Risk Factors Associated With Inferior Alveolar Nerve Injury After Extraction of Impacted Lower Mandibular Third Molars: A Prospective Cohort Study.

BACKGROUND: Inferior alveolar nerve (IAN) injury is one of the complications of impacted lower mandibular third molar (LM3) extraction. Given the unknown prognosis of IAN injuries and limited treatment options, it is critical to understand the risk factors of IAN injury before LM3 extraction. PURPOSE: The purpose of the study was to identify risk factors associated with IAN injury after LM3 extraction. STUDY DESIGN, SETTING, SAMPLE: This was a prospective cohort study including patients who underwent LM3 extraction from May to December 2021 at the authors' institution. Patients with systemic diseases, previous maxillofacial surgeries, or sensory abnormalities were excluded. PREDICTOR VARIABLE: The predictor variable is composed of several risk factors. The variables were grouped into four categories: demographic, radiographic, procedure-related, and surgeon experience. MAIN OUTCOME VARIABLE(S): The outcome variable was postoperative neurosensory disturbance coded as present or absent and was measured at 1-month (transient) and 1-year (permanent). COVARIATES: Not applicable. ANALYSES: The measurement data were represented by mean and standard deviation. The association of each variable with the presence of an IAN injury was tested by the χ2 test. Statistical significance was accepted at P < .05. RESULTS: The study sample consisted of 705 patients (37.0% male) with an average age of 28.51 ± 6.51 years. A total of 17/705 (2.4%) and 4/705 (0.57%) patients developed transient and permanent IAN injuries. The results demonstrated that the following factors were associated with higher rates of transient injury: use of chisels during surgeries (6.4%; 95% confidence interval (CI): 2.7 to 12.3; P = .02; relative risk (RR) = 11.4), LM3s located below the IAN canal (8.7%; 95% CI: 4.3 to 15.7; P < .01; RR = 7.3), compressed contact between LM3s and the IAN canal (36.4%; 95% CI: 12.3 to 78.2; P < .001; RR = 25.4), and not using corticosteroids after surgeries (3.8%; 95% CI: 1.9 to 6.5; P = .03; RR = 3.1). The only factor associated with permanent injury was compressed contact between LM3s and the IAN canal (18.2%; 95% CI: 2.2 to 62.3; P < .001; RR = 48.2). CONCLUSION AND RELEVANCE: Close proximity between LM3s and IAN canal and the use of chisels increase the risk of transient IAN injury. Corticosteroid treatment may promote nerve recovery. Compressed contact between LM3s and IAN canal is the only risk factor for permanent injury.

Dental Pulp Stem Cell-Derived Exosomes Promote Sciatic Nerve Regeneration via Optimizing Schwann Cell Function.

Repair strategies for injured peripheral nerve have achieved great progresses in recent years. However, the clinical outcomes remain unsatisfactory. Recent studies have found that exosomes secreted by dental pulp stem cells (DPSC-exos) have great potential for applications in nerve repair. In this study, we evaluated the effects of human DPSC-exos on improving peripheral nerve regeneration. Initially, we established a coculture system between DPSCs and Schwann cells (SCs) in vitro to assess the effect of DPSC-exos on the activity of embryonic dorsal root ganglion neurons (DRGs) growth in SCs. We extracted and labeled human DPSC-exos, which were subsequently utilized in uptake experiments in DRGs and SCs. Subsequently, we established a rat sciatic nerve injury model to evaluate the therapeutic potential of DPSC-exos in repairing sciatic nerve damage. Our findings revealed that DPSC-exos significantly promoted neurite elongation by enhancing the proliferation, migration, and secretion of neurotrophic factors by SCs. In vivo, DPSC-exos administration significantly improved the walking behavior, axon regeneration, and myelination in rats with sciatic nerve injuries. Our study underscores the vast potential of DPSC-exos as a therapeutic tool for tissue-engineered nerve construction.

Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans.

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1+ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

Adult-type rhabdomyoma of the lung: A case report.

ABSTRACT: Adult rhabdomyoma is an uncommon and benign striated muscle tumor consisting of striated muscular tissue. This neoplasm usually originates from cardiac muscle, and extracardiac rhabdomyoma is extremely rare. Herein, we report a case of adult rhabdomyoma in the lung, which has only been reported once in the 1970s. A 62-year-old woman presented to our hospital with a solid nodule on the right upper lobe. We performed tumor resection surgery and confirmed the diagnosis of adult rhabdomyoma by postoperative pathological examination. Herein, we report the clinical and pathologic characteristics of pulmonary adult rhabdomyoma (PAR) and review the literature about adult rhabdomyoma.

Study on the Role and Mechanism of Exosomes Derived from Dental Pulp Stem Cells in Promoting Regeneration of Myelin Sheath in Rats with Sciatic Nerve Injury.

The prognosis of peripheral nerve injury (PNI) is usually poor, and currently, there is no effective treatment for PNI. Studies have shown that exosomes derived from mesenchymal stem cells could promote nerve regeneration by optimizing the function of endogenous Schwann cells (SCs), while the mechanism is unclear. Autophagy, a highly conserved intracellular catabolic process responsible for maintaining cellular homeostasis, has been proved to be involved in the regulation of nerve repair after injury. We explored the effect of exosomes derived from dental pulp stem cells (DPSC-Exos) on the regeneration of myelin sheath in rats with sciatic nerve injury (SNI). In vitro and in vivo experiments were performed to clarify whether the effect of DPSC-Exos is associated with autophagy of SCs and to reveal the mechanism at the molecular level. Our results showed that the SCs of SNI rats exhibited the obvious autophagic characteristics, and the increase of P53 expression was an internal factor of autophagy. Our mechanism research indicated that DPSC-Exos could deliver miR-122-5p from DPSCs into SCs and suppressed the rapamycin (RAPA)-induced autophagy in SCs by inhibiting P53 expression. Rescue experiments showed that both the use of GW4869 and overexpression of exogenous P53 in SCs could reverse the inhibitory effect of DPSCs on the autophagy in SCs from co-culture system. In short, our study indicated that DPSC-Exos could promote the regeneration of the myelin sheath through suppressing the autophagy in SCs caused by PNI via miR-122-5p/P53 pathway; this provides researchers with another option for precise repair of PNI.

In situ tissue profile of rat trigeminal nerve in trigeminal neuralgia using spatial transcriptome sequencing.

BACKGROUND: Trigeminal neuralgia (TN) is the most common neuropathic disorder in the maxillofacial region. The etiology and pathogenesis of TN have not been clearly determined to date, although there are many hypotheses. OBJECTIVE: The goal of this study was to investigate the interactions between different types of cells in TN, particularly the impact and intrinsic mechanism of demyelination on the trigeminal ganglion, and to identify new important target genes and regulatory pathways in TN. METHODS: TN rat models were prepared by trigeminal root compression, and trigeminal nerve tissues were isolated for spatial transcriptome sequencing. The gene expression matrix was reduced dimensionally by PCA and presented by UMAP. Gene function annotation was analyzed by Metascape. The progression of certain clusters and the developmental pseudotime were analyzed using the Monocle package. Modules of the gene coexpression network between different groups were analyzed based on weighted gene coexpression network analysis and assigned AddModuleScore values. The intercellular communication of genes in these networks via ligand-receptor interactions was analyzed using CellPhoneDB analysis. RESULTS: The results suggested that the trigeminal ganglion could affect Schwann cell demyelination and remyelination responses through many ligand-receptor interactions, while the effect of Schwann cells on the trigeminal ganglion was much weaker. Additionally, ferroptosis may be involved in the demyelination of Schwann cells. CONCLUSIONS: This study provides spatial transcriptomics sequencing data on TN, reveals new markers, and redefines the relationship between the ganglion and myelin sheath, providing a theoretical basis and supporting data for future mechanistic research and drug development.

Low carbon city and FDI inflows: evidence from China.

Achieving the goals of "carbon peaking" and "carbon neutrality" becomes one of the important elements of the ecological civilization strategy in China. Based on the strong balanced panel data of 281 prefecture-level cities in China from 2006 to 2019, we investigate the impact of Low-carbon city pilot policy (LCCP policy) on FDI inflows by using the multi-period DID model and intermediary model. After that, we discuss the heterogenous impact in terms of both policy tools and geographic locations. Furthermore, we investigate the spillover effects of the LCCP policy on the FDI inflows of surrounding cities using the Spatial Dubin DID model. The results show that (1) the LCCP policy can significantly attract FDI through reducing compliance costs and promoting technological innovation, and the Bacon decomposition and the placebo test show that the estimation error is small and the regression result is relatively stable; (2) command-mandatory tools have negative effects on FDI, while market-oriented tools can effectively attract FDI in pilot cities, but voluntary tools have no significant effect on FDI in pilot cities; (3) the LCCP policy can significantly promote the inflows of FDI in the eastern and western regions, but it does not significantly promote the FDI in central regions; (4) there is a positive spillover effect on FDI inflows to surrounding cities.

Human Adipose Tissue Lysate-Based Hydrogel for Lasting Immunomodulation to Effectively Improve Spinal Cord Injury Repair.

The long-term inflammatory microenvironment is one of the main obstacles to inhibit acute spinal cord injury (SCI) repair. The natural adipose tissue-derived extracellular matrix hydrogel shows effective anti-inflammatory regulation because of its unique protein components. However, the rapid degradation rate and removal of functional proteins during the decellularization process impair the lasting anti-inflammation function of the adipose tissue-derived hydrogel. To address this problem, adipose tissue lysate provides an effective way for SCI repair due to its abundance of anti-inflammatory and nerve regeneration-related proteins. Thereby, human adipose tissue lysate-based hydrogel (HATLH) with an appropriate degradation rate is developed, which aims to in situ long-term recruit and induce anti-inflammatory M2 macrophages through sustainedly released proteins. HATLH can recruit and polarize M2 macrophages while inhibiting pro-inflammatory M1 macrophages regardless of human or mouse-originated. The axonal growth of neuronal cells also can be effectively improved by HATLH and HATLH-induced M2 macrophages. In vivo experiments reveal that HATLH promotes endogenous M2 macrophages infiltration in large numbers (3.5 × 105/100 µL hydrogel) and maintains a long duration for over a month. In a mouse SCI model, HATLH significantly inhibits local inflammatory response, improves neuron and oligodendrocyte differentiation, enhances axonal growth and remyelination, as well as accelerates neurological function restoration.

Bio-coatings in permeated cultivation systems: Unprecedented impacts on microalgal monoculture growth and organic matter yield.

Bio-coating, a recent and promising approach in attached microalgal cultivation systems, has garnered attention due to its efficiency in enhancing immobilized algal growth, particularly in submerged cultivation systems. However, when the cells are cultured on thin solid microporous substrates that physically separate them from the nutrient medium, it remains unclear whether the applied bio-coatings still have a significant impact on algal growth or the subsequent rates of algal organic matter (AOM) release. Therefore, this current work investigated the role of bio-coatings on the microalgal monoculture growth of one freshwater species, Chlorella vulgaris ESP 31, and one marine species, Cylindrotheca fusiformis on a hydrophilic substrate, polyvinylidene fluoride membrane in a permeated cultivation system. Wide range of bio-coating sources were adapted, with the result demonstrating that bacteria-derived coating promoted algal growth by as high as 140% when compared with the control group for both species. Interestingly, two distinct adaptation mechanisms were observed between the species, with only C. fusiformis demonstrating a positive correlation between cell growth and AOM productivity, particularly in its extracellularly bound fractions. It is worth noting that despite this specific fraction exhibiting the lowest content among all; it displayed significant relevance in terms of AOM productivity. High extracellular protein-to-polysaccharide ratio (>5.7 fold) quantified on bacterial intracellular exudate-coated membranes indirectly revealed an underlying symbiotic microalgal-bacterial interaction. This is the first study showing how bio-coating influenced AOM yield without any physical interaction between microalgae and bacteria. It further confirms the practical benefits of bio-coating in attached cultivation systems.

Deep Medullary Vein and MRI Markers Were Related to Cerebral Hemorrhage Subtypes.

BACKGROUND: To explore the performance of deep medullary vein (DMV) and magnetic resonance imaging (MRI) markers in different intracerebral hemorrhage (ICH) subtypes in patients with cerebral small vessel disease (CSVD). METHODS: In total, 232 cases of CSVD with ICH were included in this study. The clinical and image data were retrospectively analyzed. Patients were divided into hypertensive arteriopathy (HTNA)-related ICH, cerebral amyloid angiopathy (CAA)-related ICH, and mixed ICH groups. The DMV score was determined in the cerebral hemisphere contralateral to the ICH. RESULTS: The DMV score was different between the HTNA-related and mixed ICH groups (p < 0.01). The MRI markers and CSVD burden score were significant among the ICH groups (p < 0.05). Compared to mixed ICH, HTNA-related ICH diagnosis was associated with higher deep white matter hyperintensity (DWMH) (OR: 0.452, 95% CI: 0.253-0.809, p < 0.05) and high-degree perivascular space (PVS) (OR: 0.633, 95% CI: 0.416-0.963, p < 0.05), and CAA-related ICH diagnosis was associated with increased age (OR: 1.074; 95% CI: 1.028-1.122, p = 0.001). The DMV score correlated with cerebral microbleed (CMB), PVS, DWMH, periventricular white matter hyperintensity (PWMH), and CSVD burden score (p < 0.05) but not with lacuna (p > 0.05). Age was an independent risk factor for the severity of DMV score (OR: 1.052; 95% CI: 0.026-0.076, p < 0.001). CONCLUSION: DMV scores, CSVD markers, and CSVD burden scores were associated with different subtypes of ICH. In addition, DMV scores were associated with the severity of CSVD and CSVD markers.

Modified alveolar ridge preservation to promote the osteogenesis of the distal surface of second molar after mandibular impacted third molar extraction: a preliminary study.

OBJECTIVES: The objective of the retrospective study was to explore whether the use of a modified alveolar ridge preservation technique impacts osteogenesis on the distal surface of the second molar after mandibular third molar (M3) extraction. MATERIALS AND METHODS: A total of 54 patients were enrolled in this study and divided into three different groups, including modified alveolar ridge preservation (MARP) group, traditional tooth extraction (TRA) group, and classical guided bone regeneration (GBR) group. In this study, MARP was designed with the highlights of the preservation of the alveolar bone superior and lingual to M3. These patients chose different surgical methods according to their own wishes for past infection or in order to prevent pericoronitis, and the operation time and surgical cost of each group were recorded. The periodontal conditions of the ipsilateral mandibular second molar (M2) and the height of its distal alveolar bone were measured during the postoperative follow-up. RESULTS: The probing depth, clinical attachment level, and osseous defect depth on the distal surface of the ipsilateral M2 in the MARP group were better than those of the TRA group at any time of the follow-up (P < 0.05 for all), but there was no statistical difference in the measurements when compared to the GBR group at 6 months after operation (P > 0.05 for all). CONCLUSIONS: Thus, MARP therapy not only improves the regeneration of periodontal osseous defects distal to the M2 after M3 extraction but also reduces the operation time and surgical cost. CLINICAL RELEVANCE: This paper introduces a modified surgical method that can not only economically and effectively remove the impacted mandibular third molar but also obtain stable osteogenesis.

Neoadjuvant radiotherapy plus single-incision thoracoscopic surgery in the treatment of type B3 thymomas.

Background: Although minimally invasive surgery is the standard treatment for thymomas, minimally invasive thymectomy is difficult for patients with type B3 thymomas, especially for giant or aggressive lesions. These tumors are frequently treated with radical radiation therapy or surgery plus adjuvant radiotherapy. Few studies, however, have tested the efficacy of neoadjuvant radiotherapy prior to thoracoscopic surgery. Methods: Patients with type B3 thymomas >5 cm or with infiltrates into vital organs on CT-guided puncture biopsy who underwent neoadjuvant radiotherapy followed by single-incision minimally invasive thymectomy from March 2016 to July 2020 were retrospectively evaluated. Reduction ratios, TNM stage changes according to WHO stage criteria, resectability, long-term survival, and the response in terms of RECIST v1.1 criteria achieved by preoperative RT were analyzed. Results: The 11 patients who underwent neoadjuvant radiotherapy plus minimally invasive thymectomy included five men and six women, of mean age 49.5 years. Four patients had myasthenia gravis. Neoadjuvant radiotherapy consisted of 50 Gy in 25 fractions, with all patients showing varying degrees of lesion reduction after radiotherapy. Surgery was performed about 1 month after neoadjuvant radiotherapy, with none of these patients having severe radiation pneumonitis. All patients underwent radical resection of the tumor and adjacent tissue, with none experiencing tumor seeding or rupture during surgery. The median postoperative hospital stay was 3 days (range: 2-6 days) and the frequency of additional regular analgesics (including those for wound pain and neuralgia) was 2.5 times per person. On follow-up, one patient experienced pleural metastasis and one experienced pulmonary metastasis, with the other nine patients showing no evidence of tumor recurrence. Conclusion: Neoadjuvant radiotherapy followed by minimally invasive surgery was a safe and efficacious procedure for the treatment of type B3 thymomas, with less postoperative pain and faster recovery. This strategy, of tumor shrinkage prior to surgery, may make possible the easier removal of type B3 thymomas by single-incision thoracoscopy.

[Analysis of potential pathogenic factors of trigeminal neuralgia in rats].

PURPOSES: Transcriptomics-based analysis of key transcriptional molecules in the pathogenesis of trigeminal neuropathic pain was conducted to screen key molecules in the pathogenesis of trigeminal neuralgia. METHODS: Rat trigeminal nerve pathological pain model, namely chronic constriction injury of distal infraorbital nerve (IoN-CCI), was constructed and animal behaviors postsurgery were observed and analyzed. Trigeminal ganglia were collected for RNA-seq transcriptomics analysis. StringTie was used to annotate and quantify genome expression. DESeq2 was applied to compare between groups with P value less than 0.05 and fold change greater than 2 times and less than 0.5 times to screen differential genes, and display them with volcano graphs and cluster graphs. ClusterProfiler software was used to perform GO function enrichment analysis of differential genes. RESULTS: On the fifth postoperative day (POD5), the rat's face-grooming behavior increased to a peak; on the seventh postoperative day (POD7), the von-frey value dropped to the lowest value, indicating that the mechanical pain threshold of rats was significantly decreased. RNA-seq analysis of IoN-CCI rat ganglia found that the significantly up-regulated signaling pathways included B cell receptor signaling pathway, cell adhesion, complement and coagulation cascade pathways; significantly down-regulated pathways were related to systemic lupus erythematosus. Multiple genes among Cacna1s, Cox8b, My1, Ckm, Mylpf, Myoz1, Tnnc2 were involved in mediating the occurrence of trigeminal neuralgia. CONCLUSIONS: B cell receptor signaling pathway, cell adhesion, complement and coagulation cascade pathways, neuroimmune pathways are closely related to the occurrence of trigeminal neuralgia. The interaction of multiple genes among Cacna1s, Cox8b, My11, Ckm, Mylpf, Myoz1, Tnnc2 leads to the occurrence of trigeminal neuralgia.

Neoadjuvant target therapy with ensartinib in lung adenocarcinoma with EML4-ALK fusion variant: a case report and literature review.

Although neoadjuvant target therapy has been used to treat patients with non-small-cell lung cancer (NSCLC), most of these patients have mutations in the epidermal growth factor receptor (EGFR) gene. Few patients to date have received neoadjuvant target therapy for NSCLC containing variants in genes encoding anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs). Herein, we present a 51-year-old man with a lung mass in the left lower lobe with enlarged mediastinal lymph nodes. He was diagnosed with NSCLC after needle lung biopsy, with next-generation sequencing showing an echinoderm microtubule-associated protein-like 4 gene-anaplastic lymphoma kinase (EML4-ALK) fusion variant. The patient received neoadjuvant ensartinib, a second-generation ALK-TKI, for 5 months, followed by successful lobectomy through uniportal video-assisted thoracic surgery and adjuvant ensartinib. To our knowledge, few patients with ALK-positive NSCLC had received neoadjuvant treatment with ensartinib. Findings in this patient may widen indications for neoadjuvant target therapy in the treatment of resectable stage II-IIIA ALK-positive NSCLC.

Constrast-enhanced computed tomography radiomics predicts CD27 expression and clinical prognosis in head and neck squamous cell carcinoma.

Objective: This study aimed to construct a radiomics model that predicts the expression level of CD27 in patients with head and neck squamous cell carcinoma (HNSCC). Materials and methods: Genomic data and contrast-enhanced computed tomography (CT) images of patients with HNSCC were downloaded from the Cancer Genome Atlas and Cancer Imaging Archive for prognosis analysis, image feature extraction, and model construction. We explored the potential molecular mechanisms underlying CD27 expression and its relationship with the immune microenvironment and predicted CD27 mRNA expression in HNSCC tissues. Using non-invasive, CT-based radiomics technology, we generated a radiomics model and evaluated its correlation with the related genes and HNSCC prognosis. Results and conclusion: The expression level of CD27 in HNSCC may significantly influence the prognosis of patients with HNSCC. Radiomics based on contrast-enhanced CT is potentially effective in predicting the expression level of CD27.

Accumulation of RIPK1 into mitochondria is requisite for oxidative stress-mediated necroptosis and proliferation in Rat Schwann cells.

The injury of Schwann cells is an important pathological feature of peripheral neuropathy. However, the explicit molecular mechanism and blocking method remains to be explored. In this study, we identified an pivotal executor of necroptosis-RIPK1, performed an unique function in response to oxidative stress-induced injury in Rat Schwann cells. We found that after oxidative stress-simulation by H2O2, RIPK1 was activated independent of genetic up-regulation, but through the post-translational modification, including its protein levels, phosphorylation of Serine 166 and Serine 321 sites and its general ubiquitination levels. Under a confocal microscopy, we found that RIPK1 was significantly accumulated into the mitochondria. And the phosphorylation, ubiquitination levels were also elevated in mitochondrial RIPK1, as indicated by immunoprecipitation. Through the administration of N-Acetyl-L-cysteine (NAC), a ROS inhibitor, we found that the phosphorylation, ubiquitination and mitochondrial location of RIPK1 was significantly suppressed. While administration of Necrostatin-1 (Nec-1) failed to influence the levels of ROS and mitochondrial membrane potential, revealing that RIPK1 served as the down-stream regulators of ROS. Lastly, pharmacological inhibition of RIPK1 by Nec-1 attenuated the levels of necroptosis, increased proliferation, as indicated by Annexin V/PI evaluation, CCK-8 detection, TEM scanning and EdU staining. Our results indicate a previous un-recognized post-translational change of RIPK1 in response to oxidative stress in Schwann cells.

Tissue-resident CD69+ CXCR6+ Natural Killer cells with exhausted phenotype accumulate in human non-small cell lung cancer.

Natural killer (NK) cells with tissue-residency features (trNK cells) are a new subpopulation of NK cells, which plays an important role in tissue homeostasis. However, the characteristics of trNK cells in the tumor microenvironment (TME) of human cancers remain unclear. Using multicolor flow cytometry, we investigated the quantity, phenotype, and function of trNK cells in biospecimens freshly resected from 60 non-small cell lung cancer (NSCLC) patients. We successfully identified a new CD69+ CXCR6+ trNK subset with an immunomodulatory-like and exhausted phenotype, specifically accumulated in the TME of NSCLC. In vitro experiments showed that CD69+ CXCR6+ trNK cells more readily secreted IFN-γ and TNF-α spontaneously. Furthermore, the production of IFN-γ and TNF-α by tumor-infiltrating CD69+ CXCR6+ trNK cells was not induced by their reactivation in vitro, which is analogous to T-cell exhaustion. Finally, we demonstrated that the dysfunction of CD69+ CXCR6+ trNK cells could be partly ameliorated by PD-1 and CTLA-4 blockade. In summary, we identified a new dysfunctional CD69+ CXCR6+ trNK cell subset that specifically accumulates in the TME of NSCLC. Our findings suggest that CD69+ CXCR6+ trNK cells are a promising target for immune checkpoint inhibitors in the treatment of NSCLC.

Auditory verbal hallucination can be evoked by prefrontal epileptic seizure.

Auditory verbal hallucinations (AVHs) have been reported in neocortical temporal epileptic seizures and have been considered highly associated with implication of auditory cortex by epileptic discharges or electrical stimulation. Herein, we report two rare frontal epilepsy cases in which AVHs featured the habitual seizures. The epileptogenic zones of these two patients were localized in the dorsal and orbitomedial prefrontal cortex, respectively by stereoelectroencephalography (SEEG) monitoring. Comparing with the AVHs in schizophrenia, we postulated that the phenomenological similarities between the two sets of AVHs imply homology in mechanisms. Ictal SEEG confirmed that the wide involvement of prefrontal-cingulate-auditory cortical network by low-voltage fast activity corresponded the occurrence with AVHs during frontal epileptic seizures. Electrical stimulation study of one of the two cases highlighted the causal role of prefrontal-cingulate cortex in the emergence of AVHs. Based on our clinical observation, SEEG findings, and electrical cortical stimulation, we supposed that wide implication of prefrontal-cingulate-auditory cortical network during epileptic seizure underlie the emergence of AVHs, and further hypothesized that AVHs could be yielded by transient deficit of self-monitoring for inner speech in focal epileptic seizures.

The immune landscape of human thymic epithelial tumors.

Human thymic epithelial tumors (TET) are common malignancies in the anterior mediastinum with limited biological understanding. Here we show, by single cell analysis of the immune landscape, that the developmental pattern of intra-tumoral T-cells identify three types within TETs. We characterize the developmental alterations and TCR repertoires of tumor-infiltrating T cells in the context of the distinguishing epithelial tumor cell types. We demonstrate that a subset of tumor cells, featuring medullary thymic epithelial cell (TEC) phenotype and marked by KRT14/GNB3 expression, accumulate in type 1 TETs, while T-cell positive selection is inhibited. Type 2 TETs are dominated by CCL25+ cortical TEC-like cells that appear to promote T-cell positive selection. Interestingly, the CHI3L1+ medullary TEC-like cells that are the characteristic feature of type 3 TETs don't seem to support T-cell development, however, they may induce a tissue-resident CD8+ T cell response. In summary, our work suggests that the molecular subtype of epithelial tumour cells in TETs determine their tumour immune microenvironment, thus GNB3 and CHI3L1 might predict the immunological behavior and hence prognosis of these tumours.