Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma.

Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/-) or CX3CR1+ myeloid cell-specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer. SIGNIFICANCE: Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor. This article is highlighted in the In This Issue feature, p. 799.

Suppressing MDSC Infiltration in Tumor Microenvironment Serves as an Option for Treating Ovarian Cancer Metastasis.

It is still a big puzzle how ovarian cancer cells and the tumor microenvironment (TME) attract lymphocytes infiltration for facilitating metastasis, a leading cause of death from gynecological malignancies. Using genome-wide LncRNA microarray assay, here we report that a LncRNA associated with ovarian cancer metastasis (LncOVM) is highly correlated with poor prognosis and survival. LncOVM interacts with and stabilizes PPIP5K2 by suppressing ubiquitinated degradation to promote complement C5 secretion from ovarian cancer cells. The TME-enriched complement C5 attracts myeloid-derived suppressor cells (MDSCs) infiltration in TME to facilitate metastasis. Knockdown of LncOVM or PPIP5K2 inhibits tumor progression in xenograft models. Application of C5aR antibody or inhibitor (CCX168) inhibits MDSC recruitment and restores the suppression of tumorigenesis and metastasis in vivo. Our study reveals that suppression of ovarian cancer metastasis can be achieved by targeting MDSC infiltration in TME through disrupting LncOVM-PPIP5K2-complement axis, providing an option for treating ovarian cancer patients.

The Role of NMP22 and CSTB Levels in Predicting Postoperative Recurrence of Bladder Cancer.

Objective: To investigate the value of preoperative urinary nuclear matrix protein 22 (NMP22) and Cystatin B (CSTB) expressions in evaluating the postoperative recurrence of bladder cancer. Methods: The clinical case data of 102 patients with bladder cancer who underwent surgical treatment from January 2017 to January 2022 were collected, and the patients were divided into a recurrence group (n = 54) and nonrecurrence group (n = 48) according to whether the patients recurred after surgery, and the preoperative NMP22 and CSTB expression levels between the two groups were compared. Receiver operating curve (ROC) was used to analyze the evaluation value of preoperative NMP22 and CSTB expression in patients with bladder cancer postoperative recurrence. Logistic multivariate regression method was used to analyze the correlation between preoperative NMP22 and CSTB expression and postoperative bladder cancer recurrence. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of NMP22 and CSTB single detection and combined detection were evaluated for postoperative recurrence of bladder cancer. Results: The preoperative expression levels of NMP22 and CSTB in the recurrence group were significantly higher than those in the nonrecurrence group (P < 0.05). The results of ROC curve analysis showed that the AUC of preoperative NMP22 and CSTB expression levels to assess postoperative recurrence of bladder cancer was 0.696 and 0.659, respectively (P < 0.05). Logistic multivariate regression analysis showed that preoperative NMP22 and CSTB overexpression was an independent risk factor for postoperative recurrence of bladder cancer (OR = 1.042, 2.307, P < 0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of preoperative NMP22 combined with CSTB in evaluating bladder cancer recurrence after surgery were higher than those of preoperative NMP22 and CSTB alone, and the differences were statistically significant (P < 0.05). Conclusion: Preoperative NMP22 and CSTB conveying is hardly interrelated to postoperative recurrence of bladder carcinoma and has certain appraisal worth for postoperative recurrence of bladder carcinoma, and the combined testing of the two has a taller appraisal worth. NMP22 combined with CSTB detection will help to detect postoperative recurrence of bladder cancer and formulate effective treatment measures in time.

Clinically relevant orthotopic xenograft models of patient-derived glioblastoma in zebrafish.

An accurate prediction of the intracranial infiltration tendency and drug response of individual glioblastoma (GBM) cells is essential for personalized prognosis and treatment for this disease. However, the clinical utility of mouse patient-derived orthotopic xenograft (PDOX) models remains limited given current technical constraints, including difficulty in generating sufficient sample numbers from small tissue samples and a long latency period for results. To overcome these issues, we established zebrafish GBM xenografts of diverse origin, which can tolerate intracranial engraftment and maintain their unique histological features. Subsequent single-cell RNA-sequencing (scRNA-seq) analysis confirmed significant transcriptional identity to that of invading GBM microtumors observed in the proportionally larger brains of model animals and humans. Endothelial scRNA-seq confirmed that the zebrafish blood-brain barrier is homologous to the mammalian blood-brain barrier. Finally, we established a rapid and efficient zebrafish PDOX (zPDOX) model, which can predict long-term outcomes of GBM patients within 20 days. The zPDOX model provides a novel avenue for precision medicine of GBM, especially for the evaluation of intracranial infiltration tendency and prediction of individual drug sensitivity.

Phenotypic plasticity of myeloid cells in glioblastoma development, progression, and therapeutics.

Glioblastoma (GBM) is the most common and malignant type of intracranial tumors with poor prognosis. Accumulating evidence suggests that phenotypic alterations of infiltrating myeloid cells in the tumor microenvironment are important for GBM progression. Conventional tumor immunotherapy commonly targets T-cells, while innate immunity as a therapeutic target is an emerging field. Targeting infiltrating myeloid cells that induce immune suppression in the TME provides a novel direction to improve the prognosis of patients with GBM. The factors released by tumor cells recruit myeloid cells into tumor bed and reprogram infiltrating myeloid cells into immunostimulatory/immunosuppressive phenotypes. Reciprocally, infiltrating myeloid cells, especially microglia/macrophages, regulate GBM progression and affect therapeutic efficacy. Herein, we revisited biological characteristics and functions of infiltrating myeloid cells and discussed the recent advances in immunotherapies targeting infiltrating myeloid cells in GBM. With an evolving understanding of the complex interactions between infiltrating myeloid cells and tumor cells in the tumor microenvironment, we will expand novel immunotherapeutic regimens targeting infiltrating myeloid cells in GBM treatment and improve the outcomes of GBM patients.

The predictors of clinical outcomes in brainstem arteriovenous malformations after stereotactic radiosurgery.

ABSTRACT: The brainstem arteriovenous malformations (BS-AVMs) have a high morbidity and mortality and stereotactic radiosurgery (SRS) has been widely used to treat BS-AVMs. However, no consensus is reached in the explicit predictors of obliteration for BS-AVMs after SRS.To identify the predictors of clinical outcomes for BS-AVMs treated by SRS, we performed a retrospective observational study of BS-AVMs patients treated by SRS at our institution from 2006 to 2016. The primary outcomes were obliteration of nidus and favorable outcomes (AVM nidus obliteration with mRS score ≤2). For getting the outcomes more accurate, we also pooled the results of previous studies as well as our study by meta-analysis.A total of 26 patients diagnosed with BS-AVMs, with mean volume of 2.6 ml, were treated with SRS. Hemorrhage presentation accounted for 69% of these patients. Overall obliteration rate was 42% with mean follow-up of more than five years and two patients (8%) had a post-SRS hemorrhage. Favorable outcomes were observed in 8 patients (31%). Higher margin dose (>15Gy) was associated with higher obliteration (P = .042) and small volume of nidus was associated with favorable outcomes (P = .036). After pooling the results of 7 studies and present study, non-prior embolization (P = .049) and higher margin dose (P = .04) were associated with higher obliteration rate, in addition, the lower Virginia Radiosurgery AVM Scale (VRAS) was associated with favorable outcomes (P = .02) of BS-AVMs after SRS.In the BS-AVMs patients treated by SRS, higher margin dose (19-24Gy) and non-prior embolization were the independent predictors of higher obliteration rate. In addition, smaller volume of nidus and lower VRAS were the potential predictors of long-term favorable outcomes for these patients.

Endothelial Autophagy: an Effective Target for Radiation-induced Cerebral Capillary Damage.

Toxicity to central nervous system tissues is the common side effects for radiotherapy of brain tumor. The radiation toxicity has been thought to be related to the damage of cerebral endothelium. However, because of lacking a suitable high-resolution vivo model, cellular response of cerebral capillaries to radiation remained unclear. Here, we present the flk:eGFP transgenic zebrafish larvae as a feasible model to study the radiation toxicity to cerebral capillary. We showed that, in living zebrafish larvae, radiation could induce acute cerebral capillary shrinkage and blood-flow obstruction, resulting brain hypoxia and glycolysis retardant. Although in vivo neuron damage was also observed after the radiation exposure, further investigation found that they didn't response to the same dosage of radiation in vitro, indicating that radiation induced neuron damage was a secondary-effect of cerebral vascular function damage. In addition, transgenic labeling and qPCR results showed that the radiation-induced acute cerebral endothelial damage was correlated with intensive endothelial autophagy. Different autophagy inhibitors could significantly alleviate the radiation-induced cerebral capillary damage and prolong the survival of zebrafish larvae. Therefore, we showed that radiation could directly damage cerebral capillary, resulting to blood flow deficiency and neuron death, which suggested endothelial autophagy as a potential target for radiation-induced brain toxicity.

The prognostic values of neutrophil to lymphocyte ratio for outcomes in chronic obstructive pulmonary disease.

OBJECTIVE: Neutrophil to lymphocyte ratio (NLR) is considered as an inflammatory biomarker for clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). We aimed to conduct a meta-analysis to evaluate the prognostic values of NLR for the exacerbation and mortality in patients with COPD. METHODS: We searched the database of Cochrane Central Register of Controlled Trials, EMBASE, and PubMed, before September 2017. The eligible studies were retrieved by 2 authors independently following the criteria. The pooled odds ratios (ORs) of included studies were used to evaluate the prognostic values of NLR. Subgroup analyses were conducted to make the results more accurate. RESULTS: Nine studies with 5140 patients were enrolled in this analysis. The high NLR was associated with higher risk of exacerbation (OR: 3.81, 95% confidence interval [CI]: 1.20-12.13, P = .02) and mortality (OR: 2.60, 95% CI: 1.48-4.57, P < .01). By subgroup analysis, high NLR could predict the mortality in patients >70 years (OR: 2.16, 95% CI: 1.17-3.98, P = .01) but not in patients <70 years (OR: 4.08, 95% CI: 0.91-18.24, P = .07), and had a higher predictive ability in Asian group (OR: 3.64, 95% CI: 1.87-7.08, P < .01) than Eurasia group (OR: 1.82, 95% CI: 1.43-2.32, P < .01). In addition, high NLR could predict the short-term mortality (OR: 2.70, 95% CI: 1.10-6.63, P = .03) and the long-term mortality (OR: 2.61, 95% CI: 1.20-5.65, P = .02). CONCLUSIONS: The NLR may be an independent predictor for incidence of exacerbation in patients with COPD. In addition, high NLR may be associated with higher mortality in patients with COPD, especially for Asian and the patients with higher mean NLR.

Distributed adaptive neural networks leader-following formation control for quadrotors with directed switching topologies.

The leader-following formation problem is discussed for a team of quadrotors under directed switching topologies. To obtain a more general dynamic model, we describe the quadrotor system in a non-affine pure-feedback form with mismatched unknown nonlinearities. By employing an adaptive neural networks state observer to approximate the unknown nonlinear functions and to reconstruct the immeasurable inner states, we propose a novel distributed output feedback formation control protocol with the backstepping method combining with the dynamic surface control technique. From the Lyapunov stability theorem, all signals in the closed-loop formation system are proven to be cooperatively semiglobally uniformly ultimately bounded for any given bounded initial conditions. Finally, we proved that we verify the performance of the proposed formation control approach by a simulation study.

Extravasation of contrast (Spot Sign) predicts in-hospital mortality in ruptured arteriovenous malformation.

BACKGROUND AND PURPOSE: The spot sign is a highly specific and sensitive predictor of hematoma expansion in following primary intracerebral hemorrhage (ICH). Rare cases of the spot sign have been documented in patients with intracranial hemorrhage secondary to arteriovenous malformation (AVM). The purpose of this retrospective study is to assess the accuracy of spot sign in predicting clinical outcomes in patients with ruptured AVM. MATERIALS AND METHODS: A retrospective analysis of a prospectively maintained database was performed for patients who presented to West China Hospital with ICH secondary to AVM in the period between January 2009 and September 2016. Two radiologists blinded to the clinical data independently assessed the imaging data, including the presence of spot sign. Statistical analysis using univariate testing, multivariate logistic regression testing, and receiver operating characteristic curve (AUC) analysis was performed. RESULTS: A total of 116 patients were included. Overall, 18.9% (22/116) of subjects had at least 1 spot sign detected by CT angiography, 7% (8/116) died in hospital, and 27% (31/116) of the patients had a poor outcome after 90 days. The spot sign had a sensitivity of 62.5% and specificity of 84.3% for predicting in-hospital mortality (p = .02, AUC 0.734). No correlation detected between the spot sign and 90-day outcomes under multiple logistic regression (p = .19). CONCLUSIONS: The spot sign is an independent predictor for in-hospital mortality. The presence of spot sign did not correlate with the 90 day outcomes in this patient cohort. The results of this report suggest that patients with ruptured AVM with demonstrated the spot sign on imaging must receive aggressive treatment early on due to the high risk of mortality.

The Association Between the Neutrophil-to-Lymphocyte Ratio and Mortality in Patients With Acute Respiratory Distress Syndrome: A Retrospective Cohort Study.

PURPOSE: Systemic inflammation relates to the initiation and progression of acute respiratory distress syndrome (ARDS). As neutrophil-to-lymphocyte ratio (NLR) has been shown to be a prognostic inflammatory biomarker in various diseases, in this study, we sought to explore whether NLR is a prognostic factor in patients with ARDS. METHODS: A retrospective study was performed on patients diagnosed as ARDS admitted to the intensive care unit (ICU). We calculated the NLR by dividing the neutrophil count by the lymphocyte count and categorized patients into four groups based on quartile of NLR values. The association of NLR quartiles and 28-day mortality was assessed using multivariable Cox regression. Secondary outcomes included ICU mortality and hospital mortality. RESULTS: A total of 224 patients were included in the final analysis. The median (interquartile range) NLRs from first quartile to fourth quartile were as follows: 6.88 (4.61-7.94), 13.06 (11.35-14.89), 20.99 (19.09-23.19), and 39.39 (32.63-50.15), respectively. The 28-day mortalities for the same groups were as follows: 10.7%, 19.6%, 41.4%, and 53.6% (P < 0.001). Cox regression analysis showed NLR was a significant risk factor predicting 28-day mortality (first quartile, reference group; second quartile, adjusted hazard ratio [HR]= 1.674, 95% confidence interval [CI], 0.462-6.063, P = 0.432; third quartile, HR = 5.075, 95% CI, 1.554-16.576, P = 0.007; fourth quartile, HR = 5.815, 95% CI, 1.824-18.533, P = 0.003). Similar trends were observed for ICU mortality and hospital mortality. CONCLUSIONS: High NLR was associated with the poor outcome in critically ill patients with ARDS. The NLR therefore seems to be a prognostic biomarker of outcomes in critically ill patients with ARDS. Further investigation is required to validate this relationship with data collected prospectively.

The factors associated with hemorrhagic presentation in children with untreated brain arteriovenous malformation: a meta-analysis.

OBJECTIVE Rupture of arteriovenous malformations (AVMs) would result in high mortality and prevalence of disability in pediatric patients. Decisions regarding the treatment of AVMs need to weigh the risk of rupture over the course of their natural history against the possibility of creating a lesion during treatment. Multiple factors have been proposed to predict hemorrhagic presentation of pediatric patients with AVMs. The aim of this meta-analysis was to evaluate the predictors of hemorrhagic presentation in pediatric patients with AVMs. METHODS The authors searched the PubMed and EMBASE databases. Studies reporting the predictors of hemorrhagic presentation in children with untreated brain AVMs were included. The predictive ability of identified predictors was assessed by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS A higher risk of hemorrhagic presentation was found in AVMs with smaller size (< 3 cm, OR 2.97, 95% CI 1.94­4.54, p < 0.00001), deep venous drainage (OR 2.28, 95% CI 1.55­3.36, p < 0.0001), a single draining vein (OR 2.23, 95% CI 1.27­3.92, p = 0.005), a single feeder (OR 3.72, 95% CI 1.31­10.62, p = 0.01), a deep location (OR 1.82, 95% CI 1.22­2.72, p = 0.004), an infratentorial location (OR 2.25, 95% CI 1.19­4.26, p = 0.01), and diffuse morphology (OR 8.94, 95% CI 3.01­26.55, p < 0.0001). In addition, the AVMs with draining vein ectasia (OR 0.35, 95% CI 0.13­0.97, p = 0.04) and high Spetzler-Martin (SM) grade (OR 0.53, 95% CI 0.36­0.78, p = 0.001) had a lower risk of hemorrhagic presentation in pediatric patients. CONCLUSIONS Smaller AVMs, deep venous drainage, a single draining vein, a single feeder, deep/infratentorial location, diffuse morphology, and high SM grade were identified as positive predictors for hemorrhagic presentation. Particularly, patients with diffuse AVMs have a higher risk of hemorrhagic presentation than other factors and may need active treatments. However, factors such as age, sex, draining vein stenosis, and associated aneurysms were not associated with hemorrhagic presentation. ABBREVIATIONS AVM = arteriovenous malformation; CI = confidence interval; NOS = Newcastle-Ottawa Scale; OR = odds ratio; SM = Spetzler-Martin.

The Effect of Cerebrovascular Stenosis on -Peri-Hematoma Cerebral Perfusion and Clinical Outcomes in Patients with Supratentorial Spontaneous Intracerebral Hemorrhage.

BACKGROUND Many factors are associated with the cerebral hypoperfusion after spontaneous intracerebral hemorrhage (sICH), however, the effect of cerebrovascular stenosis on peri-hematoma cerebral blood flow (CBF) and 90-day poor outcomes in patients with spontaneous intracerebral hemorrhage is still unclear. MATERIAL AND METHODS From September 2016 to March 2017, we prospectively collected data on adults with supratentorial spontaneous intracerebral hemorrhages. Using the Propensity Score model, we compared the peri-hematoma CBF and 90-day poor outcomes (mRS ≥3) in the stenosis group and the control group. RESULTS Before matching, a total of 116 patients were included in this study, 25 patients in the stenosis group and 91 patients in the control group. After matching, the patients in the stenosis group had a higher absolute decrease of CBF (p=0.003), higher relative decrease of CBF (p=0.016), and higher incidence of 90-day poor outcomes (p=0.041) than the control group. With subgroup analysis, the patients with Glasgow Coma Scale from 13 to 15 (p=0.035), hematoma in the cerebral lobe (p=0.003), mean arterial pressure lower than 120 mm Hg (p=0.003), absolute decrease of CBF higher than 15 mL/100 g per minute (p=0.007), and relative decrease of CBF higher than 30% (p=0.020) had poorer outcomes. CONCLUSIONS In our series, the stenosis of main cerebral vessels decreased the peri-hematoma CBF and increased the rate of 90-day poor outcomes. Despite higher Glasgow Coma Scale, the evaluation of cerebral perfusion in patients with sICH is needed, especially for the patients with hematoma in the cerebral lobe and lower mean arterial pressure; and treatments to keep adequate cerebral perfusion are needed.

Intracerebral hemorrhage in an adult patient with Tetralogy of Fallot: Case report and review of the literature.

RATIONALE: Tetralogy of Fallot (TOF) accounts for approximately 5% of all congenital heart disease. However, only 1% of patients with TOF survive to the age of 40 years without undergoing surgery. Additionally, the relationship between intracerebral hemorrhage and unrepaired TOF remains unknown. We report a rare case of unrepaired TOF in a patient who presented with intracerebral hemorrhage, and we also present a literature review. PATIENT CONCERNS: A 40-year-old man presented with headache and right-sided limb weakness. DIAGNOSES: He was diagnosed with TOF approximately a year prior to presentation and did not undergo any definitive treatment or any symptomatic management. Head computed tomography revealed an intracerebral hematoma in the left basal ganglia. The patient was drowsy, and his blood oxygen saturation was 77%. INTERVENTIONS: Owing to his poor cardiopulmonary status, the patient did not undergo surgery and was treated with only symptomatic supportive therapy. OUTCOMES: After 2 days of therapy, his disturbance of consciousness and motor ability showed improvement. LESSONS: Literature reviews reveal that intracerebral hemorrhage is rarely observed in patients with TOF, and to date, only 3 cases have been reported. Furthermore, this patient was 40 years old and did not undergo cardiac surgery. Severe hypoxia, as well as low levels of platelets and coagulation factors in the blood could have led to intracerebral hemorrhage.

Macrophages as Nanocarriers for Drug Delivery: Novel Therapeutics for Central Nervous System Diseases.

Many central nervous system (CNS) diseases were thought to be untreatable due to the presence of the blood-brain barrier (BBB). The chemokine gradients secreted from CNS parenchyma can induce macrophage migration to the brain, induce firm adherence to the endothelium of BBB, and eventually to enter the brain parenchyma. Macrophages migrating into CNS can promote neuron regeneration, induce inflammation and angiogenesis. These properties can potentially allow macrophages to act as carriers for drug/nano formulations across the BBB, and reach the potential target sites. Many nanomaterials cannot be used for the management of CNS diseases because of their low carrying efficiency. Macrophage which transports nanomaterials to pathological sites is rendered as an attractive tool for the transportation of drugs to previously inaccessible regions within the brain parenchyma. Nanomaterials engulfed by macrophages can be released at target sites, and be used for therapeutic or diagnostic purposes. In this review, we focus on macrophages as the cell-carrier to deliver nano-drugs into CNS, describe the biological behavior of macrophages during pathological conditions and discuss the application of cell drug delivery system in recent years.