Exploring the action targets (groups) of traditional Chinese medicine (TCM) is an important proposition to promote the innovation and development of TCM, but it has attracted a lot of attention as to whether it is related to the efficacy or the disease. Our team found that the metabolomic signature molecules in the development of diabetes mellitus (DM) were significantly associated with the clinical efficacy of Yuquan Pill through a large clinical sample study. Taking this as a clue, our team intends to expand the information on the omics features of DM development, and discover the key targets (groups) and their lead compounds for the hypoglycemic effect of Yuquan Pill. The project includes: ① Based on the retrospective clinical trials, using omics technology integrated with generative artificial intelligence, mining the characteristic information of proteome and microbiome, forming driving factors together with metabolome characteristic molecules, and characterizing the molecular trajectories of diabetes evolution and their interference by Yuquan Pill; ② Taking the evolving molecular trajectories as a link and pointer, using anthropomorphic modeling and molecular biology techniques such as chemical proteomics to discover the key targets (groups) of Yuquan Pill's hypoglycemic effect, with the prospective clinical samples for validation; ③ Evaluate the overall response of key targets (groups) using graph neural network technology, and search for drug-derived/endogenous lead compounds with proven clinical pathologies and clear mechanisms of action, so as to provide a new paradigm and technology for the discovery of complex active ingredient targets (groups) of TCM that are related to their clinical efficacy, as well as for the discovery of innovative medicines.

OBJECTIVE: To analyze the clinicopathological features, molecular changes and prognostic factors in angioimmunoblastic T-cell lymphoma (AITL). METHODS: Sixty-one cases AITL diagnosed by Department of Pathology of Peking University Cancer Hospital were collected with their clinical data. Morphologically, they were classified as typeⅠ[lymphoid tissue reactive hyperplasia (LRH) like]; typeⅡ[marginal zone lymphoma(MZL)like] and type Ⅲ [peripheral T-cell lymphoma, not specified (PTCL-NOS) like]. Immunohistochemical staining was used to evaluate the presence of follicular helper T-cell (TFH) phenotype, proliferation of extra germinal center (GC) follicular dendritic cells (FDCs), presence of Hodgkin and Reed-Sternberg (HRS)-like cells and large B transformation. The density of Epstein-Barr virus (EBV) + cells was counted with slides stained by Epstein-Barr virus encoded RNA (EBER) in situ hybridization on high power field (HPF). T-cell receptor / immunoglobulin gene (TCR/IG) clonality and targeted exome sequencing (TES) test were performed when necessary. SPSS 22.0 software was used for statistical analysis. RESULTS: Morphological subtype (%): 11.4% (7/61) cases were classified as type Ⅰ; 50.8% (31/61) as type Ⅱ; 37.8% (23/61) as type Ⅲ. 83.6% (51/61) cases showed classical TFH immunophenotype. With variable extra-GC FDC meshwork proliferation (median 20.0%); 23.0% (14/61) had HRS-like cells; 11.5% (7/61) with large B transformation. 42.6% (26/61) of cases with high counts of EBV. 57.9% (11/19) TCR⁺/IG^-, 26.3% (5/19) TCR⁺/IG⁺, 10.5% (2/19) were TCR^－/IG^－, and 5.3% (1/19) TCR^－/IG⁺. Mutation frequencies by TES were 66.7% (20/30) for RHOA, 23.3% (7/30) for IDH2 mutation, 80.0% (24/30) for TET2 mutation, and 33.3% (10/30) DNMT3A mutation. Integrated analysis divided into four groups: (1) IDH2 and RHOA co-mutation group (7 cases): 6 cases were type Ⅱ, 1 case was type Ⅲ; all with typical TFH phenotype; HRS-like cells and large B transformation were not found; (2) RHOA single mutation group (13 cases): 1 case was type Ⅰ, 6 cases were type Ⅱ, 6 cases were type Ⅲ; 5 cases without typical TFH phenotype; 6 cases had HRS-like cells, and 2 cases with large B transformation. Atypically, 1 case showed TCR^－/IG^－, 1 case with TCR^－/IG⁺, and 1 case with TCR⁺/IG⁺; (3) TET2 and/or DNMT3A mutation alone group (7 cases): 3 cases were type Ⅱ, 4 cases were type Ⅲ, all cases were found with typical TFH phenotype; 2 cases had HRS-like cells, 2 cases with large B transformation, and atypically; (4) non-mutation group (3 cases), all were type Ⅱ, with typical TFH phenotype, with significant extra-GC FDC proliferation, without HRS-like cells and large B transformation. Atypically, 1 case was TCR^－/IG^－. Univariate analysis confirmed that higher density of EBV positive cell was independent adverse prognostic factors for both overall survival (OS) and progression free survival(PFS), (P=0.017 and P=0.046). CONCLUSION Pathological diagnoses of ALTL cases with HRS-like cells, large B transformation or type Ⅰ are difficult. Although TCR/IG gene rearrangement test is helpful but still with limitation. TES involving RHOA, IDH2, TET2, DNMT3A can robustly assist in the differential diagnosis of those difficult cases. Higher density of EBV positive cells counts in tumor tissue might be an indicator for poor survival.
Humans ; Epstein-Barr Virus Infections/genetics* ; Herpesvirus 4, Human/genetics* ; T-Lymphocytes, Helper-Inducer/pathology* ; Immunoblastic Lymphadenopathy/pathology* ; Lymphoma, T-Cell, Peripheral/pathology* ; Receptors, Antigen, T-Cell

Objective: To analyze the clinical features of patients with acute pulmonary embolism (APE) living in high altitude area of Yunnan province. Methods: This was a cross-sectional retrospective study. APE patients, hospitalized in our hospital between January 2017 and December 2019, were included. The selected patients were divided into low-risk group, medium-risk group and high-risk group according to risk stratification. The clinical data of patients, including demographic data, the main symptoms, risk factors of APE, heart rate and systolic blood pressure and laboratory testing results (D-dimer, cardiac troponin I (cTNI), N terminal B-type natriuretic peptide (NT-proBNP)) and echocardiography and electrocardiogram examination results, were obtained through the electronic medical record system. The clinical characteristics of selected patients were analyzed. Results: A total of 392 patients, aged (63.5±15.7) years, 224 males (57.14%), were included in this study and there were 59 low-risk, 304 medium-risk and 29 high-risk patients in this cohort. The main clinical manifestations were chest pain (157(40.05%)), dyspnea (107(27.30%)), hemoptysis (55(14.03%)), syncope as the first symptom (20(5.10%)), and only 6 cases (1.53%) presented with the typical "Virchow's triad". Most of the patients were accompanied by atypical chest tightness (223(56.89%)) and cough (208(53.06%)). The main risk factors were venous thrombosis of lower limbs (179(45.66%)), hypertension (138(35.20%)), surgery (63(16.07%)), and chronic obstructive pulmonary disease (COPD) (62(15.82%)). There were 57 cases (14.54%) of coronary heart disease, 57 cases (14.54%) of diabetes, 51 cases (13.01%) of cerebral infarction, 47 cases (12.00%) of advanced age, 15 cases (3.83%) of tumor, 7 cases (1.79%) of activity restriction, 6 cases (1.53%) of pregnancy and 4 cases (1.02%) of hormone use in this cohort. The proportion of lower extremity venous thrombosis was significantly higher in low-risk group than in medium-risk group (P<0.01), COPD was more common in high-risk and medium-risk groups than in low-risk group (P<0.01), hypertension was more common in high-risk group than in medium-and low-risk groups (P<0.01). The proportion of advanced age was significantly higher in medium-risk group than in low-risk group (P<0.01). There were no significant differences in RBC and hemoglobin level between low-, medium-and high-risk groups (P>0.05). The level of D-dimer was significantly higher in high-risk group than in medium-and low-risk groups (P<0.05). Levels of NT-proBNP and cTNI were significantly higher in high-risk group than in medium- and low-risk groups (P<0.05). Increased proportion of cTNI and NT-proBNP was significantly higher in high-risk group than in medium- and low-risk groups (P<0.05). There were 105 (26.79%) patients with pulmonary hypertension (PAH). The incidence of PAH was significantly higher in high-risk group than in low-risk group (P<0.01). There were 104 patients (26.53%) with right ventricular enlargement, and the incidence of right ventricular enlargement was significantly higher in high-risk group than in medium-and low-risk groups (P<0.01). Characteristic changes of electrocardiogram in patient with APE were T-wave inversion of limb leads (98(25.00%)), followed by S_ⅠQ_ⅢT_Ⅲ (83(21.17%)). Conclusions: The main clinical manifestations of APE in Yunnan high altitude area are chest pain and dyspnea, and syncope is the first symptom in some patients, but the typical "Virchow's triad" is rare. The most common risk factors are lower extremity venous thrombosis, hypertension, and COPD. Clinical symptoms, risk factors and laboratory examination results differ among patients with different risk stratification.
Adolescent ; Altitude ; Biomarkers ; China/epidemiology* ; Cross-Sectional Studies ; Humans ; Male ; Natriuretic Peptide, Brain ; Peptide Fragments ; Prognosis ; Pulmonary Embolism/epidemiology* ; Retrospective Studies

The combination of Shuanghuanglian injection (SHLI) and ciprofloxacin injection (CIPI) is frequently prescribed in clinical practice, but the basis for the combination is weak. In this study, isothermal titration calorimetry and ultraviolet-visible absorption spectrometry were applied to identify the molecular interactions of SHLI and its main components, chlorogenic acid and neochlorogenic acid with CIPI. Scanning electron microscopy, Fourier-transform infrared spectroscopy, and cold-spray ionization mass spectrometry were performed to confirm that this molecular interaction was related to the formation of self-assembled supramolecular systems induced by chlorogenic acid and neochlorogenic acid with CIPI through weak intermolecular bonds. The antibacterial activity toward Pseudomonas aeruginosa (P. aeruginosa) was evaluated via molecular interactions, and the inhibitory ability of SHLI, chlorogenic acid and neochlorogenic acid against P. aeruginosa was significantly reduced after interaction with CIPI. A molecular docking study demonstrated that the reduced antibacterial ability was closely related to the competitive binding of drug molecules to the same binding site of the DNA gyrase B (GyrB) subunit of P. aeruginosa. The present study uncovered the intermolecular interactions of SHLI and its main components chlorogenic acid and neochlorogenic acid with CIPI from the perspective of molecular self-assembly and contribute to the reduction of its antibacterial ability, providing a basis for the clinical combination of SHLI and CIPI.

The joint application of traditional Chinese medicine injection containing chlorogenic acid (CA) and cefotaxime sodium (CS) is sometimes appeared in clinical practice, but the scientific basis of drug molecular compatibility is still weak. This study proposes a sequential analysis strategy based on isothermal titration calorimetry (ITC), cold-spray ionization mass spectrometry (CSI-MS) and antibacterial activity test to evaluate the molecular interactions between CA and CS. The results of ITC experiments showed that the Gibbs free energy ΔG < 0 and it was driven by enthalpy change when CA titrated CS, suggesting CA could spontaneously chemically react with CS. Subsequently, the parent ions (m/z 808.143 5) of binding molecular of CA and CS was detected by CSI-MS, indicating CA could chemically bond with CS. Furtherly, the antibacterial experiments found the antibacterial ability of CS against Klebsiella pneumonia was significantly reduced (P < 0.01) by CA in mixed solution. Finally, molecular docking technology showed CA and CS have a common target of penicillin binding protein 3 (PBP3), suggesting that the phenomenon of CA reduced the antibacterial ability of CS may be related to the competitive binding of two components with PBP3. Our studies have shown that CA could spontaneously chemically bond to CS and reduced its antibacterial ability, providing scientific data for molecular interaction evaluation of CA and CS.

Humans ; Lymphoma, Large-Cell, Anaplastic/pathology* ; PAX5 Transcription Factor/genetics*

Objective: To analyze the clinical epidemiological characteristics including composition of pathogens , clinical characteristics, and disease prognosis acute bacterial meningitis (ABM) in Chinese children. Methods: A retrospective analysis was performed on the clinical and laboratory data of 1 610 children <15 years of age with ABM in 33 tertiary hospitals in China from January 2019 to December 2020. Patients were divided into different groups according to age,<28 days group, 28 days to <3 months group, 3 months to <1 year group, 1-<5 years of age group, 5-<15 years of age group; etiology confirmed group and clinically diagnosed group according to etiology diagnosis. Non-numeric variables were analyzed with the Chi-square test or Fisher's exact test, while non-normal distrituction numeric variables were compared with nonparametric test. Results: Among 1 610 children with ABM, 955 were male and 650 were female (5 cases were not provided with gender information), and the age of onset was 1.5 (0.5, 5.5) months. There were 588 cases age from <28 days, 462 cases age from 28 days to <3 months, 302 cases age from 3 months to <1 year of age group, 156 cases in the 1-<5 years of age and 101 cases in the 5-<15 years of age. The detection rates were 38.8% (95/245) and 31.5% (70/222) of Escherichia coli and 27.8% (68/245) and 35.1% (78/222) of Streptococcus agalactiae in infants younger than 28 days of age and 28 days to 3 months of age; the detection rates of Streptococcus pneumonia, Escherichia coli, and Streptococcus agalactiae were 34.3% (61/178), 14.0% (25/178) and 13.5% (24/178) in the 3 months of age to <1 year of age group; the dominant pathogens were Streptococcus pneumoniae and the detection rate were 67.9% (74/109) and 44.4% (16/36) in the 1-<5 years of age and 5-<15 years of age . There were 9.7% (19/195) strains of Escherichia coli producing ultra-broad-spectrum β-lactamases. The positive rates of cerebrospinal fluid (CSF) culture and blood culture were 32.2% (515/1 598) and 25.0% (400/1 598), while 38.2% (126/330)and 25.3% (21/83) in CSF metagenomics next generation sequencing and Streptococcus pneumoniae antigen detection. There were 4.3% (32/790) cases of which CSF white blood cell counts were normal in etiology confirmed group. Among 1 610 children with ABM, main intracranial imaging complications were subdural effusion and (or) empyema in 349 cases (21.7%), hydrocephalus in 233 cases (14.5%), brain abscess in 178 cases (11.1%), and other cerebrovascular diseases, including encephalomalacia, cerebral infarction, and encephalatrophy, in 174 cases (10.8%). Among the 166 cases (10.3%) with unfavorable outcome, 32 cases (2.0%) died among whom 24 cases died before 1 year of age, and 37 cases (2.3%) had recurrence among whom 25 cases had recurrence within 3 weeks. The incidences of subdural effusion and (or) empyema, brain abscess and ependymitis in the etiology confirmed group were significantly higher than those in the clinically diagnosed group (26.2% (207/790) vs. 17.3% (142/820), 13.0% (103/790) vs. 9.1% (75/820), 4.6% (36/790) vs. 2.7% (22/820), χ²=18.71, 6.20, 4.07, all P<0.05), but there was no significant difference in the unfavorable outcomes, mortility, and recurrence between these 2 groups (all P>0.05). Conclusions: The onset age of ABM in children is usually within 1 year of age, especially <3 months. The common pathogens in infants <3 months of age are Escherichia coli and Streptococcus agalactiae, and the dominant pathogen in infant ≥3 months is Streptococcus pneumoniae. Subdural effusion and (or) empyema and hydrocephalus are common complications. ABM should not be excluded even if CSF white blood cell counts is within normal range. Standardized bacteriological examination should be paid more attention to increase the pathogenic detection rate. Non-culture CSF detection methods may facilitate the pathogenic diagnosis.
Adolescent ; Brain Abscess ; Child ; Child, Preschool ; Escherichia coli ; Female ; Humans ; Hydrocephalus ; Infant ; Infant, Newborn ; Male ; Meningitis, Bacterial/epidemiology* ; Retrospective Studies ; Streptococcus agalactiae ; Streptococcus pneumoniae ; Subdural Effusion ; beta-Lactamases

To improve the fluidity and compactibility properties of raw powders of traditional Chinese medicine by particle modification technology, Lonicera Japonica Flos was used as a model drug, fluidized bed bottom spray technology was used, and Plasdone S-630 was used as a modifier to prepare modified particles. The powder properties, tablet compactibility parameters, disintegration time and dissolution were measured. The surface morphology of the powder particles before and after modification and compressed tablets were characterized by combining with scanning electron microscopy technology. The results showed that the particle size of Lonicera Japonica powder has been increased after particle modification, the fluidity, compressibility and compactibility of the powder have been improved to some extent, the disintegration time has also been reduced, and the dissolution in vitro is not affected. Therefore, this study can provide reference and ideas for the common problem that raw powder of traditional Chinese medicine that cannot meet the needs of preparation production due to poor powder properties such as fluidity and compressibility.

The quality evaluation of compound Chinese medicines is an important but challenging issue in this research field, which has been paid much controversial due to the constrained association with clinical efficacy. Developing a methodology for quality evaluation of compound Chinese medicines related to clinical efficacy is an important measure in research on Chinese material medica quality to ensure clinical effectiveness and safety. Therefore, based on the research concept that "originating from clinic-testing in experiment-returning to clinic", and taking Xiaoke prescription as an example, the characteristic information of metabolome, proteome and microbiome are discussed from the clinical aspect, and the integrated markers associated with clinical efficacy constructed with artificial intelligence technology. Taking the integrated markers as the link and indication are connecting the clinical and basic, the main pharmacodynamic substances and key targets of Xiaoke prescription that are related to clinical efficacy are explained. Clinical samples are used for validation. Based on the main pharmacodynamic substances and key targets, methods and key technologies for chemical and biological evaluation of the quality of Xiaoke prescription are established, providing a methodology for quality evaluation of compound Chinese medicines, including clinical efficacy response indicators (related to clinic), main pharmacodynamic substances (chemical evaluation), and key targets (biological evaluation), to provide new ideas and methods for improving the quality evaluation of compound Chinese medicines.

Objective To investigate the long-term efficacy of PEG-IFN alpha-2a (PEG-IFNα-2a)plus ribavirin (RBV)in treatment of chronic hepatitis C (CHC)patients with IL28B single nucleotide polymorphisms (SNPs)rs12979860 C/C type in different HCV genotypes.Methods A prospective study was conducted on 38 CHC patients from our hospital's Infection Department from March 2011 to September 2015.The patients were treated with PEG-IFNα-2a/RBV for 48 weeks.A 42-month follow-up of patients was performed after withdrawal of treatment.The main paramenters to value the efficacy were liver function,blood lipids,and sustained virological response (SVR).Results In the CHC patients with IL28B SNP rs12979860 C/C type,the rate of SVR in patients with antiviral therapy had no significant difference between groups 1b and 2a (73.33% and 95.65%,respectively, P＞0.05).After anti-HCV therapy,liver function indices such as ALT,AST,TBIL,TC,TG and HDL all significantly improved in the two groups (all P＜0.05).However,there was no difference in biochemical indices (ALT,GGT,bilirubin,blood lipids)between the two groups (all P＞0.05).Conclusion In CHC patients with IL28B SNP rs12979860 C/C type,the long-term efficacy of PEG-IFNα-2a/RBV is good.IFN-based antiviral therapy has a higher SVR rate,and liver function and lipid metabolism can be significantly improved.