Restoring neuronal iron homeostasis revitalizes neurogenesis after spinal cord injury.

Spinal cord injury (SCI) can lead to iron overloading and subsequent neuronal ferroptosis, which hinders the recovery of locomotor function. However, it is still unclear whether the maintenance of neuronal iron homeostasis enables to revitalize intrinsic neurogenesis. Herein, we report the regulation of cellular iron homeostasis after SCI via the chelation of excess iron ions and modulation of the iron transportation pathway using polyphenol-based hydrogels for the revitalization of intrinsic neurogenesis. The reversed iron overloading can promote neural stem/progenitor cell differentiation into neurons and elicit the regenerative potential of newborn neurons, which is accompanied by improved axon reinnervation and remyelination. Notably, polyphenol-based hydrogels significantly increase the neurological motor scores from ~8 to 18 (out of 21) and restore the transmission of sensory and motor electrophysiological signals after SCI. Maintenance of iron homeostasis at the site of SCI using polyphenol-based hydrogels provides a promising paradigm to revitalize neurogenesis for the treatment of iron accumulation-related nervous system diseases.

Posterior Mandibular Segmental Split Osteotomy: A Novel Technique for Edentulous Space Reconstruction in Patients With Skeletal Class III Malocclusion.

ABSTRACT: This study presents an innovative surgery that successfully improved the facial profile and occlusal function of a patient with a skeletal Class III malocclusion and posterior hypodontia. The patient had chief complaints of missing teeth and a protrudedjaw. A novel 1-stage surgery referred to as posterior mandibular segmental split osteotomy combined with Le Fort i osteotomy and BSSRO was used because the patient wanted to save time and was worried about periodontal complications associated with other treatment methods. As a result, a satisfying facial profile and a Class I occlusion with a normal position of the posterior dentoalveolar segment of the mandible were achieved with no adverse effects. Thus, posterior mandibular segmental split osteotomy can be considered an effective treatment for skeletal Class III malocclusion with posterior hypodontia.

The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas.

BACKGROUND: Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. METHODS: In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. RESULTS: For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. CONCLUSIONS: Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

Interfering with long non-coding RNA MIR22HG processing inhibits glioblastoma progression through suppression of Wnt/ß-catenin signalling.

Long non-coding RNAs play critical roles in tumour progression. Through analysis of publicly available genomic datasets, we found that MIR22HG, the host gene of microRNAs miR-22-3p and miR-22-5p, is ranked among the most dysregulated long non-coding RNAs in glioblastoma. The main purpose of this work was to determine the impact of MIR22HG on glioblastoma growth and invasion and to elucidate its mechanistic function. The MIR22HG/miR-22 axis was highly expressed in glioblastoma as well as in glioma stem-like cells compared to normal neural stem cells. In glioblastoma, increased expression of MIR22HG is associated with poor prognosis. Through a number of functional studies, we show that MIR22HG silencing inhibits the Wnt/ß-catenin signalling pathway through loss of miR-22-3p and -5p. This leads to attenuated cell proliferation, invasion and in vivo tumour growth. We further show that two genes, SFRP2 and PCDH15, are direct targets of miR-22-3p and -5p and inhibit Wnt signalling in glioblastoma. Finally, based on the 3D structure of the pre-miR-22, we identified a specific small-molecule inhibitor, AC1L6JTK, that inhibits the enzyme Dicer to block processing of pre-miR-22 into mature miR-22. AC1L6JTK treatment caused an inhibition of tumour growth in vivo. Our findings show that MIR22HG is a critical inducer of the Wnt/ß-catenin signalling pathway, and that its targeting may represent a novel therapeutic strategy in glioblastoma patients.

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia.

Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. Stem Cells 2019;37:504-515.

Mussel-Inspired Biocoating for Improving the Adhesion of Dental Pulp Stem Cells in Dental Pulp Regeneration.

Dental pulp engineering possesses a promising perspective to replacing lost pulp in the root canal and restoring its functions. Stable adhesion of dental pulp stem cells (DPSCs) on the root canal dentin wall is a key element required for reconstruction of a functional odontoblast layer in dental pulp regeneration. To address this challenge, dopamine-modified hyaluronic acid (DA-HA) is coated on dentin to obtain a stable adhesion of DPSCs. The dopamine segment provides adhesion ability to the coating, and the hyaluronic acid increases the biocompatibility. The results show that DPSCs can adhere on the DA-HA coated dentin slice better than those without coating. Simultaneously, DPSCs proliferation can be further promoted on the prepared coating. Therefore, the DA-HA coating may provide a possible way to immobilize odontoblast cell onto dentin surface for pulp regeneration.

Patients with true mixed growth hormone and prolactin-secreting pituitary adenoma: a case series of 12 patients.

Objective: Mixed growth hormone (GH) and prolactin (PRL) secreting adenomas are the most common type of plurihormonal pituitary adenomas. We assessed the clinical presentations and impacts of transsphenoidal surgery (TS) on patients with mixed GH and PRL adenomas including surgical outcomes, complications, and prognosis.Method and patients: Twelve patients (7 males, 5 females) were operated in the neurosurgery department of Qilu hospital affiliated to Shandong University, Shandong, China. We analyzed hormone levels of preoperation, postoperation (within 24 h) and at 12-month follow-up and correlated levels with tumor volumes.Results: The remission rate was 66.7% (8/12), the recurrence rate was 16.7% (2/12), the cause-specific mortality was 0 and the overall mortality rate was 16.7% (2/12) due to stroke and myocardial infarction respectively. A significant drop was seen in GH, PRL, and Insulin-like-growth-factor-1 (IGF-1) levels between preoperation and postoperation with mean values from 52.6 to 9.9 ng/ml (p = 0.0015), from 321.6 to 190.9 ng/ml (p = 0.0026) and from 815.7 to 230.6 ng/ml (p = 0.0004), respectively. This drop was more significant between preoperation and follow-up with mean values from 52.6 to 3.0 ng/ml (p = 0.002), from 321.6 to 61.6 ng/ml (p < 0.0001), and from 815.7 to 195.0 ng/ml (p = 0.0001), respectively. However, there was no significant correlation between tumor volume and all of the hormone levels.Conclusions: Most mixed GH and PRL adenomas are aggressive with a high risk of recurrence and mortality.

Dexamethasone-loaded hollow hydroxyapatite microsphere promotes odontogenic differentiation of human dental pulp cells in vitro.

A sustained-release system was established by synthesis of dexamethasone-loaded hollow hydroxyapatite microspheres (DHHAM). The in vitro effect of DHHAM on odontogenic differentiation of human dental pulp cells (hDPCs) was evaluated. Hollow hydroxyapatite microspheres (HHAM) are successfully manufactured using simple biomimetic one-step strategy in the presence of glycine and sodium dodecyl sulfonate. Dexamethasone (DEX) was loaded to the system after the formation of HHAM. The drug encapsulation capacity of DEX in HHAM is 40.3% and its loading efficiency is 16.7%. The cumulative release of DEX in vitro is 55% up to 35 days. Results of Real-time Polymerase Chain Reaction (Real-time PCR), alkaline phosphatase (ALP) activity and Alizarin Red S staining revealed that DHHAM can obviously promote bio-mineralization of hDPCs in the absence of osteogenic medium and enhance the gene expression of ALP, Runt-related transcription factor 2 (RUNX2), osteocalcin, dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP1). The data suggest that sustained release of DEX from DHHAM could efficiently enhance odontogenic differentiation of hDPCs.

A Modified Cosmetic Genioplasty Can Affect Airway Space Positively in Skeletal Class II Patients: Studying Alterations of Hyoid Bone Position and Posterior Airway Space.

BACKGROUND: Improving the posterior airway space is one of the most important functions of genioplasty. Studies have shown that the posterior airway space (PAS) can play an important role in the evaluation of obstructive sleep apnea syndrome (OSAS). The purpose of this study is to evaluate the airway safety of our modified technology by observing the impact on PAS in skeletal Class II patients without OSAS. METHODS: We have modified a cosmetic genioplasty, which can guarantee the continuity of the lower edge of the bilateral mandible by rotating the chin segment clockwise. Fourteen patients submitted to our modified cosmetic genioplasty alone were included in the study. The facial convexity angle and the ratio of the face were measured by analyzing photographs. The position of the hyoid bone and the width of the PAS were measured by analyzing lateral cephalograms. The volume and the cross-sectional area (CSA) of the PAS were measured using 3D reconstruction. The Wilcoxon signed-rank test and paired samples t test were used to assess the significance of differences of the data (p < 0.05). RESULTS: Soft tissue measurements were statistically different (p = 0.001) and achieved satisfactory results. The position of the hyoid bone moved up (LX: p = 0.004; LML: p = 0.056) and forward (LY: p = 0.001; LCV3: p = 0.016). The increase in the CSA had statistical significance (p < 0.005). There were significant statistical differences in the total airway volume and hypopharynx (p = 0.001), except in the oropharynx (p = 0.096). CONCLUSIONS: Our modified genioplasty not only achieved better cosmetic results by ensuring the continuity of the lower edge of the bilateral mandible but also exerted a significant positive impact on the posterior airway space for patients with skeletal class II, thus helping reduce the prevalence of OSAS. We hence suggest performing this modified cosmetic genioplasty on the skeletal class II patients with/without OSAS if necessary. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Predictors and incidence of orthostatic headache associated with lumbar drain placement following endoscopic endonasal skull base surgery.

BACKGROUND: Orthostatic headache (OH) is a potential complication of lumbar drainage (LD) usage. The incidence and risk factors for OH with the use of lumbar drainage during endoscopic endonasal procedures have not been documented. OBJECTIVE: To investigate the incidence of post-procedure OHs associated with placement of LD in patients undergoing endoscopic endonasal procedures. METHODS: We prospectively noted the placement of LDs in a consecutive series of endoscopic endonasal skull base surgeries. Charts were retrospectively reviewed, and patients were divided into two groups: those with OH and those without. The patient demographics, drain durations, imaging findings of intracranial hypotension, pathologies and need for a blood patch were compared between the two groups. RESULTS: Two hundred forty-nine patients were included in the study. Seven patients (2.8%) suffered post-dural puncture OH, which was mild to moderate and disappeared 2-8 days (median 3 days) after treatment. Blood patches were used in four patients. Significant predisposing factors were age (33.0 vs. 53.5, P = 0.014) and a strong trend for female gender (85.7% vs. 47.9%, P = 0.062). BMI and drain duration were not significant. Postoperative intracranial hypotension was diagnosed radiographically in 43% of OH patients and in 5.4% of those without OH (P = 0.003). Four (1.6%) patients required treatment with an epidural blood patch. CONCLUSION: OH associated with intracranial hypotension in patients undergoing endoscopic endonasal procedures with LDs is an infrequent complication seen more commonly in young female patients. Radiographic signs of intracranial hypotension are a specific but not sensitive test for OH.

Empowering brain tumor management: chimeric antigen receptor macrophage therapy.

Brain tumors pose formidable challenges in oncology due to the intricate biology and the scarcity of effective treatment modalities. The emergence of immunotherapy has opened new avenues for innovative therapeutic strategies. Chimeric antigen receptor, originally investigated in T cell-based therapy, has now expanded to encompass macrophages, presenting a compelling avenue for augmenting anti-tumor immune surveillance. This emerging frontier holds promise for advancing the repertoire of therapeutic options against brain tumors, offering potential breakthroughs in combating the formidable malignancies of the central nervous system. Tumor-associated macrophages constitute a substantial portion, ranging from 30% to 50%, of the tumor tissue and exhibit tumor-promoting phenotypes within the immune-compromised microenvironment. Constructing CAR-macrophages can effectively repolarize M2-type macrophages towards an M1-type phenotype, thereby eliciting potent anti-tumor effects. CAR-macrophages can recruit T cells to the brain tumor site, thereby orchestrating a remodeling of the immune niche to effectively inhibit tumor growth. In this review, we explore the potential limitations as well as strategies for optimizing CAR-M therapy, offering insights into the future direction of this innovative therapeutic approach.

Copy number gain of FAM131B-AS2 promotes the progression of glioblastoma by mitigating replication stress.

BACKGROUND: Glioblastoma (GBM) is characterized by chromosome 7 copy number gains, notably 7q34, potentially contributing to therapeutic resistance, yet the underlying oncogenes have not been fully characterized. Pertinently, the significance of long noncoding RNAs (lncRNAs) in this context has gained attention, necessitating further exploration. METHODS: FAM131B-AS2 was quantified in GBM samples and cells using qPCR. Overexpression and knockdown of FAM131B-AS2 in GBM cells were used to study its functions in vivo and in vitro. The mechanisms of FAM131B-AS2 were studied using RNA-seq, qPCR, Western blotting, RNA pull-down, coimmunoprecipitation assays, and mass spectrometry analysis. The phenotypic changes that resulted from FAM131B-AS2 variation were evaluated through CCK8 assay, EdU assay, comet assay, and immunofluorescence. RESULTS: Our analysis of 149 primary GBM patients identified FAM131B-AS2, a lncRNA located in the 7q34 region, whose upregulation predicts poor survival. Mechanistically, FAM131B-AS2 is a crucial regulator of the replication stress response, stabilizing replication protein A1 through recruitment of ubiquitin-specific peptidase 7 and activating the ataxia telangiectasia and rad3-related protein kinase pathway to protect single-stranded DNA from breakage. Furthermore, FAM131B-AS2 overexpression inhibited CD8+ T-cell infiltration, while FAM131B-AS2 inhibition activated the cGAS-STING pathway, increasing lymphocyte infiltration and improving the response to immune checkpoint inhibitors. CONCLUSIONS: FAM131B-AS2 emerges as a promising indicator for adjuvant therapy response and could also be a viable candidate for combined immunotherapies against GBMs.

Blood-Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive and lethal form of human brain tumors. Dismantling the suppressed immune microenvironment is an effective therapeutic strategy against GBM; however, GBM does not respond to exogenous immunotherapeutic agents due to low immunogenicity. Manipulating the mitochondrial electron transport chain (ETC) elevates the immunogenicity of GBM, rendering previously immune-evasive tumors highly susceptible to immune surveillance, thereby enhancing tumor immune responsiveness and subsequently activating both innate and adaptive immunity. Here, we report a nanomedicine-based immunotherapeutic approach that targets the mitochondria in GBM cells by utilizing a Trojan-inspired nanovector (ABBPN) that can cross the blood-brain barrier. We propose that the synthetic photosensitizer IrPS can alter mitochondrial electron flow and concurrently interfere with mitochondrial antioxidative mechanisms by delivering si-OGG1 to GBM cells. Our synthesized ABBPN coloaded with IrPS and si-OGG1 (ISA) disrupts mitochondrial electron flow, which inhibits ATP production and induces mitochondrial DNA oxidation, thereby recruiting immune cells and endogenously activating intracranial antitumor immune responses. The results of our study indicate that strategies targeting the mitochondrial ETC have the potential to treat tumors with limited immunogenicity.

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.

Implantable Microneedle-Mediated Eradication of Postoperative Tumor Foci Mitigates Glioblastoma Relapse.

Glioblastoma multiforme (GBM) remains incurable despite multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin (2-3 cm) of the initial resected lesion due to the unreachable residual cancerous cells. Here, a completely biodegradable microneedle for surgical cavity delivery glioblastoma-associated macrophages (GAMs)-activating immune nano-stimulator that mitigates glioblastoma relapse is reported. The residual tumor lesion-directed biocompatible microneedle releases the nano-stimulator and toll-like receptor 9 agonist in a controlled manner until the microneedles completely degrade over 1 week, efferently induce in situ phonotypic shifting of GAMs from anti- to pro-inflammatory and the tumor recurrence is obviously inhibited. The implantable microneedles offer a significant improvement over conventional transdermal ones, as they are 100% degradable, ensuring safe application within surgical cavities. It is also revealed that the T cells are recruited to the tumor niche as the GAMs initiate anti-tumor response and eradicate residual GBM cells. Taken together, this work provides a potential strategy for immunomodulating the postoperative tumor niche to mitigate tumor relapse in GBM patients, which may have broad applications in other malignancies with surgical intervention.

Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/ß-catenin pathway in glioblastoma.

BACKGROUND: Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance. METHODS: In silico analysis was performed to identify specific molecules involved in multiple processes. Glioblastoma multiforme cells were infected with knockdown/overexpression lentiviral constructs of HMGCL to assess malignant performance in vitro and in an orthotopic xenograft model. RNA sequencing was used to identify potential downstream molecular targets. RESULTS: HMGCL, as a gene, increased in GBM and was associated with poor survival in patients. Knockdown of HMGCL suppressed proliferation and invasion in vitro and in vivo. Acetyl-CoA was decreased with HMGCL knockdown, which led to reduced NFAT1 nuclear accumulation and H3K27ac level. RNA sequencing-based transcriptomic profiling revealed FOXM1 as a candidate downstream target, and HMGCL-mediated H3K27ac modification in the FOXM1 promoter induced transcription of the gene. Loss of FOXM1 protein with HMGCL knockdown led to decreased nuclear translocation and thus activity of ß-catenin, a known oncogene. Finally, JIB-04, a small molecule confirmed to bind to HMGCL, suppressed GBM tumorigenesis in vitro and in vivo. CONCLUSIONS: Changes in acetyl-CoA levels induced by HMGCL altered H3K27ac modification, which triggers transcription of FOXM1 and ß-catenin nuclear translocation. Targeting HMGCL by JIB-04 inhibited tumor growth, indicating that mediators of BCAA metabolism may serve as molecular targets for effective GBM treatment.

Intracavitary Spraying of Nanoregulator-Encased Hydrogel Modulates Cholesterol Metabolism of Glioma-Supportive Macrophage for Postoperative Glioblastoma Immunotherapy.

Glioblastoma multiforme (GBM) is notoriously resistant to immunotherapy due to its intricate immunosuppressive tumor microenvironment (TME). Dysregulated cholesterol metabolism is implicated in the TME and promotes tumor progression. Here, it is found that cholesterol levels in GBM tissues are abnormally high, and glioma-supportive macrophages (GSMs), an essential "cholesterol factory", demonstrate aberrantly hyperactive cholesterol metabolism and efflux, providing cholesterol to fuel GBM growth and induce CD8+ T cells exhaustion. Bioinformatics analysis confirms that high 7-dehydrocholesterol reductase (DHCR7) level in GBM tissues associates with increased cholesterol biosynthesis, suppressed tumoricidal immune response, and poor patient survival, and DHCR7 expression level is significantly elevated in GSMs. Therefore, an intracavitary sprayable nanoregulator (NR)-encased hydrogel system to modulate cholesterol metabolism of GSMs is reported. The degradable NR-mediated ablation of DHCR7 in GSMs effectively suppresses cholesterol supply and activates T-cell immunity. Moreover, the combination of Toll-like receptor 7/8 (TLR7/8) agonists significantly promotes GSM polarization to antitumor phenotypes and ameliorates the TME. Treatment with the hybrid system exhibits superior antitumor effects in the orthotopic GBM model and postsurgical recurrence model. Altogether, the findings unravel the role of GSMs DHCR7/cholesterol signaling in the regulation of TME, presenting a potential treatment strategy that warrants further clinical trials.

mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model.

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the "superbug" MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.

Clinical analysis of trigeminal neuralgia caused by vertebrobasilar dolichoectasia.

Our objective is to explore the clinical manifestations, imaging features, and therapy of trigeminal neuralgia (TN) caused by vertebrobasilar dolichoectasia (VBD). Clinical and imaging data of 11 cases with trigeminal neuralgia caused by VBD were retrospectively analyzed, and relevant literatures were reviewed. Of these 11 patients, 8 were male, and 10 suffered from hypertension. Imaging findings revealed that the vertebrobasilar arteries were pathologically enlarged and tortuous. Facial pain disappeared or was relieved after the microvascular decompression (MVD) in all 11 patients; no recrudescence was found with an average of 22-month follow-up. We concluded that TN caused by VBD, a rare clinical disease, mainly occurred in older men with a history of hypertension. CT, MRI, and MRA have great significance in the diagnosis of this disease; MVD is a preferred treatment method.