Single-cell sequencing reveals VEGFR as a potential target for CAR-T cell therapy in chordoma.

BACKGROUND: Chordomas are rare osseous neoplasms with a dismal prognosis when they recur. Here we identified cell surface proteins that could potentially serve as novel immunotherapeutic targets in patients with chordoma. METHODS: Fourteen chordoma samples from patients attending Xuanwu Hospital Capital Medical University were subjected to single-cell RNA sequencing. Target molecules were identified on chordoma cells and cancer metastasis-related signalling pathways characterised. VEGFR-targeting CAR-T cells and VEGFR CAR-T cells with an additional TGF-ß scFv were synthesised and their in vitro antitumor activities were evaluated, including in a primary chordoma organoid model. RESULTS: Single-cell transcriptome sequencing identified the chordoma-specific antigen VEGFR and TGF-ß as therapeutic targets. VRGFR CAR-T cells and VEGFR/TGF-ß scFv CAR-T cells recognised antigen-positive cells and exhibited significant antitumor effects through CAR-T cell activation and cytokine secretion. Furthermore, VEGFR/TGF-ß scFv CAR-T cells showed enhanced and sustained cytotoxicity of chordoma cell lines in vitro compared with VRGFR CAR-T cells. CONCLUSIONS: This study provides a comprehensive single-cell landscape of human chordoma and highlights its heterogeneity and the role played by TGF-ß in chordoma progression. Our findings substantiate the potential of VEGFR as a target for CAR-T cell therapies in chordoma which, together with modulated TGF-ß signalling, may augment the efficacy of CAR-T cells.

IL-6 from cerebrospinal fluid causes widespread pain via STAT3-mediated astrocytosis in chronic constriction injury of the infraorbital nerve.

BACKGROUND: The spinal inflammatory signal often spreads to distant segments, accompanied by widespread pain symptom under neuropathological conditions. Multiple cytokines are released into the cerebrospinal fluid (CSF), potentially inducing the activation of an inflammatory cascade at remote segments through CSF flow. However, the detailed alteration of CSF in neuropathic pain and its specific role in widespread pain remain obscure. METHODS: A chronic constriction injury of the infraorbital nerve (CCI-ION) model was constructed, and pain-related behavior was observed on the 7th, 14th, 21st, and 28th days post surgery, in both vibrissa pads and hind paws. CSF from CCI-ION rats was transplanted to naïve rats through intracisternal injection, and thermal and mechanical allodynia were measured in hind paws. The alteration of inflammatory cytokines in CCI-ION's CSF was detected using an antibody array and bioinformatic analysis. Pharmacological intervention targeting the changed cytokine in the CSF and downstream signaling was performed to evaluate its role in widespread pain. RESULTS: CCI-ION induced local pain in vibrissa pads together with widespread pain in hind paws. CCI-ION's CSF transplantation, compared with sham CSF, contributed to vibrissa pad pain and hind paw pain in recipient rats. Among the measured cytokines, interleukin-6 (IL-6) and leptin were increased in CCI-ION's CSF, while interleukin-13 (IL-13) was significantly reduced. Furthermore, the concentration of CSF IL-6 was correlated with nerve injury extent, which gated the occurrence of widespread pain. Both astrocytes and microglia were increased in remote segments of the CCI-ION model, while the inhibition of astrocytes in remote segments, but not microglia, significantly alleviated widespread pain. Mechanically, astroglial signal transducer and activator of transcription 3 (STAT3) in remote segments were activated by CSF IL-6, the inhibition of which significantly mitigated widespread pain in CCI-ION. CONCLUSION: IL-6 was induced in the CSF of the CCI-ION model, triggering widespread pain via activating astrocyte STAT3 signal in remote segments. Therapies targeting IL-6/STAT3 signaling might serve as a promising strategy for the widespread pain symptom under neuropathological conditions.

Effects of oncolytic viruses and viral vectors on immunity in glioblastoma.

Glioblastoma (GBM) is regarded as an incurable disease due to its poor prognosis and limited treatment options. Virotherapies were once utilized on cancers for their oncolytic effects. And they are being revived on GBM treatment, as accumulating evidence presents the immunogenic effects of virotherapies in remodeling immunosuppressive GBM microenvironment. In this review, we focus on the immune responses induced by oncolytic virotherapies and viral vectors in GBM. The current developments of GBM virotherapies are briefly summarized, followed by a detailed depiction of their immune response. Limitations and lessons inferred from earlier experiments and trials are discussed. Moreover, we highlight the importance of engaging the immune responses induced by virotherapies into the multidisciplinary management of GBM.

Efficient Construction of Symmetrical Diaryl Sulfides via a Supported Pd Nanocatalyst-Catalyzed C-S Coupling Reaction.

Aryl sulfides play an important role in pharmaceuticals, biologically active molecules and polymeric materials. Herein, a general and efficient protocol for Pd@COF-TB (a kind of Pd nanocatalyst supported by a covalent organic framework)/DIPEA-catalyzed one-pot synthesis of symmetrical diaryl sulfides through a C-S coupling reaction from aryl iodides and Na2S2O3 is developed. More importantly, the addition of N,N-diisopropylethylamine (DIPEA) can not only enhance the catalytic activity of a Pd@COF-TB nanocatalyst, but also effectively inhibit the formation of biphenyl byproducts, which are a product of Ullmann reaction. Besides, it has been confirmed that the aryl Bunte salts generated in situ from Na2S2O3 and aryl iodides are the sulfur sources involved in this C-S coupling reaction. With the strategy proposed in this work, a variety of symmetrical diaryl sulfides could be obtained in moderate to excellent yields with a high tolerance of various functional groups. Moreover, a possible mechanism of this Pd nanoparticle-catalyzed C-S coupling reaction is proposed based on the results of controlling experiments.

Current evidence and challenges of systematic therapies for adult recurrent glioblastoma: Results from clinical trials.

Recurrence is a major concern for adult patients with glioblastomas (GBMs), and the prognosis remains poor. Although several therapies have been assessed, most of them have not achieved satisfactory results. Therefore, there is currently no standard treatment for adult recurrent GBM (rGBM). Here, we review the results of clinical trials for the systematic therapy of rGBM. Regorafenib, rindopepimut and neoadjuvant programmed death 1 (PD-1) inhibitors are promising agents for rGBM, while regorafenib is effective in both O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated patients. Temozolomide rechallenge and alkylating agents combined with bevacizumab can be useful for patients with MGMT methylation, and patients with isocitrate dehydrogenase (IDH) mutations or second recurrence can benefit from vocimagene amiretrorepvec (Toca 511). Some phase I trials on targeted therapy and immunotherapy have shown positive results, and results from further studies are expected. In addition to the analysis of existing clinical trial results, forthcoming trials should be well designed, and patients are encouraged to participate in appropriate clinical trials.

Conventional magnetic resonance imaging-based radiomic signature predicts telomerase reverse transcriptase promoter mutation status in grade II and III gliomas.

PURPOSE: Telomerase reverse transcriptase (TERT) promoter mutation status is an important biomarker for the precision diagnosis and prognosis prediction of lower grade glioma (LGG). This study aimed to construct a radiomic signature to noninvasively predict the TERT promoter status in LGGs. METHODS: Eighty-three local patients with pathology-confirmed LGG were retrospectively included as a training cohort, and 33 patients from The Cancer Imaging Archive (TCIA) were used as for independent validation. Three types of regions of interest (ROIs), which covered the tumor, peri-tumoral area, and tumor plus peri-tumoral area, were delineated on three-dimensional contrast-enhanced T1 (3D-CE-T1)-weighted and T2-weighted images. One hundred seven shape, first-order, and texture radiomic features from each modality under each ROI were extracted and selected through least absolute shrinkage and selection operator. Radiomic signatures were constructed with multiple classifiers and evaluated using receiver operating characteristic (ROC) analysis. The tumors were also stratified according to IDH status. RESULTS: Three radiomic signatures, namely, tumoral radiomic signature, tumoral plus peri-tumoral radiomic signature, and fusion radiomic signature, were built, all of which exhibited good accuracy and balanced sensitivity and specificity. The tumoral signature displayed the best performance, with area under the ROC curves (AUC) of 0.948 (0.903-0.993) in the training cohort and 0.827 (0.667-0.988) in the validation cohort. In the IDH subgroups, the AUCs of the tumoral signature ranged from 0.750 to 0.940. CONCLUSION: The MRI-based radiomic signature is reliable for noninvasive evaluation of TERT promoter mutations in LGG regardless of the IDH status. The inclusion of peri-tumoral area did not significantly improve the performance.

Anaesthetic management of a large paraganglioma resection in a woman with isolated L-looped transposition of the great arteries: a case report.

BACKGROUND: Reports of anaesthetic management of paraganglioma resection in patients with isolated L-transposition of the great arteries (L-TGA) are rare. We focus on the preoperative evaluation, intraoperative management, and postoperative care of a frail patient with "physiologically corrected" L-TGA for paraganglioma resection. CASE PRESENTATION: We performed general anaesthesia for a 46-year-old patient with "physiologically corrected" L-TGA undergoing open large retroperitoneal paraganglioma resection. Although the preoperative medical therapy had attained its goals, the patient went through three periods of severe episodic hypertension and tachycardia as tumour manipulation released catecholamines. Goal-directed fluid therapy based on pulse pressure variation (PPV) and point-of-care transesophageal echocardiography (TEE) imaging enabled anaesthesiologists to make rapid judgments and to regulate blood pressure in a timely manner, thereby reducing the risk of heart failure caused by massive rapid fluid bolus therapy. The patient was transferred to the intensive care unit because of intraoperative hemodynamic changes and significant blood loss. Despite transient myocardial injury (elevated troponin I), no lethal arrhythmia or complications occurred perioperatively, and the patient recovered well and was discharged 1 week later. CONCLUSIONS: Goal-directed fluid therapy combined with the adoption of TEE could effectively guide fluid administration, which is helpful for anaesthesia management during operation. We recommend the routine use of TEE in such cases.

On-chip simultaneous sensing of humidity and temperature with a dual-polarization silicon microring resonator.

It is still challenging to realize an on-chip optical sensor that can detect humidity and temperature at the same time. In this paper, we demonstrate a silicon-based dual-polarization micro-ring resonator (MRR) with a polyvinyl-alcohol (PVA) upper-cladding, which enables the simultaneous measurement of humidity and temperature. Due to the significant polarization-dependence of the silicon-on-insulator (SOI) nanophotonic waveguide, the transverse electric (TE) and transverse magnetic (TM) polarization modes have quite different sensitivities towards the changes of ambient relative humidity (RH) and temperature. Sensitivity, resolution, stability and cross-sensitivity are analyzed for the present dual-parameter sensor. The RH and temperature response sensitivity are measured to be 97.9 pm/%RH, 325.1 pm/%RH, 69.0 pm/°C and 30.6 pm/°C for TE and TM polarizations, respectively. To the best of our knowledge, it is the first on-chip optical sensor enabling the simultaneous measurement of RH and temperature.

Prediction of Recurrence after Transsphenoidal Surgery for Cushing's Disease: The Use of Machine Learning Algorithms.

BACKGROUND: There are no reliable predictive models for recurrence after transsphenoidal surgery (TSS) for Cushing's disease (CD). OBJECTIVES: This study aimed to develop machine learning (ML)-based predictive models for CD recurrence after initial TSS and to evaluate their performance. METHOD: A total of 354 CD patients were included in this retrospective, supervised learning, data mining study. Predictive models for recurrence were developed according to 17 variables using 7 algorithms. Models were evaluated based on the area under the receiver operating characteristic curve (AUC). RESULTS: All patients were followed up for over 12 months (mean ± SD 43.80 ± 35.61). The recurrence rate was 13.0%. Age (p < 0.001), postoperative morning serum cortisol nadir (p = 0.002), and postoperative (p < 0.001) and preoperative (p = 0.04) morning adrenocorticotropin (ACTH) level were significantly related to recurrence. AUCs of the 7 models ranged from 0.608 to 0.781. The best performance (AUC = 0.781, 95% CI 0.706, 0.856) appeared when 8 variables were introduced to the random forest (RF) algorithm, which was much better than that of logistic regression (AUC = 0.684, p = 0.008) and that of using only postoperative morning serum cortisol (AUC = 0.635, p < 0.001). According to the feature selection algorithms, the top 3 predictors were age, postoperative serum cortisol, and postoperative ACTH. CONCLUSIONS: Using ML-based models for prediction of the recurrence after initial TSS for CD is feasible, and RF performs best. The performance of most of ML-based models was significantly better than that of some conventional models.

Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation.

Defective autophagy of monocytes or macrophages might result in NLRP3 inflammasome activation and cause vascular metabolic inflammation. However, the mechanism underlying the initiation of the autophagy response to hyperlipidaemia remains unclear. Sirtuin 3 (SIRT3), an NAD-dependent deacetylase, is sensitive to the metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated autophagy in regulating NLRP3 inflammasome activation. We determined that the inhibition of autophagy and the activation of the NLRP3 inflammasome were concomitant with reduced SIRT3 levels both in peripheral blood monocytes from obese humans and in palmitate-treated THP-1 cells. Furthermore, we demonstrated that SIRT3 could form a molecular complex with ATG5, while SIRT3 overexpression altered the acetylation of endogenous ATG5. ATG5 acetylation inhibited autophagosome maturation and induced NLRP3 inflammasome activation. In parallel, SIRT3 overexpression in THP-1 cells decreased the palmitate-induced generation of mitochondrial reactive oxygen species, restored autophagy, and attenuated NLRP3 inflammasome activation. The incubation of human aortic endothelial cells (HAECs) with macrophage-conditioned medium (MCM) induced HAEC expression of vascular cell adhesion molecule-1, intercellular adhesion molecule 1, α-smooth muscle actin, and collagen-1. The effect of MCM could be reversed by the addition of neutralizing anti-IL-1ß antibody or the overexpression of SIRT3. Consistent with this, en face analyses displayed a marked increase in α-SMC-positive endothelial cells in SIRT3-/- mice with acute hyperlipidaemia. Taken together, these findings revealed that SIRT3-deficient macrophages displayed impaired autophagy and accelerated NLRP3 inflammasome activation and endothelial dysfunction.

Haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice.

AIMS: To investigate whether haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice. METHODS AND RESULTS: Experiments were performed using irradiated LDL receptor-deficient (LDLR-/-) mice with marrow from either TLR4-deficient (TLR4-/-) or age-matched wild-type (WT) mice. After 12 weeks of being fed a high-cholesterol diet, TLR4-/-→LDLR-/- mice developed fewer atherosclerotic lesions in the aorta compared to WT→LDLR-/- mice. This effect was associated with an increase in multilocular lipid droplets and mitochondria in perivascular adipose tissue (PVAT). Immunofluorescence analysis confirmed that there was an increase in capillary density and M2 macrophage infiltration, accompanied by a decrease in tumour necrosis factor (TNF)-α expression in the localized PVAT of TLR4-/-→LDLR-/- mice. In vitro studies indicated that bone marrow-derived macrophages (BMDMs) from WT mice demonstrated an M1-like phenotype and expression of inflammatory cytokines induced by palmitate. These effects were attenuated in BMDMs isolated from TLR4-/- mice. Furthermore, brown adipocytes incubated with conditioned medium (CM) derived from palmitate-treated BMDMs, exhibited larger and more unilocular lipid droplets, and reduced expression of brown adipocyte-specific markers and perilipin-1 compared to those observed in brown adipocytes exposed to CM from palmitate-treated BMDMs of TLR4-/- mice. This decreased potency was primarily due to TNF-α, as demonstrated by the capacity of the TNF-α neutralizing antibody to reverse these effects. CONCLUSIONS: These results suggest that haematopoietic-specific deletion of TLR4 promotes PVAT homeostasis, which is involved in reducing macrophage-induced TNF-α secretion and increasing mitochondrial biogenesis in brown adipocytes.

High sensitivity temperature sensor based on cascaded silicon photonic crystal nanobeam cavities.

We present the design, fabrication and characterization of a high sensitivity temperature sensor based on cascaded silicon photonic crystal (PhC) nanobeam cavities. Two PhC nanobeam cavities, one with stack width modulated structure and the other one with parabolic-beam structure are utilized to increase the sensitivity. Most of the light is designed to be confined in the cladding and the core for these two cavities, respectively. Due to the positive thermo-optic (TO) coefficient of silicon and the negative TO coefficient of SU-8 cladding, the wavelength responses red shift for parabolic-beam cavity and blue shift for stack width modulated cavity as the increase of the ambient temperature, respectively. Thus, the sensitivity for the temperature sensor can be improved greatly since the difference in resonant wavelength shifts is detected for the temperature sensing. The experimental results show that the sensitivity of the temperature sensor is about 162.9 pm/°C, which is almost twice as high as that of the conventional silicon based resonator sensors.

Simultaneous measurement of refractive index and temperature using a dual polarization ring.

We present the design, fabrication, and characterization of a dual polarization silicon-on-insulator (SOI) microring resonator (MRR) for simultaneous measurement of refractive index (RI) and temperature. Due to the different energy distribution of transverse electric (TE) and transverse magnetic (TM) modes for the SOI waveguide, the TE and TM polarizations can have quite different sensitivities toward the changes of ambient RI and temperature. By using a gapless asymmetric coupling section, TE0 mode and TM0 mode have been excited simultaneously in the MRR. We demonstrated the feasibility ofobtaining RI and temperature simultaneously with a single measurement, achieving a RI sensitivity of 104 nm/RIU (refractive index unit) and a temperature sensitivity of 78.7 pm/°C for TE0 mode and a RI sensitivity of 319 nm/RIU and a temperature sensitivity of 34.1 pm/°C for TM0 mode.

Chemerin-induced mitochondrial dysfunction in skeletal muscle.

Chemerin is a novel adipocyte-derived factor that induces insulin resistance in skeletal muscle. However, the effect of chemerin on skeletal muscle mitochondrial function has received little attention. In the present study, we investigated whether mitochondrial dysfunction is involved in the pathogenesis of chemerin-mediated insulin resistance. In this study, we used recombinant adenovirus to express murine chemerin in C57BL/6 mice. The mitochondrial function and structure were evaluated in isolated soleus muscles from mice. The oxidative mechanism of mitochondrial dysfunction in cultured C2C12 myotubes exposed to recombinant chemerin was analysed by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction. The overexpression of chemerin in mice reduced the muscle mitochondrial content and increased mitochondrial autophagy, as determined by the increased conversion of LC3-I to LC3-II and higher expression levels of Beclin1 and autophagy-related protein-5 and 7. The chemerin treatment of C2C12 myotubes increased the generation of mitochondrial reactive oxygen species, concomitant with a reduced mitochondrial membrane potential and increased the occurrence of mitochondrial protein carbonyls and mitochondrial DNA deletions. Knockdown of the expression of chemokine-like receptor 1 or the use of mitochondria-targeting antioxidant Mito-TEMPO restored the mitochondrial dysfunction induced by chemerin. Furthermore, chemerin exposure in C2C12 myotubes not only reduced the insulin-stimulated phosphorylation of protein kinase B (AKT) but also dephosphorylated forkhead box O3α (FoxO3α). Chemerin-induced mitochondrial autophagy likely through an AKT-FoxO3α-dependent signalling pathway. These findings provide direct evidence that chemerin may play an important role in regulating mitochondrial remodelling and function in skeletal muscle.

Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats.

OBJECTIVE: Obesity-induced vascular dysfunction is related to chronic low-grade systemic inflammation. Recent studies indicate that NLRP3, a multiprotein complex formed by NOD-like receptor (NLR) family members, is a key component mediating internal sterile inflammation, but the role in obesity-related vascular dysfunction is largely unknown. In the present study, we investigate whether NLRP3 activation is involved in vascular inflammation in obese Otsuka Long-Evans Tokushima Fatty rats (OLETF). METHODS AND RESULTS: Male OLETF with their control Long-Evans Tokushima Otsuka rats (LETO) were studied at 3 and 12 months of age. Aortic relaxation in response to acetylcholine decreased gradually with age in both strains, with early and persistent endothelium dysfunction in obese OLETF compared with age-matched LETO controls. These changes are associated with parallel changes of aortic endothelial nitric oxide synthase (eNOS) content, macrophage accumulation and intimal thickening. NLRP3 increased in OLETF rats compared to LETO. Consistent with inflammasome activation, the conversion of procaspase-1 to cleaved and activated forms as well as IL-1ß markedly increased in OLETF rats. Additionally, we observed increased expression of dynamin-related protein-1 (Drp1) and decreased fusion-relative protein optic atropy-1(OPA1). Altered mitochondrial dynamics was associated with elevated oxidative stress level in OLETF aortas. CONCLUSIONS: These results demonstrate that obesity seems to accelerate endothelial dysfunction in OLETFs via the activation of NLRP3 and mitochondrial dysfunction.

Determining bifurcations to explosive synchronization for networks of coupled oscillators with higher-order interactions.

We determine bifurcations from gradual to explosive synchronization in coupled oscillator networks with higher-order coupling using self-consistency analysis. We obtain analytic bifurcation values for generic symmetric natural frequency distributions. We show that nonsynchronized, drifting, oscillators are non-negligible and play a crucial role in bifurcation. As such, the entire natural frequency distribution must be accounted for, rather than just the shape at the center. We verify our results for Lorentzian- and Gaussian-distributed natural frequencies.

Exoskeleton-Assisted Rehabilitation and Neuroplasticity in Spinal Cord Injury.

Spinal cord injury (SCI) results in neurological deficits below the level of injury, causing motor dysfunction and various severe multisystem complications. Rehabilitative training plays a crucial role in the recovery of individuals with SCI, and exoskeleton serves as an emerging and promising tool for rehabilitation, especially in promoting neuroplasticity and alleviating SCI-related complications. This article reviews the classifications and research progresses of medical exoskeletons designed for SCI patients and describes their performances in practical application separately. Meanwhile, we discuss their mechanisms for enhancing neuroplasticity and functional remodeling, as well as their palliative impacts on secondary complications. The potential trends in exoskeleton design are raised according to current progress and requirements on SCI rehabilitation.

Postoperative Spinal 18 F-FDG PET Pseudoprogression Mimicking Malignancy.

ABSTRACT: A 60-year-old woman presented with left upper limb weakness. Spinal MRI revealed C2-C3 heterogeneous mass with no hypermetabolic foci on 18 F-FDG PET. Total resection was performed, and the pathology showed gliosis. Her limb weakness worsened 3 months after surgery. Spinal MRI revealed long intramedullary mass from medulla oblongata to C5, which showed obvious hypermetabolism under 18 F-FDG PET with an SUV max of 7.11, but 18 F-FET PET indicated mild hypermetabolism with an SUV max of 2.29. Malignancy was suspected, and C2-C4 biopsy was performed. The pathology results confirmed the diagnosis of gliosis, and the postoperative spinal 18 F-FDG PET results were considered pseudoprogression.

Comparison of Edge of Lamina Block with Thoracic Paravertebral Block and Retrolaminar Block for Analgesic Efficacy in Adult Patients Undergoing Video-Assisted Thoracic Surgery: A Prospective Randomized Study.

Background: A novel ultrasound-guided paravertebral block, the edge laminar block (ELB) was reported recently. However, it was unclear how effective ELB was in comparison with traditional blocking methods. We conducted a trial to compare the analgesic efficacy of ELB with the thoracic paravertebral block (TPVB) and the retrolaminar block (RLB) in patients undergoing video-assisted thoracic surgery (VATS). Methods: We identified 90 patients who were scheduled for VATS and randomly assigned them to three groups: ELB group (Group E), TPVB group (Group T), and RLB group (Group R). Each group underwent ELB, TPVB, and RLB, respectively, under ultrasound guidance before general anesthesia induction. All patients received post-operative routine analgesia protocol. Our primary outcome was the extent of dermatomal sensory loss on the midclavicular, midaxillary, and scapular lines, measured using a pinprick 15 minutes after the nerve block. Secondary outcomes included the intraoperative dose of sufentanil, the numerical rating scale (NRS) scores assessed in the post-anesthesia care unit (PACU) and at 6, 12, and 24 hours post-operatively, and pethidine administrated as analgesic rescue dose. Results: The percentages of nerve block range reaching the midclavicular line, midaxillary line, and scapular line in Group E were 96.7%, 93.3%, 93.3%, and 60% in Group T and 30%, 56.7%, and 96.7% in Group R, respectively. Group E had wider dermatomal sensory loss on the midclavicular line and midaxillary line compared to Group R (P < 0.001) and had a wider range compared to Group T on the scapular line (P < 0.001). There was no significant difference in the intraoperative use of sufentanil in the three groups. Post-operative NRS scores at each time point were significantly lower in Group E than those in the other two groups (P < 0.01). Conclusion: ELB had a wider nerve block range and applied better post-operative analgesia in comparison with TPVB and RLB.

Single-cell transcriptomic analyses provide insights into the cellular origins and drivers of brain metastasis from lung adenocarcinoma.

BACKGROUND: Brain metastasis (BM) is the most common intracranial malignancy causing significant mortality, and lung cancer is the most common origin of BM. However, the cellular origins and drivers of BM from lung adenocarcinoma (LUAD) have yet to be defined. METHODS: The cellular constitutions were characterized by single-cell transcriptomic profiles of 11 LUAD primary tumor (PT) and 10 BM samples (GSE131907). Copy number variation (CNV) and clonality analysis were applied to illustrate the cellular origins of BM tumors. Brain metastasis-associated epithelial cells (BMAECs) were identified by pseudotime trajectory analysis. By using machine-learning algorithms, we developed the BM-index representing the relative abundance of BMAECs in the bulk RNA-seq data indicating a high risk of BM. Therapeutic drugs targeting BMAECs were predicted based on the drug sensitivity data of cancer cell lines. RESULTS: Differences in macrophages and T cells between PTs and BMs were investigated by single-cell RNA (scRNA) and immunohistochemistry and immunofluorescence data. CNV analysis demonstrated BM was derived from subclones of PT with a gain of chromosome 7. We then identified BMAECs and their biomarker, S100A9. Immunofluorescence indicated strong correlations of BMAECs with metastasis and prognosis evaluated by the paired PT and BM samples from Peking Union Medical College Hospital. We further evaluated the clinical significance of the BM-index and identified 7 drugs that potentially target BMAECs. CONCLUSIONS: This study clarified possible cellular origins and drivers of metastatic LUAD at the single-cell level and laid a foundation for early detection of LUAD patients with a high risk of BM.