Tertiary lymphoid structures(TLSs),also known as tertiary lymphoid structures or ectopic lymphoid structures,are organized ag-gregates of immune cells that develop later in life in non-lymphoid tissues and that are structurally and functionally similar to secondary lymphoid structures.Additionally,TLSs are often associated with non-neoplastic diseases,such as autoimmune diseases and chronic inflam-matory disorders.The presence of TLSs in a variety of tumors has been revealed in recent studies to be strongly associated with patient pro-gnosis;however,its role in predicting prognosis varied in different types of tumors,which may be related to the location,maturity,and func-tion of TLSs in tumor tissue.Currently,a comprehensive identification of the state profile of TLSs is insufficient,which limits our assessment of its potential as a prognostic marker.In this study,we comprehensively analyzed the distribution characteristics of TLSs in different tumor types and explored its role in tumor therapy,as well as the potential and value of TLS as a prognostic predictive marker.

Acid-base dissociation constant (pK_a) is a key physicochemical parameter in chemical science, especially in organic synthesis and drug discovery. Current methodologies for pK_a prediction still suffer from limited applicability domain and lack of chemical insight. Here we present MF-SuP-pK_a (multi-fidelity modeling with subgraph pooling for pK_a prediction), a novel pK_a prediction model that utilizes subgraph pooling, multi-fidelity learning and data augmentation. In our model, a knowledge-aware subgraph pooling strategy was designed to capture the local and global environments around the ionization sites for micro-pK_a prediction. To overcome the scarcity of accurate pK_a data, low-fidelity data (computational pK_a) was used to fit the high-fidelity data (experimental pK_a) through transfer learning. The final MF-SuP-pK_a model was constructed by pre-training on the augmented ChEMBL data set and fine-tuning on the DataWarrior data set. Extensive evaluation on the DataWarrior data set and three benchmark data sets shows that MF-SuP-pK_a achieves superior performances to the state-of-the-art pK_a prediction models while requires much less high-fidelity training data. Compared with Attentive FP, MF-SuP-pK_a achieves 23.83% and 20.12% improvement in terms of mean absolute error (MAE) on the acidic and basic sets, respectively.

Purpose: The aim of our study was to investigate the value of baseline and preoperative neutrophil-to-lymphocyte ratio (NLR) in predicting the pathological response and disease-free survival (DFS) of neoadjuvant chemotherapy alone or combined with programmed cell death-1 (PD-1) checkpoint inhibitors in patients with resectable non‒small cell lung cancer (NSCLC). Materials and Methods: Resectable NSCLC patients who underwent neoadjuvant chemotherapy alone or combined with PD-1 checkpoint inhibitors between January 2018 and January 2020 were included. Peripheral venous blood samples of the patients were collected within 3 days prior to the first neoadjuvant treatment and within 3 days prior to surgery. Results: A total of 79 patients in neoadjuvant chemotherapy combined with PD-1 checkpoint inhibitors group and 89 patients in neoadjuvant chemotherapy alone group were included. Thirty-five point four percent of the patients achieved pathological complete response (pCR) in neoadjuvant chemotherapy combined with PD-1 checkpoint inhibitors group, whereas only 9.0% reached pCR in the group of neoadjuvant chemotherapy. High NLR level were correlated with poor pathological response and DFS in neoadjuvant chemotherapy or combined with PD-1 checkpoint inhibitors group. Multivariate analysis revealed that baseline NLR could independently predict pathological response and DFS in the neoadjuvant chemotherapy combined with PD-1 checkpoint inhibitors group. Conclusion High NLR level were correlated with poor pathological response and shorter DFS in patients with NSCLC undergoing neoadjuvant chemotherapy or combined with PD-1 checkpoint inhibitors. Meanwhile, baseline NLR could independently predict response to pathological response and DFS, revealing its potential as a screening tool in NSCLC patients who received neoadjuvant chemotherapy combined with PD-1 checkpoint inhibitors.

OBJECTIVES: This work aimed to construct N6-methyladenosine (m⁶A) regulator-based prognostic signature and evaluate the prognostic value and the intervention on tumor immune microenvironment of this m⁶A risk signature. METHODS: Using transcriptome and clinical data of head and neck squamous cell carcinoma (HNSCC) from The Cancer Genome Atlas (TCGA), we profiled m⁶A regulators and constructed an m⁶A risk signature. The relationship between m⁶A modulation and immune function was studied by differential gene expression, cell type enrichment, and correlation analyses. RESULTS: Fifteen m⁶A regulators had aberrant expression in HNSCC. A three-gene m⁶A prognostic signature (i.e., YTHDC2, IGF2BP2, and HNRNPC) was constructed and identified as an independent prognostic indicator for HNSCC. The m⁶A regulator signature-based high-risk group revealed pro-tumoral immune microenvironment due to the dysregulation of immune-related gene expression, abnormal enrichment of multiple immunocytes, and production of immunoregulatory factors. CONCLUSIONS This comprehensive analysis of m⁶A regulators and tumor immune landscape in HNSCC revealed that the m⁶A signature of YTHDC2, IGF2BP2, and HNRNPC could serve as a promising biomarker for monitoring HNSCC development and may be a potential target for tumor therapy in the future.
Humans ; Squamous Cell Carcinoma of Head and Neck/genetics* ; Gene Expression Regulation, Neoplastic ; Prognosis ; Head and Neck Neoplasms/genetics* ; Tumor Microenvironment/genetics* ; RNA-Binding Proteins/genetics* ; Heterogeneous-Nuclear Ribonucleoprotein Group C/genetics* ; RNA Helicases

Klebsiella pneumoniae(K.pneumoniae)is an important pathogen that can cause severe hospital-and community-acquired infections.To systematically investigate its methylation features,we determined the whole-genome sequences of 14 K.pneumoniae strains covering varying serotypes,multilocus sequence types,clonal groups,viscosity/virulence,and drug resistance.Their methy-lomes were further characterized using Pacific Biosciences single-molecule real-time and bisulfite technologies.We identified 15 methylation motifs[13 N6-methyladenine(6mA)and two 5-methylcytosine(5mC)motifs],among which eight were novel.Their corresponding DNA methyl-transferases were also validated.Additionally,we analyzed the genomic distribution of GATC and CCWGG methylation motifs shared by all strains,and identified differential distribution pat-terns of some hemi-/un-methylated GATC motifs,which tend to be located within intergenic regions(IGRs).Specifically,we characterized the in vivo methylation kinetics at single-base resolu-tion on a genome-wide scale by simulating the dynamic processes of replication-mediated passive demethylation and MTase-catalyzed re-methylation.The slow methylation of the GATC motifs in the replication origin(oriC)regions and IGRs implicates the epigenetic regulation of replication initiation and transcription.Our findings illustrate the first comprehensive dynamic methylome map of K.pneumoniae at single-base resolution,and provide a useful reference to better understand epigenetic regulation in this and other bacterial species.

The rapid spread of carbapenemase-producing Klebsiella pneumoniae(cpKP)poses seri-ous threats to public health;however,the underlying genetic basis for its dissemination is still unknown.We conducted a comprehensive genomic epidemiology analysis on 420 cpKP isolates col-lected from 70 hospitals in 24 provinces/autonomous regions/municipalities of China during 2009-2017 by short-/long-read sequencing.The results showed that most cpKP isolates were categorized into clonal group 258(CG258),in which ST11 was the dominant clone.Phylogenetic analysis revealed three major clades including the top one of Clade 3 for CG258 cpKP isolates.Additionally,carbapenemase gene analysis indicated that blaKPC was dominant in the cpKP isolates,and most blaKPC genes were located in five major incompatibility(Inc)groups of blaKPC-harboring plasmids.Importantly,three advantageous combinations of host-blaKPC-carrying plasmid(Clade 3.1+3.2-IncFⅡpHN7A8,Clade 3.1+3.2-IncFⅡpHN7A8:IncR,and Clade 3.3-IncFⅡpHN7A8:InCpA1763-KPC)were identified to confer cpKP isolates the advantages in both genotypes(strong correlation/coevolution)and phenotypes(resistance/growth/competition)to facilitate the nationwide spread of ST11/CG258 cpKP.Intriguingly,Bayesian skyline analysis illustrated that the three advanta-geous combinations might be directly associated with the strong population expansion during 2007-2008 and subsequent maintenance of the population of ST11/CG258 cpKP after 2008.We then examined drug resistance profiles of these cpKP isolates and proposed combination treatment regimens for CG258/non-CG258 cpKP infections.Thus,the findings of our systematical analysis shed light on the molecular epidemiology and genetic basis for the dissemination of ST11/CG258 cpKP in China,and much emphasis should be given to the close monitoring of advantageous cpKP-plasmid combinations.

Objective To analyze the application value and clinical experience of intraoperative ultrasound in microsurgical resection of supratentorial cavernous malformations.Methods From March 2018 to March 2019,31 patients with supratentorial cavernous malformations were operated with assistance of intraoperative ultrasound in our hospital.Intraoperative ultrasound could clearly show the locations and sizes of the lesions,and relations of lesions with surrounding structures to choose appropriate surgical routes.The degrees of resection were judged and complications were recorded.The patients were followed up for 3-6 months,and modified Rankin scale (mRS) was used to evaluate the prognoses.Results In these 31 patients,35 cavernous hemangiomas were diagnosed by MR imaging before surgery;33 lesions were removed surgically,and the other two lesions located in the contralateral side of the operative field were not removed.The accuracy of intraoperative ultrasound guiding the lesions was up to 100％.There were no postoperative infections or deaths.During follow-up,mRS score of 28 patients was 0;the other 3 patients with postoperative neurological impairment recovered partially during follow-up.Conclusion With the help of real-time monitoring of intraoperative ultrasound and location technique of small pieces of hemostatic yam,patients with supratentorial cavernous malformations could acquire satisfactory prognosis through meticulous microsurgery.

Objective: To identify the independent risk factors of esophageal varices (EV) in cirrhosis by endoscopic ultrasonography (EUS), and further to establish a risk assessment model for predicting EV occurrence and evaluate the clinical predictive value of the model. Methods: A retrospective cohort study was used in this study. Data of patients with cirrhosis without varicosity, who were hospitalized in Tianjin Second People's Hospital from September 2014 to March 2017 were collected. The location, diameter, and number of esophageal collateral circulation were measured by EUS. The non-selective beta blocker (NSBB) medication history and antiviral therapy were recorded. The time of the first EUS examination was taken as the starting point and the follow-up period was set up as 18 months. The end point was the occurrence of EV or the end of follow-up. The independent risk factors of EV occurrence were determined by univariate and multivariate logistic regression analysis, and the risk assessment model of EV occurrence was constructed. The predictive value of evaluation model for disease was studied by ROC analysis. Hosmer-Lemeshow goodness of fit was used to test the fitting efficiency of the evaluation model. Results: A total of 638 subjects were recruited initially, 13 of them were lost in the course of the study. Finally, 625 cases were included in the study. Among them, 369 cases did not develop EV (the non-progress group) and 256 cases developed EV (the progress group). (1) Multivariate logistic regression analysis showed that 7 independent risk factors were selected into the risk assessment model of EV occurrence, and were assigned corresponding scores: no NSBB (3 points), no antiviral treatment (2 points), Child-Pugh stage B (1 point), the diameter of peri-ECV>2 mm (1 point), the number of peri-ECV≥5 (3 points), the diameter of para-ECV≥5 mm (4 points), and the number of para-ECV≥5 (4 points). (2) In the risk assessment model, the risk factor scores ranged from 1 to 4 with a total score of 0-18. The predicted incidence of EV increased from 0.003 to 1.000 with the increase of the score. (3) In the risk assessment model, the total risk score ≤2 was assigned into low-risk group, 3-5 into medium-risk group, and ≥6 into high-risk group. The actual EV incidence of each risk stratification was 2.78% in the low-risk group, 36.36% in the medium-risk group and 93.91% in the high-risk group, respectively. (4) The ROC analysis showed that area under curve (AUC) was 0.947 (P<0.05), suggesting that the risk assessment model had a good effect on predicting disease progression. Hosmer-Lemeshow test showed that P was 0.450, suggesting that the model fitted well. Conclusion The risk assessment model based on EUS can accurately predict the occurrence of EV, and is simple and easy to use. The model can provide scientific basis for the prevention and rational treatment of EV in liver cirrhosis.

Lung cancer is the most common malignant tumor in the world. In order to improve the survival rate of patients with advanced lung cancer, more effective treatment methods are needed,in which immunotherapy has a broad therapeutic prospect. In recent years, immune-checkpoint inhibitors have received extensive attention in the treatment of lung cancer. Significant progress has been made in the development of a variety of first-line and second-line treatments, and significant advances have been made in the treatment of advanced lung cancer. With the successful application of immune-checkpoint inhibitors, neoadjuvant therapy has attracted extensive attention. In addition, the successful application of combined therapies such as immune combined immunization, immune combined tyrosine kinase inhibitor (TKI) and immune combined chemotherapy improved the survival rate of patients to some extent. However, pseudo progression and drug resistance has become a non-negligible problem in the immunotherapy of non-small cell lung cancer, which is worthy of further study. Although immune-checkpoint inhibitors have once again brought attention to tumor immunotherapy, their side effects are also worthy of attention. The recent advances in the application of immune-checkpoint inhibitors in lung cancer were summarized in order to provide a theoretical basis for its clinical application.

The paper probed into key challenges in talents introduction of hospitals ,especially introduction strategy and practical considerations.In its"MVPPS"(Money ,Value ,Platform ,Promise , Service)theory framework ,V(value)is the core ,and P(platform)is the key ,while P(promise)and M (money ,remuneration)are the cornerstone.The hospital can attract excellent talents by means of common value ,reasonable material conditions ,ideal development platform and service ,and promises fulfilled ,thus achieving fast disciplines development .