for serum biochemical marker and inflammatory factor detection; pathology evaluation; and gut microbiome and metabolomics analysis. Spearman's correlation analysis was performed to determine possible correlations between differential gut microbiota and differential serum metabolites between groups. RESULTS: Nogo-B deficiency attenuated the effects of the HFD, including weight gain, liver weight gain, impaired glucose tolerance, hepatic steatosis, elevated serum lipid biochemicals levels, and liver function. Nogo-B deficiency suppressed M1 polarization and promoted M2 polarization, thus inhibiting inflammatory responses. Furthermore, Nogo-B-/--HFD-fed mice presented increased gut microbiota richness and diversity, decreased Firmicutes/Bacteroidota (F/B) ratios, and altered serum metabolites compared with those of WT-HFD-fed mice. During analysis, several differential gut microbiota, including Lachnoclostridium, Harryflintia, Odoribacter, UCG-009, and unclassified_f_Butyricoccaceae, were screened between groups. These microbiota were found to be positively correlated with upregulated purine metabolism and bile acid metabolites in Nogo-B deficiency, while they were negatively correlated with downregulated corticosterone and tricarboxylic acid cyclic metabolites in Nogo-B deficiency. CONCLUSION: Nogo-B deficiency delayed NAFLD progression, as demonstrated by reduced hepatocellular lipid accumulation, attenuated inflammation and liver injury, and ameliorated gut microbiota dysbiosis and metabolic disorders. Importantly, Odoribacter was strongly positively correlated with ALB and taurodeoxycholic acid, suggesting that it played a considerable role in the influence of Nogo-B on the progression of NAFLD, a specific feature of NAFLD in Nogo-B-/- mice. The regulation of bile acid metabolism by the gut microbiota may be a potential target for Nogo-B deficiency to ameliorate NAFLD.

Iron-laden macrophage-mediated paracrine pro-fibrotic signaling induces lung fibroblast activation.

Idiopathic pulmonary fibrosis (IPF) is a devastating condition characterized by progressive lung scarring and uncontrolled fibroblast proliferation, inevitably leading to organ dysfunction and mortality. While elevated iron levels have been observed in patients and animal models of lung fibrosis, the mechanisms linking iron dysregulation to lung fibrosis pathogenesis, particularly the role of macrophages in orchestrating this process, remain poorly elucidated. Here we evaluate iron metabolism in macrophages during pulmonary fibrosis using both in vivo and in vitro approaches. In murine bleomycin- and amiodarone-induced pulmonary fibrosis models, we observed significant iron deposition and lipid peroxidation in pulmonary macrophages. Intriguingly, the ferroptosis regulator glutathione peroxidase 4 (GPX4) was upregulated in pulmonary macrophages following bleomycin instillation, a finding corroborated by single-cell RNA sequencing analysis. Moreover, macrophages isolated from fibrotic mouse lungs exhibited increased transforming growth factor (TGF)-ß1 expression that correlated with lipid peroxidation. In vitro, iron overload in bone marrow-derived macrophages triggered lipid peroxidation and TGF-ß1 upregulation, which was effectively suppressed by ferroptosis inhibitors. When co-cultured with iron-overloaded macrophages, lung fibroblasts exhibited heightened activation, evidenced by increased α-smooth muscle actin and fibronectin expression. Importantly, this pro-fibrotic effect was attenuated by treating macrophages with a ferroptosis inhibitor or blocking TGF-ß receptor signaling in fibroblasts. Collectively, our study elucidates a novel mechanistic paradigm in which the accumulation of iron within macrophages initiates lipid peroxidation, thereby amplifying TGF-ß1 production, subsequently instigating fibroblast activation through paracrine signaling. Thus, inhibiting iron overload and lipid peroxidation warrants further exploration as a strategy to suppress fibrotic stimulation by disease-associated macrophages.

Improvement of accumulated dose distribution in combined cervical cancer radiotherapy with deep learning-based dose prediction.

Purpose: Difficulties remain in dose optimization and evaluation of cervical cancer radiotherapy that combines external beam radiotherapy (EBRT) and brachytherapy (BT). This study estimates and improves the accumulated dose distribution of EBRT and BT with deep learning-based dose prediction. Materials and methods: A total of 30 patients treated with combined cervical cancer radiotherapy were enrolled in this study. The dose distributions of EBRT and BT plans were accumulated using commercial deformable image registration. A ResNet-101-based deep learning model was trained to predict pixel-wise dose distributions. To test the role of the predicted accumulated dose in clinic, each EBRT plan was designed using conventional method and then redesigned referencing the predicted accumulated dose distribution. Bladder and rectum dosimetric parameters and normal tissue complication probability (NTCP) values were calculated and compared between the conventional and redesigned accumulated doses. Results: The redesigned accumulated doses showed a decrease in mean values of V50, V60, and D2cc for the bladder (-3.02%, -1.71%, and -1.19 Gy, respectively) and rectum (-4.82%, -1.97%, and -4.13 Gy, respectively). The mean NTCP values for the bladder and rectum were also decreased by 0.02‰ and 0.98%, respectively. All values had statistically significant differences (p < 0.01), except for the bladder D2cc (p = 0.112). Conclusion: This study realized accumulated dose prediction for combined cervical cancer radiotherapy without knowing the BT dose. The predicted dose served as a reference for EBRT treatment planning, leading to a superior accumulated dose distribution and lower NTCP values.

PSO/SDF-1 composite hydrogel promotes osteogenic differentiation of PDLSCs and bone regeneration in periodontitis rats.

Periodontitis is an inflammatory disease characterized by the destruction of periodontal tissues, and the promotion of bone tissue regeneration is the key to curing periodontitis. Psoralen is the main component of Psoralea corylifolia Linn, and has multiple biological effects, including anti-osteoporosis and osteogenesis. We constructed a novel hydrogel loaded with psoralen (PSO) and stromal cell-derived factor-1 (SDF-1) for direct endogenous cell homing. This study aimed to evaluate the synergistic effects of PSO/SDF-1 on periodontal bone regeneration in patients with periodontitis. The results of CCK8, alkaline phosphatase (ALP) activity assay, and Alizarin Red staining showed that PSO/SDF-1 combination treatment promoted cell proliferation, chemotaxis ability, and ALP activity of PDLSCs. qRT-PCR and western blotting showed that the expression levels of alkaline phosphatase (ALP), dwarf-associated transcription factor 2 (RUNX2), and osteocalcin (OCN) gene were upregulated. Rat periodontal models were established to observe the effect of local application of the composite hydrogel on bone regeneration. These results proved that the PSO/SDF-1 combination treatment significantly promoted new bone formation. The immunohistochemical (IHC) results confirmed the elevated expression of ALP, RUNX2, and OCN osteogenic genes. PSO/SDF-1 composite hydrogel can synergistically regulate the biological function and promote periodontal bone formation. Thus, this study provides a novel strategy for periodontal bone regeneration.

Targeting Liver Xor by GalNAc-siRNA Is an Effective Strategy for Hyperuricemia Therapy.

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy.

Amplifying protection against acute lung injury: Targeting both inflammasome and cGAS-STING pathway by Lonicerae Japonicae Flos-Forsythiae Fructus drug pair.

Objective: Acute lung injury (ALI) is characterized by inflammation and currently lacks an efficacious pharmacological intervention. The medicine combination of Lonicerae Japonicae Flos (LJF) and Forsythiae Fructus (FF) demonstrates combined properties in its anti-infective, anti-inflammatory, and therapeutic effects, particularly in alleviating respiratory symptoms. In previous studies, Chinese medicine has shown promising efficacy in lipopolysaccharides (LPS)-induced ALI. However, there have been no reports of LJF and FF pairing for lung injury. The aim of this study is to compare the efficacy of herb pair Lonicerae Japonicae Flos-Forsythiae Fructus (LF) with LJF or FF alone in the treatment of ALI, and to explore whether LJF and FF have a combined effect in the treatment of lung injury, along with the underlying mechanism involved. Methods: A total of 36 mice were divided into six groups (control, model, LJF, FF, LF, dexamethasone) based on the treatments they received after undergoing sham-operation/LPS tracheal instillation. H&E staining and pulmonary edema indexes were used to evaluate lung injury severity. Alveolar exudate cells (AECs) were counted based on cell count in bronchoalveolar lavage fluid (BALF), and neutrophil percentage in BALF was measured using flow cytometry. Myeloperoxidase (MPO) activity in BALF was measured using enzyme-linked immunosorbent assay (ELISA), while the production of IL-1ß, TNF-α, and IL-6 in the lung and secretion level of them in BALF were detected by quantitative polymerase chain reaction (qPCR) and ELISA. The effect of LJF, FF, and LF on the expression of Caspase-1 and IL-1ß proteins in bone marrow derived macrophages (BMDMs) supernatant was assessed using Western blot method under various inflammasome activation conditions. In addition, the concentration of IL-1ß and changes in lactatedehydrogenase (LDH) release levels in BMDMs supernatant after LJF, FF, and LF administration, respectively, were measured using ELISA. Furthermore, the effects of LJF, FF and LF on STING and IRF3 phosphorylation in BMDMs were detected by Western blot, and the mRNA changes of IFN-ß, TNF-α, IL-6 and CXCL10 in BMDMs were detected by qPCR. Results: LF significantly attenuated the damage to alveolar structures, pulmonary hemorrhage, and infiltration of inflammatory cells induced by LPS. This was evidenced by a decrease in lung index score and wet/dry weight ratio. Treatment with LF significantly reduced the total number of neutrophil infiltration by 75% as well as MPO activity by 88%. The efficacy of LF in reducing inflammatory factors IL-1ß, TNF-α, and IL-6 in the lungs surpasses that of LJF or FF, approaching the effectiveness of dexamethasone. In BMDMs, the co-administration of 0.2 mg/mL of LJF and FF demonstrated superior inhibitory effects on the expression of nigericin-stimulated Caspase-1 and IL-1ß, as well as the release levels of LDH, compared to individual treatments. Similarly, the combination of 0.5 mg/mL LJF and FF could better inhibit the phosphorylation levels of STING and IRF3 and the production of IFN-ß, TNF-α, IL-6, and CXCL10 in response to ISD stimulation. Conclusion: The combination of LJF and FF increases the therapeutic effect on LPS-induced ALI, which may be mechanistically related to the combined effect inhibition of cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NOD-like receptor family protein 3 (NLRP3) inflammasomes pathways by LJF and FF. Our study provides new medicine candidates for the clinical treatment of ALI.

Hybrid Membrane-Camouflaged Biomimetic Immunomodulatory Nanoturrets with Sequential Multidrug Release for Potentiating T Cell-Mediated Anticancer Immunity.

Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel Escherichia coli (E. coli) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg2+. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.

Airways epithelial exposure to Streptococcus pneumoniae in the presence of the alarmin IL-33 induces a novel subset of pro-inflammatory ILC2s promoting a mixed inflammatory response.

BACKGROUND: We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert with epithelial alarmins such as IL-33. Details of the pathogenesis of this murine surrogate remain however unexplored. METHODS: Airways inflammation was induced by repeated, intranasal exposure of Il-4-/-, Rag1-/- and Rag2-/-Il2rg-/- mice (in which B lymphocyte IgE switching, adaptive and innate immunity are respectively ablated) as well as wild type mice to inactivated SP, IL-33 or both. Airways pathological changes were analysed, and the subsets and functions of locally accumulated ILC2s investigated by single cell RNA sequencing and flow cytometry. RESULTS: In the presence of IL-33, repeated exposure of the airways to inactivated SP caused marked eosinophil- and neutrophil-rich inflammation and local accumulation of ILC2s, which was retained in the Il-4-/- and Rag1-/- deficient mice but abolished in the Rag2-/-Il2rg-/- mice, an effect partly reversed by adoptive transfer of ILC2s. Single cell sequencing analysis of ILC2s recruited following SP and IL-33 exposure revealed a Klrg1+Ly6a+subset, expressing particularly elevated quantities of the pro-inflammatory cytokine IL-6, type 2 cytokines (IL-5 and IL-13) and MHC class II molecules, promoting type 2 inflammation as well as involved in neutrophil-mediated inflammatory responses. CONCLUSION: Local accumulation of KLRG1+Ly6a+ ILC2s in the lung tissue is a critical aspect of the pathogenesis of airways eosinophilic and neutrophil-rich inflammation induced by repeated exposure to SP in the presence of the epithelial alarmin IL-33.