Objective To investigate the effects of hypoxia on the transcriptional phenotype and ultrastructure of tumor-associated macrophages(TAMs)in glioma.Methods CD14+monocytes were isolated from healthy human peripheral blood samples collected from the Blood Bank of the First Affiliated Hospital of Army Medical University,and the cells were induced to differentiate into TAMs through co-culture with glioma cell-conditioned medium.Hypoxic TAM models were established using varying concentrations of cobalt chloride hexahydrate(CoCl2,50～400 μmol/L)or hypoxic conditions(1%,5%,10%O2)for 48 h,while normoxic TAM models(21%O2)served as controls.RT-qPCR and transcriptome sequencing were employed to analyze transcriptional changes in TAMs under normoxic and hypoxic conditions.Gene set enrichment analysis(GSEA)was applied to compare the differences in angiogenesis,glycolysis and other hypoxia-responsive pathways between the 2 conditions.Transmission electron microscopy(TEM)or immunofluorescence staining was conducted to assess the ultrastructural alterations in cytoskeleton,endoplasmic reticulum(ER),and mitochondria in normoxic and hypoxic TAMs(1%O2).Results Hypoxic TAMs exhibited up-regulated transcription of hypoxia-responsive markers(oxygen transport,glycolysis,pro-angiogenesis),with the effects correlating with hypoxia severity(P<0.05).GSEA revealed significant up-regulation of hypoxia,angiogenesis regulation,glycolysis and gluconeogenesis,and starvation stress pathways,alongside down-regulation of innate immunity,macrophage activation,cytoskeleton,and protein maturation pathways in hypoxic TAMs(P<0.05).TEM and immunofluorescence staining demonstrated obvious ultrastructure changes,including disrupted cytoskeletal organization,shortened rough ER with reduced ribosomes,mitochondrial swelling with cristae damage,and diminished ER-mitochondria contacts in hypoxic TAMs.Conclusion CoCl2 and hypoxia induce a hypoxic transcriptional phenotype in TAMs,which may potentially associated with ultrastructural remodeling of the cytoskeleton,ER,and mitochondria.

Background::Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson’s disease (PD) risk factors; however, no comprehensive analyses of these genes in patients with PD have been undertaken. Therefore, we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD.Methods::Whole-exome sequencing (WES) was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls. Additionally, whole-genome sequencing (WGS) was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls.Results::We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts, respectively. Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD. However, the significance did not pass the Bonferroni correction. Meanwhile, 72 and 1730 common variants were found in the WES and WGS cohorts, respectively. Unfortunately, single-variant logistic association analyses did not identify significant associations between common variants and PD. Conclusions::Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients. However, we highlight the complexity of PD and the need for extensive research elucidating its etiology.

Objective:To explore the predictive factors for adverse clinical outcomes in critically ill adult patients with autoimmune encephalitis by analyzing their clinical characteristics and prognosis.Methods:Clinical data of patients diagnosed with " confirmed" or " possible" autoimmune encephalitis who were hospitalized in the intensive care unit (ICU) of the Department of Neurology at the Second Xiangya Hospital of Central South University from January 2015 to December 2023 were retrospectively collected. The neurological function of patients at 3, 6, and 12 months of onset was followed up, and the modified Rankin Scale (mRS) at 12 months was used as an evaluation index for clinical prognosis; Further analysis was conducted on the relationship between clinical features, auxiliary examinations, and prognosis.Results:The 12-month survival rate of critically ill adult patients with autoimmune encephalitis in our center was 90.7%(117/129), and the 6-month poor prognosis rate was 28.7%(37/129). Univariate logistic regression analysis found that age of onset ( P<0.01), presence of tumors ( P<0.01), mechanical ventilation ( P<0.01), Glasgow Coma Scale (GCS) at ICU admission ( P<0.01), Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score ( P<0.01), cerebrospinal fluid glucose ( P<0.01), cerebrospinal fluid protein level ( P=0.02), epileptic waves in electroencephalography (EEG) ( P=0.03), use of glucocorticoids ( P=0.04), and time interval between initiation of intravenous immunoglobulin (IVIG) and onset ( P=0.04) were associated with prognosis. The results of multiple logistic regression analysis showed that mechanical ventilation [ P=0.01, area under the curve (AUC)=0.72)], APACHE Ⅱ score ( P=0.04, AUC=0.68), cerebrospinal fluid protein content ( P=0.04, AUC=0.65), and the time interval between initiation of IVIG and onset ( P=0.02, AUC=0.64) were independent predictive factors for the prognosis of adult critical autoimmune encephalitis. The prognostic prediction model for adult critical autoimmune encephalitis established by combining these four indicators has a higher AUC (0.85). Conclusions:Mechanical ventilation, APACHE Ⅱ score, cerebrospinal fluid protein level, and the time interval between initiation of IVIG and onset are predictive factors for poor clinical outcomes in critically ill autoimmune encephalitis in adults; The prognostic prediction model for adult critical autoimmune encephalitis established by combining these four indicators can identify patients with poor prognosis early, which is beneficial for early comprehensive management and intervention treatment to improve patient prognosis.

Objective: To investigate the trends in incidence, mortality and disease burden of prostate cancer among residents at ages of 60 years and older in Zhangjiagang City, Jiangsu Province from 2006 to 2022, so as to provide insights into improvements in the prostate cancer control strategy. Methods: The incidence and mortality of prostate cancer among residents at ages of 60 years and older in Zhangjiagang City from 2006 to 2022 were collected from the Chronic Diseases Monitoring and Management System in the National Health Information Platform of Zhangjiagang City, and the crude incidence and mortality of prostate cancer were calculated and standardized to data from the sixth national population census in China in 2010. Based on the disease burden of prostate cancer captured from the 2019 Global Burden of Disease Study datasets, the years of life lost due to premature death (YLL) and years of life lived with disability (YLD) and disability-adjusted life years (DALY) due to prostate cancer were measured, and trends in incidence, mortality and disease burden of prostate cancer were analyzed using average annual percent change (AAPC). Results: The crude incidence, standardized incidence, crude mortality, standardized mortality, crude DALY rate and standardized DALY rate of prostate cancer were 89.85/105, 83.87/105, 32.31/105, 25.45/105, 546.39/105 and 483.50/105 among residents at ages of 60 years and older in Zhangjiagang City from 2006 to 2022, which all appeared a tendency towards a rise (AAPC=5.346%, 4.219%, 6.648%, 3.697%, 4.198% and 2.200%, all P<0.05). The crude incidence, mortality and DALY rate of prostate cancer all appeared a tendency towards a rise with age (all P<0.05), with a tendency towards a rise seen for the crude incidence of prostate cancer among residents at ages of 60 to 64 years, 65 to 69 years and 70 to 74 years (AAPC=4.888%, 8.086% and 3.005%, all P<0.05), and a tendency towards a rise for the crude mortality and DALY rate among residents at ages of 80 years and older (AAPC=10.243% and 9.693%, both P<0.05). Conclusion The incidence and mortality of prostate cancer showed a tendency towards a rise among residents at ages of 60 years and older in Zhangjiagang City from 2006 to 2022, and the disease burden due to prostate cancer continued to increase, with a more remarkable increasing tendency seen for the incidence of prostate cancer among residents at ages of 60 to 74 years and for the mortality among residents at ages of 80 years and older.

Objective:Machine learning is not only an important branch of artificial intelligence, but also supporting technologies for bioinformatics analysis. In the presence work, four machine-learning-predictive model for the drug-sensitivity of Klebsiella pneumoniae to imipenem were established based on matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and the diagnostic effect of these methods was exmained. Methods:A retrospective study was performed and the data of MALDI-TOF-MS and imipenem sensitivity of a total number of 684 cases Klebsiella pneumoniae isolated from clinical specimens in the laboratory of microbiology department of Tianjin Haihe Hospital from 2019 January to 2020 December were collected. The mass spectrometry and imipenem sensitivity data of 70 cases identified as imipenem-sensitive and 70 resistant cases were simple randomly selected to establish the training set model; whereas 30 cases of sensitive and 30 cases of resistant cases were randomly selected to establish the test set model. Mass spectral peak data were subjected to Orthogonal Partial least squares Discriminant Analysis (OPLS-DA). The training set data model was established by machine learning least absolute shrinkage and selection operator (LASSO) algorithm, Logistic Regression (LR) algorithm, Support vector machines (SVM) algorithm, neural network (NN) algorithm. The area under the curve (AUC) and confusion matrix of training set and test set model were calculated and selected by Grid search and 10-fold Cross-validation respectively, the accuracy of the prediction model was verified by test set confusion matrix. Results:The R2Y and Q2 of OPLS-DA were 0.546 3 and 0.017 8. The AUC of the best training set and test set models were 1.000 0 and 0.858 1, 1.000 0 and 0.820 1, 0.940 8 and 0.756 1, 1.000 0 and 0.697 2 evaluated by LASSO, LR, SVM and NN model respectively. The accuracy of the model were 99% (69/70), 100% (70/70), 91% (64/70) and 100% (70/70) for prediction of drug resistance, 100% (70/70), 100% (70/70), 90% (63/70) and 100% (70/70) for drug sensitivity prediction, the correct rate were 99% (139/140), 100% (140/140), 91% (127/140) and 100% (140/140) in training set, the test set showed that the accuracy were 93% (28/30), 87% (26/30), 60% (18/30) and 60% (18/30) for prediction of drug resistance, 100% (30/30), 80% (24/30), 93% (28/30) and 67% (20/30) for drug sensitivity prediction, the correct rate were 97% (58/60), 83% (50/60), 77% (46/60) and 63% (38/60) by LASSO, LR, SVM and NN model respectively.Conclusion:The LASSO prediction model of Klebsiella pneumoniae sensitivity to imipenem established in this study has a high accuracy rate and has potential clinical decision support ability.

Diabetic microvascular complications are the main reason for the high mortality of diabetic patients. There is still a great shortage of existing therapeutic drugs, so there is an urgent need for more effective new drugs. Janus kinase/signal transducer and activator of transcription (JAK/STAT) is involved in the progression of diabetic microvascular complications, which can be improved by regulating this pathway. Therefore, this article reviews the progress of JAK/STAT in diabetic microvascular complications (diabetic kidney disease, diabetic retinopathy, diabetic peripheral neuropathy), and summarizes the potential drugs that intervene JAK/ stat to improve diabetic microvascular complications in recent years from three aspects of therapeutic drugs, preclinical drugs, and traditional Chinese medicine, in order to provide ideas for drug development and treatment of diabetic microvascular complications.

Objective:To accurately and effectively identify the most critical needs of extracorporeal membrane oxygenation (ECMO) treatment for patients with severe cardiopulmonary diseases, and to better carry out continuous improvement of medical service quality an patients' satisfaction.Methods:Patients who underwent ECMO and transferred from 56 medical institutions in the Henan Provincial People's Hospital Critical Care Medicine Specialist Alliance [the patients who were transported before applying quality function deployment (QFD) from June 2017 to May 2018 were enrolled as the control group, and patients who were transported after applying QFD from June 2018 to May 2019 were the observation group], medical staff in the alliance hospitals, ECMO transfer teams and transfer driver teams were enrolled as the subjects of the survey. QFD was applied to convert the collected requirements into quality improvement elements for targeted improvement measures.Results:A total of 125 questionnaires were distributed in this survey, and 116 valid questionnaires were collected, including 91 from patients (including 27 from the control group and 64 from the observation group), 10 from the medical staff of the alliance hospitals, 10 from the ECMO transport teams and 5 from the transport driver teams. The questionnaire recovery rate was 92.8%. The improvement elements of ECMO treatment for patients with critical cardiopulmonary diseases were ranked according to the importance, and the top five were as follows: the accuracy of the first diagnosis, the specialization of ECMO team, the guarantee of vehicle safety, the seamless responses, and the smooth coordinated rescue protocol.Conclusion:The top five improvement elements should be prioritized in ECMO treatment of patients with critical cardiopulmonary disease in all hospitals of the Alliance to ensure more accurate and timely treatment.

Objective:To evaluate the clinical value of 18F-FDG PET/CT findings in patients with T1-2 lung adenocarcinoma spread through air spaces (STAS). Methods:From June 2018 to June 2020, a total of 80 patients (36 males, 44 females; age: 19-84 (59.9±11.8) years) with surgically and pathologically confirmed T1-2 lung adenocarcinomas in Jiangmen Central Hospital were enrolled retrospectively. All patients underwent 18F-FDG PET/CT examination preoperatively and were divided into STAS positive and negative groups according to the histopathological diagnosis. Independent-sample t test, Mann-Whitney U test, χ2 test and Fisher exact test were used to analyze differences of gender, age, tumor biomarker, SUV max, SUV mean, features showed on high resolution CT (HRCT; including diameter, lesion location, morphology, density, lobulated sharp, spiculated sign, vacuole sign, air bronchgram sign, pleural traction and para-emphysema), and pathologic findings (micropapillary pattern, lymphvascular inversion, pleural inversion and lymph node metastasis) between the two groups, and then multivariate logistic regression was performed. The ROC curve was employed to evaluate the predictive value of parameters for STAS of T1-2 lung adenocarcinomas. Results:Among the 80 patients with T1-2 lung adenocarcinomas, 12 (15.0%) were STAS positive and 68 (85.0%) were STAS negative. Significant differences were shown in SUV max, SUV mean, micropapillary pattern, lymphvascular inversion and lymph node metastasis between the two groups ( z values: -2.60, -2.17; χ2 values: 29.56, 9.28, 17.40, P<0.001 or P<0.05). SUV max (odds ratio ( OR): 1.348 (95% CI: 1.071-1.695), P=0.011), micropapillary pattern ( OR=47.444 (95% CI: 4.592-490.214), P=0.001) and lymph node metastasis ( OR=8.201 (95% CI: 1.129-59.576), P=0.038) were independent risk factors for STAS positive in multivariation logistic regression analysis. The optimum cut-off value for SUV max was 3.85 in the ROC analysis with the AUC of 0.737 (95% CI: 0.614-0.859), the sensitivity of 11/12, the specificity of 55.9%(38/68) and the accuracy of 61.2%(49/80). The AUC of the SUV max combined with micropapillary pattern and lymph node metastasis was 0.945 (95% CI: 0.892-0.999) with the sensitivity of 11/12, the specificity of 88.2%(60/68) and the accuracy of 88.7%(71/80). Conclusions:The PET/CT characteristics may be useful in differentiating STAS status among patients with T1-2 lung adenocarcinoma. SUV max >3.85, pathological papillary pattern and lymph node metastasis are independent risk factors to predict STAS.

Objective:To investigate the expression of Macrophage migration-inhibitory factors (MIF) in hepatocellular carcinoma (HCC) tissues and its interaction with ERK1/2 signaling pathway, so as to establish a theoretical basis for further studying the molecular mechanism of MIF promoting HCC.Methods:From February 2020 to August 2021, 52 cases of hepatocellular carcinoma (HCC) tissues based on hepatitis B cirrhosis (HBV-LC) and 52 cases of adjacent tissues in Tianjin Medical University Cancer Hospital and 940th Hospital of Joint Logistic Support Force of PLA were collected as the experimental group, including 39 males and 13 females, aged 35-65 years. And 20 cases of normal liver tissue were selected as the control group. Immunohistochemistry was used to detect the expression of MIF, ERK1/2 and p-ERK1/2 proteins in liver tissues of the two groups, and in situ hybridization was used to detect the expression of ERK1/2 nucleic acid in liver tissues of the two groups.HepG2 HCC cells and L-02 normal hepatocytes were co-cultured with different concentrations of rMIF, the expression and phosphorylation levels of ERK1/2 and JNK1 proteins in the two kinds of liver cells were detected by Western-blot, and the expression levels of ERK1/2 nucleic acids in the two kinds of liver cells were detected by RT-PCR. One-way ANOVA was used for measurement data and χ 2 test was used for counting data. Results:The expressions of MIF, ERK1/2, p-ERK1/2 and ERK1/2 mRNA were significantly increased in HCC and para-cancer tissues (the expression of MIF in HCC group was 78.8%, and that in adjacent group was 75.0%; ERK1/2 80.8% in HCC group and ERK1/2 71.8% in paracancerous group. The expression of p-ERK1/2 75.0 % in HCC group and 46.2% in paracancerous group were respectively detected. ERK1/2 mRNA was expressed in HCC group 76.9%, ERK1/2 mRNA expression in paracancerous group 78.8%), and the differences were statistically significant compared with normal liver tissues ( P<0.05), but there was no significant difference between HCC and para-cancer tissues ( P>0.05). The expressions of ERK1/2, p-ERK1/2 and ERK1/2 mRNA in HepG2 HCC cells were significantly increased with the increase of rMIF concentration, and the increase was most obvious when rMIF concentration was 200 ng/ml, and the difference was statistically significant compared with L-02 normal hepatocytes ( P<0.05). Conclusion:MIF, ERK1/2 and p-ERK1/2 are highly expressed in HCC tissues and HepG2 HCC cells, suggesting that MIF promotes the occurrence and development of hepatocellular carcinoma through ERK1/2 signaling pathway.

Background: Interferon lambda receptor 1 (IFNLR1) is a type II cytokine receptor that clings to interleukins IL-28A, IL29B, and IL-29 referred to as type III IFNs (IFN-λs). IFN-λs act through the JAK-STAT signaling pathway to exert antiviral effects related to preventing and curing an infection. Although the immune function of IFN-λs in virus invasion has been described, the molecular mechanism of IFNLR1 in that process is unclear. Objectives: The purpose of this study was to elucidate the role of IFNLR1 in the pathogenesis and treatment of porcine reproductive and respiratory syndrome virus (PRRSV). Methods: The effects of IFNLR1 on the proliferation of porcine alveolar macrophages (PAMs) during PRRSV infection were investigated using interference and overexpression methods. Results: In this study, the expressions of the IFNLR1 gene in the liver, large intestine, small intestine, kidney, and lung tissues of Dapulian pigs were significantly higher than those in Landrace pigs. It was determined that porcine IFNLR1 overexpression suppresses PRRSV replication. The qRT-PCR results revealed that overexpression of IFNLR1 upregulated antiviral and IFN-stimulated genes. IFNLR1 overexpression inhibits the proliferation of PAMs and upregulation of p-STAT1. By contrast, knockdown of IFNLR1 expression promotes PAMs proliferation. The G0/G1 phase proportion in IFNLR1-overexpressing cells increased, and the opposite change was observed in IFNLR1-underexpressing cells. After inhibition of the JAK/STAT signaling pathway, the G2/M phase proportion in the IFNLR1-overexpressing cells showed a significant increasing trend. In conclusion, overexpression of IFNLR1 induces activation of the JAK/STAT pathway, thereby inhibiting the proliferation of PAMs infected with PRRSV. Conclusion Expression of the IFNLR1 gene has an important regulatory role in PRRSVinfected PAMs, indicating it has potential as a molecular target in developing a new strategy for the treatment of PRRSV.