Inflammatory dendritic cells restrain CD11b+CD4+ CTLs via CD200R in human NSCLC.

CD4+ cytotoxic T lymphocytes (CD4+ CTLs) are suggested to play a crucial role in inflammatory diseases, including cancer, but their characteristics in human non-small cell lung cancer (NSCLC) remain unknown. Here, using the cell surface marker CD11b, we identify CD11b+CD4+ CTLs as a cytotoxic subset of CD4+ T cells in multiple tissues of NSCLC patients. In addition, tumor-infiltrating CD11b+CD4+ CTLs show a dysfunctional phenotype with elevated expression of CD200 receptor (CD200R), a negatively immunomodulatory receptor. CD4+ regulatory T (Treg) cells restrain the anti-tumor role of CD11b+CD4+ CTLs via CD200. Mechanistically, inflammatory dendritic cells promote the CD200R expression of CD11b+CD4+ CTLs by secreting interleukin-1ß (IL-1ß). Finally, we demonstrate that CD200 blockade can revive the tumor-killing role of CD11b+CD4+ CTLs and prolong the survival of tumor-bearing mice. Taken together, our study identifies CD11b+CD4+ CTLs in NSCLC with decreased cytotoxicity that can be reinvigorated by CD200 blockade, suggesting that targeting CD200 is a promising immunotherapy strategy in NSCLC.

MicroRNA (let-7b-5p)-targeted DARS2 regulates lung adenocarcinoma growth by PI3K/AKT signaling pathway.

Background: The aberrant intracellular expression of a mitochondrial aspartyl-tRNA synthetase 2 (DARS2) has been reported in human cancers. Nevertheless, its critical role and detailed mechanism in lung adenocarcinoma (LUAD) remain unexplored. Methods: Initially, The Cancer Genome Atlas (TCGA)-based Gene Expression Profiling Interactive Analysis (GEPIA) database (http://gepia.cancer-pku.cn/) was used to analyze the prognostic relevance of DARS2 expression in LUAD. Further, cell counting kit (CCK)-8, immunostaining, and transwell invasion assays in LUAD cell lines in vitro, as well as DARS2 silence on LUAD by tumorigenicity experiments in vivo in nude mice, were performed. Besides, we analyzed the expression levels of p-PI3K (phosphorylated-Phosphotylinosital3 kinase), PI3K, AKT (Protein Kinase B), p-AKT (phosphorylated-Protein Kinase B), PCNA (proliferating cell nuclear antigen), cleaved-caspase 3, E-cadherin, and N-cadherin proteins using the Western blot analysis. Results: LUAD tissues showed higher DARS2 expression compared to normal tissues. Upregulation of DARS2 could be related to Tumor-Node-Metastasis (TNM) stage, high lymph node metastasis, and inferior prognosis. DARS2 silence decreased the proliferation, migration, and invasion abilities of LUAD cells. In addition, the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved-caspase 3 and E-cadherin expressions in LUAD cells, coupled with the inactivation of the PI3K/AKT signaling pathway. Moreover, DARS2 silence impaired the tumorigenicity of LUAD in vivo. Interestingly, let-7b-5p could recognize DARS2 through a complementary sequence. Mechanistically, the increased let-7b-5p expression attenuated the promo-oncogenic action of DARS2 during LUAD progression, which were inversely correlated to each other in the LUAD tissues. Conclusion: In summary, let-7b-5p downregulated DARS2 expression, regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.

Analysis for discharge within 2 days after thoracoscopic anatomic lung cancer surgery.

OBJECTIVES: The risk and beneficial factors of early discharge after thoracoscopic anatomic lung cancer surgery are unknown, and this study aims to investigate predictors and associated 30-day readmission for early discharge. METHODS: We performed a single-center retrospective analysis of 10,834 consecutive patients who underwent thoracoscopic anatomic lung cancer surgery. Two groups were determined based on discharge date: "discharged by postoperative Day 2" and "discharged after postoperative Day 2." Univariable and multivariable analysis were conducted to identify predictors for discharge. Using propensity score matching (PSM) to compare 30-day readmission rate between two cohorts. RESULTS: A total of 1911 patients were discharged by postoperative Day 2. Multivariable analysis identified older age (odds ratio (OR) = 1.014, p < 0.001), male sex (OR = 1.183, p = 0.003), larger tumor size (OR = 1.248, p < 0.001), pleural adhesions (OR = 1.638, p = 0.043), lymph nodes calcification (OR = 1.443, p = 0.009), advanced clinical T stage (vs. T < 2, OR = 1.470, p = 0.010), lobectomy resection (vs. segmentectomy resection, OR = 2.145, p < 0.001) and prolonged operative time (OR = 1.011, p < 0.001) as independent risk factors for discharge after postoperative Day 2. Three adjustable variables including higher FEV1 /FVC (OR = 0.989, p = 0.001), general anesthesia (GA) plus thoracic paravertebral blockade (vs. GA alone, OR = 0.823, p = 0.006) and uni-portal thoracoscopic surgery (vs. multi-portal, OR = 0.349, p < 0.001) were associated with a decreased likelihood of discharge after postoperative Day 2. Before and after a 1:1 PSM, discharged by postoperative Day 2 did not increase the risk of 30-day readmission compared to counterparts. CONCLUSIONS: Carefully selected patients can be safely discharged within 2 days after thoracoscopic anatomic lung cancer surgery. Three modifiable variables may be favorable for promoting discharge by postoperative Day 2.

Predictive Factors for Gleason Score Upgrading in Patients with Prostate Cancer after Radical Prostatectomy: A Systematic Review and Meta-Analysis.

INTRODUCTION: Previous studies have revealed that Gleason score upgrading (GSU) was closely related to an increased biochemical recurrence rate and adverse oncologic outcomes in patients with prostate cancer (PC). Therefore, we performed a meta-analysis to determine the predictive factors for GSU following radical prostatectomy (RP). METHODS: We performed an extensive literature search using PubMed, Embase, and Cochrane in September 2022. In order to calculate the pooled odds ratio (OR), standardized mean difference (SMD), and 95% confidence intervals, a fixed effect or a DerSimonian and Laird random effect was applied. RESULTS: Twenty-six studies included 18,745 PC patients that were available for further analysis. Our results revealed that GSU was significantly correlated with age (summary SMD = 0.13; p = 0.004), prostate volume (PV) (summary SMD = -0.19;p < 0.001), preoperative PSA (p-PSA) (summary SMD = 0.18; p < 0.001), PSA density (PSAD) (summary SMD = 0.40; p < 0.001), number of positive cores (summary SMD = 0.28; p = 0.001), percentage of positive cores (summary SMD = 0.36; p < 0.001), Prostate Imaging Reporting and Data System (PI-RADS) scores (>3/≤3) (summary OR = 2.27; p = 0.001), clinical T stage (>T2/≤T2) (summary OR = 1.73; p < 0.001), positive surgical margins (PSM) (summary OR = 2.12; p < 0.001), extraprostatic extension (EPE) (summary OR = 2.73; p < 0.001), pathological T stage (>T2/≤T2) (summary OR = 3.45; p < 0.001), perineural invasion (PNI) (summary OR = 2.40; p = 0.008), and neutrophil to lymphocyte ratio (NLR) (summary SMD = 0.50; p < 0.001). However, we found that GSU was not significantly correlated with body mass index (BMI) (summary SMD = -0.02; p = 0.602). Moreover, our sensitivity and subgroup analyses showed that the findings were reliable. CONCLUSIONS: Age, PV, p-PSA, PSAD, number of positive cores, percentage of positive cores, PI-RADS score, clinical T stage, PSM, EPE, pathological T stage, PNI, and NLR are independent factors predicting GSU following RP. The findings may be helpful in risk stratification and personalized treatment in PC patients.

NMI: a potential biomarker for tumor prognosis and immunotherapy.

N-Myc and STAT Interactor protein (NMI) is an interferon inducible protein participating in various cellular activities, and is widely involved in the process of tumorigenesis and progression. Studies have shown that the loss of NMI expression in breast cancer can promote its progression by inducing epithelial-mesenchymal transition (EMT). However, the expression level of NMI in other tumors and its impact on immune cell infiltration, patient prognosis, and drug treatment are still unclear. Here, we analyzed the role of NMI in pan-cancer through multiple omics data. We found that NMI was abnormally expressed in a variety of tumor tissues. The expression of NMI was closely related to the unique molecular and immunotyping, diagnosis and prognosis of various tumor tissues. In addition, we identified the main proteins that interact with NMI, and focused on the relationship between the clinical parameters of lower grade glioma (LGG) and NMI expression. Subsequently, we found that the expression of NMI was correlated with the infiltration of multiple immune cells and the expression of immune checkpoints. Finally, we also found that the expression of NMI was correlated with the sensitivity to multiple antitumor drugs. In conclusion, our comprehensive pan-cancer analysis of NMI revealed that it is a potential molecular marker for tumor diagnosis and treatment, plays an important role in tumor immunity, and is a promising molecular target for cancer treatment.

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.

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.

Oncolytic adenovirus promotes vascular normalization and nonclassical tertiary lymphoid structure formation through STING-mediated DC activation.

Inducing a full antitumor immune response in the tumor microenvironment (TME) is essential for successful cancer immunotherapy. Here, we report that an oncolytic adenovirus carrying mIL-15 (Ad-IL15) can effectively induce antitumor immune response and inhibit tumor growth in a mouse model of cancer. We found that Ad-IL15 facilitated the activation and infiltration of immune cells, including dendritic cells (DCs), T cells and natural killer (NK) cells, in the TME. Unexpectedly, we observed that Ad-IL15 also induced vascular normalization and tertiary lymphoid structure formation in the TME. Moreover, we demonstrated these Ad-IL15-induced changes in the TME were depended on the Ad-IL15-induced activation of the STING-TBK1-IRF3 pathway in DCs. Taken together, our findings suggest that Ad-IL15 is a candidate for cancer immunotherapy that promotes immune cell activation and infiltration, tumor vascular normalization and tertiary lymphoid structure formation in the TME.

A random forest algorithm predicting model combining intraoperative frozen section analysis and clinical features guides surgical strategy for peripheral solitary pulmonary nodules.

Background: Intraoperative frozen section (FS) analysis has been used to guide the extent of resection in patients with solitary pulmonary nodules (SPNs), but its accuracy varies greatly among different hospitals. Artificial intelligence (AI) and multidimensional data technology are developing rapidly these years, meanwhile, surgeons need better methods to guide the surgical strategy of SPNs. We established predicting models combining FS results with multidimensional perioperative clinical features using logistic regression analysis and the random forest (RF) algorithm to get more accurate extent of SPN resection. Methods: Patients with peripheral SPNs who underwent FS-guided surgical resection at the Shanghai Chest Hospital (January 2017-December 2018) were retrospectively examined (N=3,089). The accuracy of intraoperative FS-guided resection extent was analyzed and used as Model 1. The clinical features (sex, age, CT features, tumor markers, smoking history, lesion size and nodule location) of patients were collected, and Models 2 and 3 were established using logistic regression and RF algorithms to combine the FS with clinical features. We confirmed the performance of these models in an external validation cohort of 117 patients from Hwa Mei Hospital, University of Chinese Academy of Science (Ningbo No. 2 Hospital). We compared the effectiveness in classifying low/high-risk groups of SPN among them. Results: The accuracy of FS analysis was 61.3%. Model 3 exhibited the best diagnostic accuracy and had an area under the curve of 0.903 in n the internal validation cohort and 0.919 in the external validation cohort. The calibration plots and net reclassification index (NRI) of Model 3 also exhibited significantly better performance than the other models. Improved diagnostic accuracy was observed in in both internal and external validation cohort. Conclusions: Using an RF algorithm, clinical characteristics can be combined with intraoperative FS analysis to significantly improve intraoperative judgment accuracy for low- and high-risk tumors, and may serve as a reliable complementary method when FS evaluation is equivocal, improving the accuracy of the extent of surgical resection.

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients.

BACKGROUND: Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. METHODS: In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. RESULTS: DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. CONCLUSIONS: We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.

Treatment of a genetic brain disease by CNS-wide microglia replacement.

Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.

Anti-IgE effect of small-molecule-compound arctigenin on food allergy in association with a distinct transcriptome profile.

BACKGROUND: Excessive production of IgE plays a major role in the pathology of food allergy. In an attempt to identify anti-IgE natural products, Arctium Lappa was one of the most effective herbs among approximately 300 screened medicinal herbs. However, little is known about its anti-IgE compounds. OBJECTIVE: To identify compounds from Arctium Lappa for targeted therapy on IgE production and explore their underlying mechanisms. METHODS: Liquid-liquid extraction and column chromatographic methods were used to purify the compounds. IgE inhibitory effects were determined on IgE-producing human myeloma U266 cells, peanut-allergic murine model and PBMCs from food-allergic patients. Genes involved in IgE inhibition in PBMCs were studied by RNA sequencing. RESULTS: The main compounds isolated were identified as arctiin and arctigenin. Both compounds significantly inhibited IgE production in U266 cells, with arctigenin the most potent (IC50=5.09µg/mL). Arctigenin (at a dose of 13 mg/kg) markedly reduced peanut-specific IgE levels, blocked hypothermia and histamine release in a peanut-allergic mouse model. Arctigenin also significantly reduced IgE production and Th2 cytokines (IL-5, IL-13) by PBMCs. We found 479 differentially expressed genes in PBMCs with arctigenin treatment (p < .001 and fold-change ≥1.5), involving 24 gene ontology terms (p < .001, FDR <0.05); cell division was the most significant. Eleven genes including UBE2C and BCL6 were validated by qPCR. CONCLUSION: Arctigenin markedly inhibited IgE production in U266 cells, peanut-allergic murine model and PBMCs from allergic patients by down-regulating cell division, cell cycle-related genes and up-regulating anti-inflammatory factors.

Modality-Specific Modulation of Temperature Representations in the Spinal Cord after Injury.

Different types of tissue injury, such as inflammatory and neuropathic conditions, cause modality-specific alternations on temperature perception. There are profound changes in peripheral sensory neurons after injury, but how patterned neuronal activities in the CNS encode injury-induced sensitization to temperature stimuli is largely unknown. Using in vivo calcium imaging and mouse genetics, we show that formalin- and prostaglandin E2-induced inflammation dramatically increase spinal responses to heating and decrease responses to cooling in male and female mice. The reduction of cold response is largely eliminated on ablation of TRPV1-expressing primary sensory neurons, indicating a crossover inhibition of cold response from the hyperactive heat inputs in the spinal cord. Interestingly, chemotherapy medication oxaliplatin can rapidly increase spinal responses to cooling and suppress responses to heating. Together, our results suggest a push-pull mechanism in processing cold and heat inputs and reveal a synergic mechanism to shift thermosensation after injury.SIGNIFICANCE STATEMENT In this paper, we combine our novel in vivo spinal cord two-photon calcium imaging, mouse genetics, and persistent pain models to study how tissue injury alters the sensation of temperature. We discover modality-specific changes of spinal temperature responses in different models of injury. Chemotherapy medication oxaliplatin leads to cold hypersensitivity and heat hyposensitivity. By contrast, inflammation increases heat sensitivity and decreases cold sensitivity. This decrease in cold sensitivity results from the stronger crossover inhibition from the hyperactive heat inputs. Our work reveals the bidirectional change of thermosensitivity by injury and suggests that the crossover inhibitory circuit underlies the shifted thermosensation, providing a mechanism to the biased perception toward a unique thermal modality that was observed clinically in chronic pain patients.

CD38 identifies pre-activated CD8+ T cells which can be reinvigorated by anti-PD-1 blockade in human lung cancer.

BACKGROUND: CD38 has been observed expressing in activated T cells, while the features and functions of CD38+ T cells in human NSCLC are still unclear. METHODS: Here we uncovered the correlation between CD38 expression and survival and immune infiltration levels in tumor of NSCLC. Then, we collected samples from 51 NSCLC patients to study the biological feature and response to anti-PD-1 of tumor-infiltrating CD38+ CD8+ T cells in vitro. RESULTS: We found CD38 expression correlated with the survival and immune infiltration levels of NSCLC. It is interesting that CD38+ CD8+ T cells enriched in the tumors expressed higher level of cytotoxic molecule, cytokines and PD-1 than CD38- CD8+ T cells. Moreover, PD-1+ subset in tumor-infiltrating CD38+ CD8+ T cells expressed higher level of activated markers than PD-1+ CD38- CD8+ T cells. Next, we found tumor-infiltrating CD38+ CD8+ T cells expressed higher level of CD103, IFN-γ, TNF-α and perforin than CD38- CD8+ T cells when were reactivated in vitro. Finally, we observed that CD38+ CD8+ T cells isolated from tumors could be reinvigorated by anti-PD-1 in vitro. CONCLUSIONS: Our findings demonstrate that CD38 expression defines a subset of CD8+ T cells enriched in tumors of NSCLC which have paradoxical phenotypes and response to anti-PD-1. Our results suggest a pre-priming of these cells is may exist in tumor and consequentially facilitate it acquiring both anti-tumor potency and exhausted phenotype which can be reinvigorated by PD-1 blockade.

miRNA-218-5p increases cell sensitivity by inhibiting PRKDC activity in radiation-resistant lung carcinoma cells.

BACKGROUND: Non-small cell lung carcinoma (NSCLC) is a malignancy with the highest mortality rate. Currently, surgery combined with radiotherapy is the first choice in the clinical treatment of lung carcinoma (LC); however, long-term radiotherapy leads to radiation resistance in patients, resulting in treatment failure. METHODS: In this study, a new microRNA-218-5p (miRNA-218-5p) was identified, and its function in LC was investigated. RESULTS: Reverse transcription quantitative polymerase chain reaction (RT-qPCR) results revealed that miRNA-218-5p was downregulated in LC. Overexpression or inhibition of miRNA-218-5p in LC and targeted binding of protein kinase, DNA-activated, catalytic polypeptide (PRKDC) to miRNA-218-5p were confirmed by comprehensive bioinformatic analysis. Exosomes from A549 and H1299 cells were cocultured with miRNA-218-5p and then cotransfected into radiation-resistant A549R and H1299R cells; the proliferation of radiation-resistant LC cells was found to be effectively inhibited and apoptosis was induced. Overexpression of miRNA-218-5p and X-irradiation could enhance the radiosensitivity of LC cells. Exogenous miRNA-218-5p derived from A549 and H1299 cells could be transfected into radiation-resistant LC cells and could inhibit PRKDC expression, thus accelerating DNA damage, apoptosis, and radiation sensitization of LC cells. CONCLUSIONS: miRNA-218-5p could induce apoptosis and enhance the radiosensitivity of LC cells through regulatory activities, thus suggesting its application as a potential target for LC treatment.

The surgical perspective in neoadjuvant immunotherapy for resectable non-small cell lung cancer.

BACKGROUND: The recent novel conception of neoadjuvant immunotherapy has generated interest among surgeons worldwide, especially the lack of experience involving surgical treatment for the neoadjuvant immunotherapy population. METHODS: Patients with non-small cell lung cancer (NSCLC), who underwent neoadjuvant immunotherapy or chemo-immunotherapy, were retrospectively collected between September 2018 and April 2020. Demographic data, pathological and clinical features, therapeutic regimens and outcome data of all individuals were collected by retrospective chart review. Operative details, information of neoadjuvant therapy, were also abstracted. RESULTS: In total, 31 patients were included in the final analysis. The patients' median age was 61 years. In total, 29 of the patients were males, while 2 were females. Patients received a median of 3 doses before resection. The median duration from final treatment to surgery was 34 days. After neoadjuvant treatment, post-treatment computed tomography scan showed that 24 patients had partial response. In total, 12 of 31 patients had a major pathological response, 15 pathological downstaging. Three patients had no residual viable tumor. A positive surgical margin was identified in 7 cases. One or more postoperative complications occurred in 18 of all 31 patients. In total, 26 patients underwent next-generation sequencing before surgery in total. Among them, 2 patients were detected STK11 mutations, none of whom had a major pathological response by final pathological examination. CONCLUSIONS: Pulmonary resection after neoadjuvant immunotherapy or chemo-immunotherapy for resectable NSCLC appears to be safe with low operative mortality and morbidity rate in the current population.

Systemic Immune Dysregulation Correlates With Clinical Features of Early Non-Small Cell Lung Cancer.

Background: Systemic immune dysregulation correlates with cancer progression. However, the clinical implications of systemic immune dysregulation in early non-small cell lung cancer (NSCLC) remain unclear. Methods: Using a panel of 9 markers to identify 12 parameters in the peripheral blood of 326 patients (34 in the discovery group and 292 in the validation group), we investigated systemic immune dysregulation in early NSCLC. Then, we analyzed the impact of surgery on the systemic immune state of these patients. Finally, we analyzed correlations between systemic immune dysregulation and the clinical features of early NSCLC. Results: We found striking systemic immune dysregulation in the peripheral blood of early NSCLC patients. This dysregulation was characterized by a significant decrease in total lymphocytes, T cells, quiescent T cells, CD4+ T cells, and NKT cells. We also observed increased proportions of activated lymphocytes and activated T cells. Systemic immune dysregulation was increased after surgery. Furthermore, systemic immune dysregulation was correlated with multiple clinical features, such as sex, age, smoking history, pathological type, tumor stage, surgical approach, tumor differentiation, and epidermal growth factor receptor (EGFR) mutation. Finally, we observed that systemic immune dysregulation was correlated with complications and systemic inflammatory response syndrome (SIRS) in early NSCLC patients. Conclusions: Our results reveal systemic immune dysregulation occurring in early NSCLC and demonstrate the correlation between these dysregulations and clinical features. Our findings suggest that systemic immune dysregulation is involved in cancer development and may be a promising candidate for high-risk screening and treatment strategies for early NSCLC.

P-STAT3 and IL-17 in tumor tissues enhances the prognostic value of CEA and CA125 in patients with lung adenocarcinoma.

AIM: The present study aimed to examine the capability of p- signal transducer and activator of transcription (STAT)3 and interleukin-17 (IL-17), along with two known tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125), for disease prognosis. Moreover, the associations among biomarkers and clinicopathological parameters were evaluated to uncover the potential mechanisms responsible for their correlations with lung adenocarcinoma (LAD) prognosis. METHODS: Five LAD-related parameters were used in the study: CEA, CA125, STAT3, p-STAT3, and IL-17. Spearman and chi-square correlation tests were used to explore the relationships between some clinicopathological variables and parameter expression levels and the associations among these five parameters. RESULTS: The disease-specific survival decreased with the positive expression of CEA, CA125, p-STAT3, and IL-17, with no significant difference in the expression level of STAT3. Combinations of p-STAT3 and IL-17, CEA and p-STAT3, CEA and IL-17, CA125 and p-STAT3, and CA125 and IL-17 had higher predictive values in LAD prognosis. The correlation analyses indicated the synergic activities of STAT3, p-STAT3, and IL-17 and the coordinated expression of CEA, CA125, p-STAT3, and IL-17. The tumor-node-metastasis (TNM) stage significantly correlated with the levels of CA125 and p-STAT3. CONCLUSIONS: Elevated levels of CEA, CA125, p-STAT3, and IL-17 alone and/or combinations of p-STAT3 and IL-17, CEA and p-STAT3, CEA and IL-17, CA125 and p-STAT3, and CA125 and IL-17 were recommended as the prognostic predictors of unfavorable clinical outcomes in patients with postoperative LAD. Also, p-STAT3 and IL-17 combined with CA125 and CEA helped in predicting the overall survival of patients with LAD and informing the TNM stage.

Effects of Exercise on Inflammatory Cytokines in Patients with Type 2 Diabetes: A Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: Inflammation is involved in the pathogenesis of type 2 diabetes (T2DM) and the occurrence of insulin resistance. The purpose of this study was to investigate the effects of exercise on inflammatory factors in patients with T2DM. METHODS: A systematic review was conducted on five databases, Cochrane, Embase, Pubmed, Web of Science, and EBSCO. All randomized controlled trials (RCTs) published between establishment of the database and November 2020 without restrictions on language were included. Studies evaluated the effects of exercise intervention on inflammatory cytokines in patients with T2DM were selected. RESULTS: Twenty-three randomized controlled trials (1350 patients) were included in our meta-analysis. Exercise can significantly reduce the level of C-reactive protein (CRP) (MD: -0.79, 95% CI: -1.26 to -0.33, p = 0.0008), tumor necrosis factor-α (TNF-α) (MD: -2.33, 95% CI: -3.39 to -1.27, p < 0.0001), and interleukin-6 (IL-6) (MD: -0.42, 95% CI: -0.60 to -0.24, p < 0.0001) in T2DM patients. CONCLUSION: The findings of this review suggest that exercise reduces inflammatory cytokines (CRP, TNF-α, and IL-6) in T2DM patients. More studies with high methodological qualities and large sample sizes need to be done to confirm which forms of exercise are most effective.

Differential Co-release of Two Neurotransmitters from a Vesicle Fusion Pore in Mammalian Adrenal Chromaffin Cells.

Co-release of multiple neurotransmitters from secretory vesicles is common in neurons and neuroendocrine cells. However, whether and how the transmitters co-released from a single vesicle are differentially regulated remains unknown. In matrix-containing dense-core vesicles (DCVs) in chromaffin cells, there are two modes of catecholamine (CA) release from a single DCV: quantal and sub-quantal. By combining two microelectrodes to simultaneously record co-release of the native CA and ATP from a DCV, we report that (1) CA and ATP were co-released during a DCV fusion; (2) during kiss-and-run (KAR) fusion, the co-released CA was sub-quantal, whereas the co-released ATP was quantal; and (3) knockdown and knockout of the DCV matrix led to quantal co-release of both CA and ATP even in KAR mode. These findings strongly imply that, in contrast to sub-quantal CA release in chromaffin cells, fast synaptic transmission without transmitter-matrix binding is mediated exclusively via quantal release in neurons.