Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal.

The negative role of the activated stimulator of IFN genes (STING) has been uncovered in autoinflammatory disease and cancer. However, the role of STING in virus-related carcinogenesis is not well known. Herein, HPV(+) tongue squamous cell carcinoma (TSCC) (n=25) and HPV(-) TSCC samples (n=25) were randomly collected and were verified by in situ hybridization (ISH) and p16 immunohistochemistry (IHC) to assess the expression and activated status of STING through IHC. The results showed that the expression of STING was up-regulated during the development of TSCC. Interestingly, although the expression of STING showed no difference between HPV(+/-) TSCC samples, the activated status of STING with dark staining around the nucleus was observed in HPV(+) TSCC samples. The role of activated STING was analyzed in three cell lines by siRNA and indicated that activated STING had no impact on cell viability or apoptosis but promoted the induction of several immunosuppressive cytokines, e.g., IL-10, IDO and CCL22, which facilitated the infiltration of regulatory T cells (Tregs). Moreover, increased infiltration of Foxp3(+) Tregs along with increased expression of CCL22 was confirmed in HPV(+) TSCC samples. An inhibitor of the MAPK/AP-1 pathway (U0126) and the silencing of c-jun significantly suppressed CCL22 induction and the recruitment of Tregs by activated STING. Furthermore, down-regulated miR-27 was verified in independent fresh TSCC samples (n=50) and eight cell lines, which enhanced STING activation and led to increased CCL22 expression for Tregs recruitment in the TSCC microenvironment. Therefore, our findings provided distinct insight into the side effects of activated STING in HPV-related carcinogenesis.

Mission-oriented determination of regional weapon maintenance demand in simulation.

Determining maintenance demand ahead of mission is crucial to practical weapon maintenance, particularly to regional warship weapon maintenance. Attention is paid only to reliability, and the nature of mission or the consequence of damage is ignored while determining the regional warship weapon maintenance demand. For this reason, a method for determining regional maintenance demand based on simulation is put forward in this paper. Regional weapon maintenance system is first analyzed to build a mission-oriented maintenance demand model with the concept of mission-induced failure. Subsequently, the Anylogic platform is employed because of its advantages including agent modeling simulation and visualized process display. Four types of agent are designed for the regional maintenance system. The process of determining maintenance demand based on simulation is established on this basis. An example is eventually taken to calculate and verify the universality and effectiveness of the simulation model.

Two cavernous hemangiomas masquerading as single space occupying tumors in the orbital apex were removed under nasal endoscope: A case report.

INTRODUCTION AND IMPORTANCE: This report details the unusual presentation of two hidden cavernous hemangiomas in the orbital apex, initially appearing as one tumor. The rarity and diagnostic complexity of this case underscore the need for meticulous surgical exploration and verification in orbital apex tumors. CASE PRESENTATION: A physical examination of an elderly male with a three-year history of headaches revealed a space-occupying lesion in the left orbital apex. Imaging confirmed a tumor in the extraconical space above the optic nerve. Initial nasal endoscopy removed an orbital apex tumor, pathologically confirmed as a cavernous hemangioma. CLINICAL DISCUSSION: Postoperative examination revealed incomplete tumor removal, prompting a second surgery for full excision. This case underscores the diagnostic and management challenges of orbital apex tumors, especially when imaging indicates a single mass. The endoscopic transsphenoidal approach for cavernous hemangiomas in the medial orbital apex, as illustrated in this case, appears promising. CONCLUSION: Clinicians must be aware of the potential for multiple tumors in orbital apex cases, even if imaging does not explicitly reveal them. This case highlights the importance of thorough surgical exploration and illustrates the effectiveness of endoscopic methods in intricate orbital apex surgeries.

Construction of α-Amino Azines via Thianthrenation-Enabled Photocatalyzed Hydroarylation of Azine-Substituted Enamides with Arenes.

α-Amino azines are widely found in pharmaceuticals and ligands. Herein, we report a practical method for accessing this class of compounds via photocatalyzed hydroarylation of azine-substituted enamides with the in situ-generated aryl thianthrenium salts as the radical precursor. This reaction features a broad substrate scope, good functional group tolerance, and mild conditions and is suitable for the late-stage installation of α-amino azines in complex structures.

The loss of dopaminergic neurons in DEC1 deficient mice potentially involves the decrease of PI3K/Akt/GSK3ß signaling.

Here we study the effects of differentiated embryonic chondrocyte gene 1(DEC1) deficiency on midbrain dopaminergic(DA) neurons in the substantia nigra pars compacta(SNpc) through behavioral, histological and molecular analysis. We have found that compared to the age-matched WT mice, DEC1 deficient mice show a decrease in locomotor activity and motor coordination, which shows the main features of Parkinson's disease(PD). But there is no significant difference in spatial learning and memory skills between WT and DEC1 KO mice. Compared to the age-matched WT mice, DEC1 deficient mice exhibit the loss of DA neurons in the SNpc and reduction of dopamine and its metabolites in the striatum. The activated caspase-3 and TH/TUNEL+ cells increase in the SNpc of 6- and 12-month-old DEC1 KO mice compared to those of the age-matched WT mice. But we haven't found any NeuN/TUNEL+ cell increase in the hippocampus of the above two types of mice at the age of 6 months. Furthermore, DEC1 deficiency leads to a significant inhibition of PI3K/Akt/GSK3ß signaling pathway. Additionally, LiCl could rescue the DA neuron loss of midbrain in the 6-month-old DEC1 KO mice. Taken together, the loss of DA neurons in the DEC1 deficient mice potentially involves the downregulation of PI3K/Akt/GSK3ß signaling.

Disulfide bridge-targeted metabolome mining unravels an antiparkinsonian peptide

Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics, thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials. However, the success rate is decreasing, presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely 'overlooked' during the characterization effort. Here, we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP (ribosomally synthesized and post-translationally modified peptide), named acalitide, by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules. Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease (AcaB)-catalyzed lactamization of AcaA, an unprecedented precursor peptide. Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy. Taken together, the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson's disease that is globally prevailing in an alarming manner.

Real-time Analysis of Organic Composition of Oral and Nasal Breath Air by High Resolution Mass Spectrometry / 分析化学

Human exhaled breath has great application prospects,e.g.,monitoring pharmacokinetics,disease diagnosis,due to its advantages such as non-invasive and high-frequency sampling.Breath samples can be collected from the oral and nasal cavity.However,the oral and nasal environment affect the chemical composition of breath sample.Therefore,the investigation on the chemical composition of mouth-exhaled breath and nose-exhaled breath is crucial for selection of appropriate sampling strategy for individual studies.In this work,secondary electrospray ionization-high resolution mass spectrometry(SESI-HRMS)was applied to analysis of respiratory metabolomics in real time.A quantitative analysis approach was established for 9 kinds of volatile organic compounds(VOCs)e.g.2-butanone,2-pentanone,ethyl acetate,methyl methacrylate,toluene,styrene,mesitylene,isoprene and limonene.The limit of detection was 2.3?240.8 ng/m3.The intra-day(n=6)and inter-day(n=18)relative standard deviations were 0.6%?4.6%and 4.3%?12.2%,respectively.Nine healthy subjects were recruited to investigate the chemical composition of mouth-exhaled and nose-exhaled breath.The results showed the good performance in quantitative analysis of 9 VOCs in breath air.It was found that the number of unique component(m/z)detected in mouth-exhaled breath(167)was 2.2 times greater than that detected in nose-exhaled breath(76),which might result from the complex environment in oral cavity.The signal intensity of commun component(163)was significantly different between mouth-exhaled breath and nose-exhaled breath.Additionally,the elemental composition analysis showed that the proportion of polar compounds detected in nose-exhaled breath was higher than that in mouth-exhaled breath.This study demonstrated that there was significant differences in the chemical composition between mouth-exhaled and nose-exhaled breath,which provided a theoretical basis for selection of exhalation mode.

Importance of comprehensive management of anastomotic site after ultra-low anal sphincter-preservation surgery / 中华胃肠外科杂志

Intersphincteric resection (ISR) surgery increases the rate of anal sphincter preservation in patients with ultra-low rectal cancers. However, the anastomotic site of ISR surgery is at risk for structural healing complications such as anastomotic leakage, anastomotic dehiscence, secondary anastomotic stenosis, chronic presacral sinus, rectovaginal fistula, and rectourethral fistula, which can lead to a persistent defunctioning ostomy or a secondary permanent colostomy. This article systematically describes the preoperative high-risk factors and characteristics of anastomotic site structural healing complications after ISR surgery, as well as the management of the anastomotic site during various stages including hospitalization, from discharge to one month after surgery, from one month after surgery to before stoma reversal, and after stoma reversal. This is to provide a clearer understanding of the risks associated with the anastomotic site at different stages of the healing process and to timely detect and actively manage related complications, thereby reducing the rate of permanent colostomy and truly achieving the dual goals of "survival benefit" and "quality of life improvement" in ISR surgery.

Effect of Jianpi Huoxue Jiedu recipe on upper limb edema of spleen deficiency and dampness stagnation, blood stasis and toxin internal knot type after modified radical operation of breast cancer / 中国医师杂志

Objective:To explore the therapeutic effect of Jianpi Huoxue Jiedu recipe on upper limb edema of spleen deficiency and dampness stagnation, blood stasis and toxin internal knot type after modified radical surgery for breast cancer.Methods:From January 2020 to May 2022, a total of 60 patients with upper limb edema of spleen deficiency and dampness stagnation, blood stasis and toxin internal knot type after modified radical surgery for breast cancer were selected and treated in Longyan Hospital of Traditional Chinese Medicine Affiliated to Xiamen University. They were divided into control group and observation group according to random number table, with 30 cases in each group. The control group was treated with routine western medicine comprehensive swelling reduction surgery, while the observation group was treated with a combination of Jianpi Huoxue Jiedu recipe (1 dose/day, warmly-taken in the morning and evening) for one month on the basis of the control group. The clinical efficacy, traditional Chinese medicine (TCM) syndrome score, edema diameter, breast cancer quality of life scale (FACT), and joint range of motion were compared between the two groups after treatment.Results:After one month of treatment, the total clinical effective rate of the observation group (93.33%) was significantly higher than that of the control group (70.00%, P<0.05). After treatment, the TCM syndrome scores (upper limb swelling, pain, fullness, sense of restraint, skin keratinization, itching, heaviness, stuffiness, and fatigue) of both groups of patients decreased compared to those before treatment, and the observation group was lower than the control group (all P<0.05). After treatment, the diameter of edema in the affected limbs was significantly reduced in both groups of patients, and the diameter of 10 cm above the wrist and elbow stripes in the observation group was smaller than that in the control group (all P<0.05). After treatment, the FACT scores of the two groups of patients significantly decreased, and the FACT scores of the observation group were lower than those of the control group (all P<0.05). After treatment, the joint activity of the two groups of patients significantly increased, and the joint activity of the observation group was greater than that of the control group (all P<0.05). Conclusions:The clinical efficacy of Jianpi Huoxue Jiedu recipe combined with western medicine in treating upper limb edema of spleen deficiency and dampness stagnation, blood stasis and toxin accumulation type after modified radical operation of breast cancer is better than that of western medicine alone. It can significantly improve the clinical symptoms, signs, quality of life, and joint mobility of upper limbs of patients, and reduce upper limb edema.

Chinese Medicine Intervention in Diabetic Cardiomyopathy Based on Autophagy：A Review / 中国实验方剂学杂志

Autophagy is a lysosome-dependent intracellular degradation process，and it is a key mechanism of diabetic cardiomyopathy （DCM）. Autophagy has dual regulatory effects on DCM. Under physiological conditions，normal autophagy can promote the decomposition of damaged cardiomyocytes and metabolites，so as to reduce the damage of harmful substances to the body and provide energy for cardiomyocytes. Under pathological conditions，the inhibited autophagy of cardiomyocytes will cause the accumulation of damaged cells and metabolites，which will cause damage to cardiomyocytes and eventually aggravate cardiac dysfunction in the patients with DCM. However，the over autophagy of cardiomyocytes will lead to autophagic death of a large number of cardiomyocytes and result in pathological myocardial remodeling and cardiac dysfunction，thus promoting the progression of DCM. Therefore，the restoration of a normal autophagy level is the key means to protect cardiomyocytes and improve the prognosis of DCM. Chinese medicine can regulate autophagy to treat DCM. Specifically，it can promote autophagy （making up for deficiency） or inhibit autophagy （removing excess） to restore the balance of autophagy，thereby alleviating DCM.

Evolution of Research Related to Macrophage Polarization in Atherosclerosis:A Visualization Analysis / 中国医学科学院学报

Objective To explore the research status,hotspots,and development tendency of macrophage polarization (MP) in atherosclerosis (AS) by systematically reviewing and visually analyzing the articles published recently in this field,so as to provide new ideas for the basic research and translational research on MP in the prevention and treatment of AS.Methods SCI-Expanded was used as the data source for the retrieval of the articles involving MP in AS from 2012 to 2022.CiteSpace 6.1.R3 was employed to visualize the node information of the publishing country/region,institutions,authors,keywords,and citations.Results A total of 381 papers were included.The number of publications in the world showed an increasing trend year by year.China and the United States were leading this field in the number and centrality of publications,and Shandong University in China contributed the largest number of publications.The analysis of the key words and citations showed that the hotspots and frontiers in this field mainly included the pathogenesis of AS,MP markers,macrophage plasticity regulation,and potential therapeutic targets for AS.Conclusions The research on MP in AS was booming during 2012-2022.The differential gene expression and the molecular mechanism of targeted therapy of MP in AS are the research trends in this field,which will provide new measures for the prevention and treatment of AS.

Laparoscopic versus open pelvic exenteration for locally advanced rectal cancer: analysis of short- and long-term effects / 中华胃肠外科杂志

Objective: To explore the feasibility, safety, and short- and long-term efficacy of laparoscopic pelvic exenteration (LPE) in treating locally advanced rectal cancer. Methods: The clinical data of 173 patients who had undergone pelvic exenteration (PE) for locally advanced rectal cancer that had been shown by preoperative imaging or intraoperative exploration to have invaded beyond the mesorectal excision plane and adjacent organs in the Cancer Hospital, Chinese Academy of Medical Sciences (n=64) and Peking University First Hospital (n=109) from 2010 January to 2021 December were collected retrospectively. Laparoscopic PE (LPE) had been performed on 82 of these patients and open PE (OPE) on 91. Short- and long-term outcomes (1-, 3-, and 5-year overall and disease-free survival and 1- and 3-year cumulative local recurrence rates) were compared between these groups. Results: The only statistically significant difference in baseline data between the two groups (P>0.05) was administration of neoadjuvant therapy. Compared with OPE, LPE had a significantly shorter operative time (319.3±129.3 minutes versus 417.3±155.0 minutes, t=4.531, P<0.001) and less intraoperative blood loss (175 [20-2000] ml vs. 500 [20-4500] ml, U=2206.500, P<0.001). The R0 resection rates were 98.8% and 94.5%, respectively (χ2=2.355, P=0.214). At 18.3% (15/82), and the incidence of perioperative complications was lower in the LPE group than in the OPE group (37.4% [34/91], χ2=7.727, P=0.005). The rates of surgical site infection were 7.3% (6/82) and 23.1% (21/91) in the LPE and OPE group, respectively (χ2=8.134, P=0.004). The rates of abdominal wound infection were 0 and 12.1% (11/91) (χ2=10.585, P=0.001), respectively, and of urinary tract infection 0 and 6.6% (6/91) (χ2=5.601, P=0.030), respectively. Postoperative hospital stay was shorter in the LPE than OPE group (12 [4-60] days vs. 15 [7-87] days, U=2498.000, P<0.001). The median follow-up time was 40 (2-88) months in the LPE group and 59 (1-130) months in the OPE group. The 1-, 3-, and 5-year overall survival rates were 91.3%, 76.0%, and 62.5%, respectively, in the LPE group, and 91.2%, 68.9%, and 57.6%, respectively, in the OPE group. The 1, 3, and 5-year disease-free survival rates were 82.8%, 64.9%, and 59.7%, respectively, in the LPE group and 76.9%, 57.8%, and 52.7%, respectively, in the OPE group. The 1- and 3-year cumulative local recurrence rates were 5.1% and 14.1%, respectively, in the LPE group and 8.0% and 15.1%, respectively, in the OPE group (both P>0.05). Conclusions: In locally advanced rectal cancer patients, LPE is associated with shorter operative time, less intraoperative blood loss, fewer perioperative complications, and shorter hospital stay compared with OPE. It is safe and feasible without compromising oncological effect.

Differentiation and Treatment of Bipolar Disorder based on Qi， Phlegm， Fire and Deficiency / 中医杂志

Bipolar disorder （BD） is considered to be mainly related to qi， phlegm， fire and deficiency. Binding constraint of liver qi is the initial cause， while phlegm and qi interact obstruction as well as phlegm and fire interact binding is the key pathogenesis of the transformation between depression and mania， and deficiency of both qi and yin is the main reason of the protracted course of disease. In clinical practice， BD is divided into binding constraint of liver qi pattern， phlegm and qi interact obstruction pattern， phlegm and fire interact binding pattern， and deficiency of both qi and yin pattern， which can be treated with Jinyu Shugan Powder （金玉疏肝散）， Kaiyu Wendan Decoction （开郁温胆汤）， Qingxin Huatan Decoction （清心化痰汤）， and Baihe Shengmai Beverage （百合生脉饮） in their modifications respectively； moreover， Guanye Jinsitao （Herba Hyperici Perforati） is usually used to rectify qi， relieve phlegm and clear heat. It is also suggested to put focus on the prevention and treatment of qi， phlegm and heat simultaneously， and modify the medicinals flexibly in accordance with the pathogenesis evolution and the abnormal exuberance.

Influencing factors of refractory anastomotic stenosis after laparoscopic intersphincteric resec-tion for rectal cancer and construction of nomogram prediction model / 中华消化外科杂志

Objective:To investigate the influencing factors of refractory anastomotic stenosis after laparoscopic intersphincteric resection (Ls-ISR) for rectal cancer and construction of nomogram prediction model.Methods:The retrospective case-control study was conducted. The clinicopatho-logical data of 495 patients who underwent Ls-ISR for rectal cancer in two medical centers, including 448 patients in Peking University First Hospital and 47 patients in Cancer Hospital Chinese Academy of Medical Sciences, from June 2012 to December 2021 were collected. There were 311 males and 184 females, aged 61 (range, 20-84)years. Observation indicators: (1) incidence of anastomotic stenosis; (2) influencing factors of refractory anastomotic stenosis after Ls-ISR; (3) construction and evaluation of nomogram prediction model for refractory anastomotic stenosis after Ls-ISR. Follow-up was conducted using outpatient examination and telephone interview to detect the incidence of postoperative anastomotic leakage and anastomotic stenosis up to August 2022. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. Univariate and multivariate analyses were conducted using the Logistic regression model. Factors with P<0.10 in univariate analysis were included in multivariate analysis. The R software (3.6.3 version) was used to construct nomogram prediction model. The receiver operating characteristic (ROC) curve was drawn and the area under curve (AUC) was used to evaluate the efficacy of nomogram prediction model. Results:(1) Incidence of anastomotic stenosis. All 495 patients underwent Ls-ISR successfully, without conversion to laparotomy, and all patients were followed up for 47(range, 8-116)months. During the follow-up period, there were 458 patients without anas-tomotic stenosis, and 37 patients with anastomotic stenosis. Of the 37 patients, there were 15 cases with grade A anastomotic stenosis, 3 cases with grade B anastomotic stenosis and 19 cases with grade C anastomotic stenosis, including 22 cases being identified as the refractory anastomotic stenosis. Fifteen patients with grade A anastomotic stenosis were relieved after anal dilation treat-ment. Three patients with grade B anastomotic stenosis were improved after balloon dilation and endoscopic treatment. Nineteen patients with grade C anastomotic stenosis underwent permanent stoma. During the follow-up period, there were 42 cases with anastomotic leakage including 17 cases combined with refractory anastomotic stenosis, and 453 cases without anastomotic leakage including 5 cases with refractory anastomotic stenosis. There was a significant difference in the refractory anastomotic stenosis between patients with and without anastomotic leakage ( χ2=131.181, P<0.05). (2) Influencing factors of refractory anastomotic stenosis after Ls-ISR. Results of multivariate analysis showed that neoadjuvant therapy, distance from tumor to anal margin ≤4 cm, clinic N+ stage were independent risk factors of refractory anastomotic stenosis after Ls-ISR ( hazard ratio=7.297, 3.898, 2.672, 95% confidence interval as 2.870-18.550, 1.050-14.465, 1.064-6.712, P<0.05). (3) Construction and evaluation of nomogram prediction model for refractory anastomotic stenosis after Ls-ISR. Based on the results of multivariate analysis, neoadjuvant therapy, distance from tumor to anal margin and clinic N staging were included to constructed the nomogram prediction model for refractory anastomotic stenosis after Ls-ISR. Results of ROC curve showed the AUC of nomogram prediction model for refractory anastomotic stenosis after Ls-ISR was 0.739 (95% confidence interval as 0.646-0.833). Conclusions:Neoadjuvant therapy, distance from tumor to anal margin ≤4 cm, clinic N+ stage are independent risk factors of refractory anastomotic stenosis after Ls-ISR. Nomogram prediction model based on these factors can predict the incidence of refractory anastomotic stenosis after Ls-ISR.

Molecular mechanism of Leucopaxillus giganteus against breast cancer based on network pharmacology and in vitro experiments / 中国药理学通报

Aim To study the mechanism of the ethanol extract from Leucopaxillus giganteus (LGEE) in treating breast cancer based on network pharmacology and molecular experimental validation. Methods Some chromatographic methods were used to isolate the chemical constituents of LGEE, and their structures were elucidated based on spectral data. The antitumor activities of LGEE were determined by MTT assay. The predicted targets of LGEE were selected by TCMSP and Pharmmaper, and Genecards database was used to screen the targets. GO and KEGG analysis of target genes were performed. Molecular docking was used to test the binding of active components to core targets. Western blotting was used to validate the regulating function of chlorogenic acid on CHEK2 and CASP3 targets of MDA-MB-231 cells. Results Thirteen compounds were identified including clitocine, chlorogenic acid and so on. LGEE displayed anticancer activities against MDA-MB-231 with the inhibition percent (87. 35 ± 1. 55)%, at the concentration of 200 mg· L

Role of Eukaryotic Translation Elongation Factor 1 Family Members in the Tumorigenesis and Progression of Lung Adenocarcinoma / 中国医学科学院学报

Objective To investigate the role and mechanism of eukaryotic translation elongation factor 1(EEF1) family members (EEF1D,EEF1A1,and EEF1A2) in lung adenocarcinoma (LUAD) based on public databases.Methods We examined EEF1 member expression levels in human LUAD samples via The Cancer Genome Atlas in the UCSC Xena browser and the Clinical Proteomic Tumor Analysis Consortium.We analyzed the mRNA and protein levels of EEF1D,EEF1A1,and EEF1A2 and their correlations with pathological variables via the Mann-Whitney U test.The Kaplan-Meier curves were established to assess the prognostic values of EEF1D,EEF1A1,and EEF1A2.The single-sample gene set enrichment analysis algorithm was employed to explore the relationship between the expression levels of EEF1 members and tumor immune cell infiltration.Spearman and Pearson correlation analyses were performed to examine the relationship between the expression levels of EEF1 members and those of the genes in the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.The immunohistochemical assay was employed to determine the expression levels of EEF1D,EEF1A1,and EEF1A2 in the LUAD tissue (n=75) and paracancer tissue (n=75) samples.Results The mRNA and protein levels of EEF1D,EEF1A1,and EEF1A2 showed significant differences between tumor and paracancer tissues (all P<0.001).The patients with high protein levels of EEF1A1 showed bad prognosis in terms of overall survival (P=0.039),and those with high protein levels of EEF1A2 showed good prognosis in terms of overall survival (P=0.012).The influence of the mRNA level of EEF1D on prognosis was associated with pathological characteristics.The expression levels of EEF1 members were significantly associated with the infiltration of various immune cells and the expression of key molecules in the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.Conclusion EEF1D,EEF1A1,and EEF1A2 are associated with the progression of LUAD,serving as the candidate prognostic markers for LUAD.

Impeding the combination of astrocytic ASCT2 and NLRP3 by talniflumate alleviates neuroinflammation in experimental models of Parkinson's disease

Alanine-serine-cysteine transporter 2 (ASCT2) is reported to participate in the progression of tumors and metabolic diseases. It is also considered to play a crucial role in the glutamate-glutamine shuttle of neuroglial network. However, it remains unclear the involvement of ASCT2 in neurological diseases such as Parkinson's disease (PD). In this study, we demonstrated that high expression of ASCT2 in the plasma samples of PD patients and the midbrain of MPTP mouse models is positively correlated with dyskinesia. We further illustrated that ASCT2 expressed in astrocytes rather than neurons significantly upregulated in response to either MPP+ or LPS/ATP challenge. Genetic ablation of astrocytic ASCT2 alleviated the neuroinflammation and rescued dopaminergic (DA) neuron damage in PD models in vitro and in vivo. Notably, the binding of ASCT2 to NLRP3 aggravates astrocytic inflammasome-triggered neuroinflammation. Then a panel of 2513 FDA-approved drugs were performed via virtual molecular screening based on the target ASCT2 and we succeed in getting the drug talniflumate. It is validated talniflumate impedes astrocytic inflammation and prevents degeneration of DA neurons in PD models. Collectively, these findings reveal the role of astrocytic ASCT2 in the pathogenesis of PD, broaden the therapeutic strategy and provide a promising candidate drug for PD treatment.

Predictive value of HACOR score on the clinical outcome of non-invasive positive pressure ventilation in the treatment of chronic obstructive pulmonary disease with pulmonary encephalopathy / 中华危重病急救医学

Objective:To explore the predictive value of HACOR score [heart rate (H), acidosis (A), consciousness (C), oxygenation (O), and respiratory rate (R)] on the clinical outcome of non-invasive positive pressure ventilation in patients with pulmonary encephalopathy due to chronic obstructive pulmonary disease (COPD).Methods:A prospective study was conducted. The patients with COPD combined with pulmonary encephalopathy who were admitted to Henan Provincial People's Hospital from January 1, 2017 to June 1, 2021 and initially received non-invasive positive pressure ventilation were enrolled. Besides non-invasive positive pressure ventilation, standard medical treatments were delivered to these patients according to guidelines. The need for endotracheal intubation was judged as failure of non-invasive ventilation treatment. Early failure was defined as the need for endotracheal intubation within 48 hours of treatment, and late failure was defined as the need for endotracheal intubation 48 hours and later. The HACOR score at different time points after non-invasive ventilation, the length of intensive care unit (ICU) stay, the total length of hospital stay, and the clinical outcome were recorded. The above indexes of patients with non-invasive ventilation were compared between successful and failed groups. The receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive effect of HACOR score on the failure of non-invasive positive pressure ventilation in the treatment of COPD with pulmonary encephalopathy.Results:A total of 630 patients were evaluated, and 51 patients were enrolled, including 42 males (82.35%) and 9 females (17.65%), with a median age of 70.0 (62.0, 78.0) years old. Among the 51 patients, 36 patients (70.59%) were successfully treated with non-invasive ventilation and discharged from the hospital eventually, and 15 patients (29.41%) failed and switched to invasive ventilation, of which 10 patients (19.61%) were defined early failure, 5 patients (9.80%) were late failure. The length of ICU and the total length of hospital stay of the non-invasive ventilation successful group were significantly longer than those of the non-invasive ventilation failure group [length of ICU stay (days): 13.0 (10.0, 16.0) vs. 5.0 (3.0, 8.0), total length of hospital stay (days): 23.0 (12.0, 28.0) vs. 12.0 (9.0, 15.0), both P < 0.01]. The HACOR score of patients at 1-2 hours in the non-invasive ventilation failure group was significantly higher than that in the successful group [10.47 (6.00, 16.00) vs. 6.00 (3.25, 8.00), P < 0.05]. However, there was no significant difference in HACOR score before non-invasive ventilation and at 3-6 hours between the two groups. The ROC curve showed that the area under the ROC curve (AUC) of 1-2 hour HACOR score after non-invasive ventilation for predicting non-invasive ventilation failure in COPD patients with pulmonary encephalopathy was 0.686, and the 95% confidence interval (95% CI) was 0.504-0.868. When the best cut-off value was 10.50, the sensitivity was 60.03%, the specificity was 86.10%, positive predictive value was 91.23%, and negative predictive value was 47.21%. Conclusions:Non-invasive positive pressure ventilation could prevent 70.59% of COPD patients with pulmonary encephalopathy from intubation. HACOR score was valuable to predict non-invasive positive pressure ventilation failure in pulmonary encephalopathy patients due to COPD.

GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease

Peripheral bacterial infections without impaired blood-brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease (PD). Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation. However, how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown. In this study, we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS. GSDMD in peripheral myeloid cells promoted microglial immune training, thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner. Furthermore, pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models. Collectively, these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD. Based on these findings, GSDMD may serve as a therapeutic target for patients with PD.

Characteristics and Functional Differences of Intestinal Flora in Type 2 Diabetes Mellitus Patients with Dampness Heat Trapping Spleen Syndrome and Qi-Yin Deficiency Syndrome： An Analysis Based on High-throughput Sequencing Technology / 中国实验方剂学杂志

ObjectiveTo explore the structural characteristics and functional differences of intestinal flora in patients with type 2 diabetes mellitus （T2DM） of dampness heat trapping spleen（DHTS） syndrome and Qi-Yin deficiency（QYD） syndrome. MethodFrom June 2018 to January 2020，62 T2DM patients with DHTS syndrome and 60 with QYD syndrome were selected from Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine. Serum and fecal samples were collected to compare body mass index（BMI），glucose and lipid metabolism，fasting insulin （FINS） and fasting C-peptide （FCP） levels，and homeostasis model assessment of insulin resistance（HOMA-IR） of the two syndrome types. Fecal samples were extracted for DNA database construction，and 16S rDNA high-throughput sequencing was used to analyze and compare the intestinal flora and metabolic pathways. Result① The BMI，fasting plasma glucose（FPG），2-hour postprandial blood glucose （2 h PBG），total cholesterol（TC），triglyceride（TG），low density lipoprotein（LDL），FINS，FCP，and HOMA-IR were higher in patients with DHTS syndrome than in patients with QYD syndrome，and the high density lipoprotein（HDL） of the former was lower than that of the latter，（P<0.05，P<0.01）. ② In terms of species composition and differences，Bacteroidetes， Clostridia and Gammaproteobacteria were dominant at the class level，and the relative abundance of Clostridia，Mollicutes and Verrucomicrobiae in QYD syndrome group was higher than that in DHTS syndrome group. At the order level，Bacteroidales，Clostridiales and Enterobacteriales were mainly found. The relative abundance of Clostridiales，Erysipelotrichales and Verrucomicrobiales in QYD syndrome group was obviously higher than that in DHTS syndrome group，while Aeromonadales in the former was lower than that in the latter （P<0.05）. At the family level，Bacteroidaceae，Prevotellaceae and Ruminococcaceae were predominant. The relative abundance of Ruminococcaceae，Porphyromonadaceae and Erysipelotrichaceae in QYD syndrome group was higher than that in DHTS syndrome group（P<0.05）. At the genus level，Bacteroides，Prevotella and Parabacteroides were mainly found. The relative abundance of Parabacteroides，Butyrivibrio and Ruminiclostridium in QYD syndrome group was higher than that in DHTS syndrome group，while that of Klebsiella and Megasphaera in DHTS syndrome group was higher than that in QYD syndrome group（P<0.05）. ③ Through Venn analysis of operational taxonomic units（OTU），it was found that there were 49 OTUs in patients with DHTS syndrome patients and 47 OTUs in QYD syndrome patients. ④ The results of OTU β diversity and α analysis showed that Shannon and Simpson indexes had statistical differences，while Ace and Chao indexes had no statistical differences. The intestinal microbial diversity of patients with QYD syndrome was higher than that of patients with DHTS syndrome（P<0.05）. The analysis of similarities （ANOSIM） showed that the difference of β diversity between the two groups was significant（P<0.05）. ⑤ Linear discriminant analysis Effect Size（LEfSe） results demonstrated that Klebsiella，Megasphaera and Aeromonadales could be selected as the key biomarkers for DHTS syndrome； 14 bacteria such as Ruminiclostridium，Burkholderiaceae，Lautropia，Butyrivibrio，Erysipelotrichales can be selected as the key biomarkers for QYD syndrome. ⑥Functional annotation and analysis showed that the DHTS syndrome involved 9 metabolic pathways，including arginine and proline metabolism，lipopolysaccharide biosynthesis，nicotinic acid and nicotinamide metabolism，while the QYD syndrome involved 10 metabolic pathways，including acarbose and valinomycin biosynthesis，glucagon signaling pathway and NOD-like receptor signaling pathway. ConclusionThere are obvious differences in intestinal flora and functions in T2DM patients of DHTS syndrome and QYD syndrome，which can be used as reference for traditional Chinese medicine （TCM） syndrome differentiation and the target of TCM treatment.