Cytotoxicity, usually represented by cell viability, is a crucial parameter for evaluating drug safety in vitro. Accurate prediction of cell viability/cytotoxicity could accelerate drug development in the early stage. In this study, by integrating cellular transcriptome and cell viability data using four machine learning algorithms (support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM)) and two ensemble algorithms (voting and stacking), highly accurate prediction models of 50% and 80% cell viability were developed with area under the receiver operating characteristic curve (AUROC) of 0.90 and 0.84, respectively; these models also showed good performance when utilized for diverse cell lines. Concerning the characterization of the employed Feature Genes, the models were interpreted, and the mechanisms of bioactive compounds with a narrow therapeutic index (NTI) can also be analyzed. In summary, the models established in this research exhibit superior capacity to those of previous studies; these models enable accurate high-safety substance screening via cytotoxicity prediction across cell lines. Moreover, for the first time, Cytotoxicity Signature (CTS) genes were identified, which could provide additional clues for further study of mechanisms of action (MOA), especially for NTI compounds.

Objective To explore the correlation between brachial and ankle pulse wave conduction velocity(baPWV)and cardiac structure and function in patients with type 2 diabetes mellitus(T2DM).Methods A total of 443 patients with T2DM who were treated in The Endocrinology Department of Gansu Provincial People's Hospital were enrolled in this study from June 2022 to October 2023.All the patients were divided into simple T2DM group(T2DM,baPWV<1400 cm/s,n=221)and atherosclerosis group(AS,baPWV≥1400 cm/s,n=222)based on baPWV.The cardiac ultrasound diagnostic instrument was used to record left ventricular ejection fraction(LVEF),end diastolic left ventricular diameter(LVd),end diastolic interventricular septal thickness(IVSd),end diastolic left ventricular posterior wall thickness(LVPWd),ratio of early to late diastolic peak velocity of mitral valve annulus(E/A),and ratio of early diastolic peak velocity of mitral valve orifice to early diastolic peak velocity of mitral valve annulus(E/E').Results Age,DM duration,SBP,DBP,HbA1c,TG,ABI,LVEF,IVSd,LVPWd,E/A<1,E/E'＞14,were higher in AS group than in T2DM group(P<0.05 or P<0.01).Spearman correlation analysis shows that E/A<1 was positively correlated with age,DM duration,BMI,SBP,DBP,and ABI(P<0.05 or P<0.01),while negatively correlated with baPWV(P<0.01).Pearson correlation analysis shows that LVPWd was positively correlated with age,DM duration,BMI,SBP,DBP,baPWV,and Scr(P<0.05 or P<0.01).Logistic regression analysis shows that baPWV,ABI,and SBP were the influencing factors for left ventricular diastolic dysfunction.The analysis of the working characteristic curve of the subjects shows that the area under the curve of baPWV,SBP and ABI for predicting left ventricular diastolic dysfunction is 0.647,0.643,and 0.624,with the best cutoff points being 1398.5 cm/s,125.5 mmHg,and 1.107.Conclusions baPWV is closely related to cardiac structure and function in T2DM patients.As baPWV increases,the risk of left ventricular diastolic insufficiency and hypertrophy rises.

Objective To analyse the effect on implementation of the International Guidelines for Clinical Treatment of Pressure Injuries within leadership-staff-performance improvement-information technology(LSPI)framework of quality improvement,therefore to provide theoretical insights in promoting the transformation of prevention and treatment practice guidelines to clinical practices.Methods A pre-and post-control study was in this study.A total of 101 005 inpatients admitted to our hospital between July 2019 and June 2020 were assigned to a control group,and the other 110 824 patients who were hospitalised between July 2020 and June 2021 were assigned to a trial group.The two groups were compared in terms of the promptness rate and accuracy of primary risk assessment,response rate of high-risk patients and incidence of pressure injury before and after implementation of the guideline.Results After implementation of the guideline,the promptness rate and the accuracy of primary risk assessment and the rate of preventive measures in high-risk patients increased from 86.73%to 96.25%,93.46%to 98.69%and 94.21%to 98.15%,respectively.The incidence of hospital pressure injury decreased from 0.77‰ to 0.29 ‰.All the differences were statistically significant(all P＜0.05).Conclusions Implementation of the International Guidelines for the Clinical Treatment of Pressure Injuries within the LSPI framework of quality improvement can improve the quality of process management in pressure injury and reduce the incidence of pressure injuries.Therefore,it can facilitate the guideline-based code of practice in the clinical practices.

Objective To explore the difference of serum inflammatory factors in patients with first episode schizo-phrenia,patients with relapse episode schizophrenia and healthy people,and the correlation between serum inflam-matory factors with negative symptoms in patients with schizophrenia,so as to provide reference for clinical inter-vention.Methods A total of 86 patients with first episode schizophrenia(first episode group),80 patients with re-lapse episode schizophrenia(relapse episode group)and 82 healthy people(control group)were included in the study.The difference of serum inflammatory factors among the three groups and the correlation between serum inflammatory factors with negative symptoms were analyzed.Results There were significant differences in serum interleukin(IL)-1β and IL-16 levels among the three groups(P<0.05).The analysis and comparison between the two groups showed that the serum IL-1β in first episode group was significantly higher than that in relapse episode group and control group(P<0.05),serum IL-16 in first episode group and relapse episode group was significantly higher than that in control group(P<0.05).Serum IL-1β was negatively correlated with PANSS general psycho-pathological scale factor score in first episode group(P<0.05),and serum IL-16 was positively correlated with PANSS negative symptom scale factor score in relapse episode group(P<0.05).IL-16 level might be an inde-pendent risk factor affecting the onset of first episode group and relapse episode group(P<0.05).Conclusion There are differences in serum levels of IL-1β and IL-16 between patients with schizophrenia and healthy people.Serum IL-16 levels in patients with relapse episode schizophrenia are associated with negative symptoms.IL-16 lev-el may be an independent risk factor for schizophrenia.

Objective To investigate the effect of laser engraving personalized nasal patch applied to patients with nasal catheter indentation.Methods A total of 124 patients who underwent esophageal cancer surgery in the First Hospital of Lanzhou University from February 2022 to February 2023 and required indwelling nasal catheter were selected as study objects,and were divided into experimental group and control group according to random number table method,with 62 cases in each group.The control group used conventionally cut nasal patches to fix the nasal catheters,and the experimental group used laser engraved personalized nasal patches.Catheter displacement or slippage under the fixation device,nasal patch rolled edges and number of replacement,nasal medical device-related pressure injury,medical adhesive-related skin lesions and patients'comfort were observed in two groups.Results The rate of catheter displacement,number of rolled edges of nasal patches and numbers of replacement in experimental group were significantly lower than those in control group(P<0.05).The incidence of nasal mucosal indentation,nasal pain,nasal pressure injury and medical adhesive related skin lesions in experimental group were significantly lower than those in control group(P<0.05).The comfort of patients at the physiological level of experimental group was significantly better than that of control group(P<0.05).Conclusion Laser engraved personalized nasal patches can reduce the frequency of clinical nasal catheter displacement,nasal patch rolled edges and number of replacement,reduce the occurrence of nasal medical device related pressure injuries and medical adhesive-related skin lesions,and increase patients'comfort.

Objective:To investigate the mechanism of downregulated programmed cell death 10 ( PDCD10) expression mediating glioblastoma multiforme (GBM) resistance to temozolomide (TMZ). Methods:U87, LN229 and T98g cell lines were transfected with PDCD10 small interfering RNA or negative small interfering RNA. TMZ-resistant cell lines were constructed using 300 μmol/L TMZ (transfected T98g cell line) and 150 μmol/L TMZ (transfected U87 and LN229 cell lines), respectively: TMZ-resistant U87 cell line transfected with PDCD10 small interfering RNA (shPDCD10-U87-RG cells), TMZ-resistant U87 cell line transfected with negative small interfering RNA (EV-U87-RG cells), shPDCD10-T98g-RG cells, EV-T98g-RG cells, shPDCD10-LN229-RG cells and EV-LN229-RG cells. Flow cytometry and real-time quantitative polymerase chain reaction (qRT-PCR) were used to detect the transfection efficiency of TMZ-resistant cell lines and PDCD10 expressions; MTT assay and colony formation assay were used to verify the drug-resistant ability of TMZ-resistant cell lines. Bioinformatics analysis was performed to detect the correlations of PDCD10 with key genes ( MSH6 and PMS2) in mismatch repair (MMR) system, and drug resistant mechanism was explored by detecting the cell cycle and neurosphere formation ability of drug-resistant cells. Results:(1) qRT-PCR showed that compared with that in EV-U87-RG cells, the PDCD10 expression in shPDCD10-U87-RG cells was statistically down-regulated by (32.85±1.14)% ( t=2.925, P=0.049); compared with that in EV-T98g-RG cells, the PDCD10 expression in shPDCD10-T98g-RG cells was significantly down-regulated by (57.17±1.81)% ( t=3.179, P=0.043); compared with that in EV-LN229-RG cells, the PDCD10 expression in shPDCD10-LN229-RG cells was significantly down-regulated by (33.68±1.34)% ( t=3.085, P=0.045). (2) MTT assay showed that compared with the EV-U87-RG cells, the shPDCD10-U87-RG cells had significantly increased viability ( P<0.05); compared with the EV-T98g-RG cells, the shPDCD10-T98g-RG cells had significantly increased viability ( P<0.05). Among the same kind of cells, the viability 3 d after wash-out was significantly increased compared with that at 72 h after TMZ treatment ( P<0.05). Colony formation assay showed that cell lines with down-regulated PDCD10 expression had higher tumorigenic ability. (3) Compared with EV-U87-RG cells and EV-T98g-RG cells, cells with down-regulated PDCD10 expression (shPDCD10-U87-RG cells and shPDCD10-T98g-RG cells) escaped from TMZ-induced G2/M arrest, resulting in TMZ resistance. (4) Bioinformatics analysis revealed that the PDCD10 expression was positively correlated with MSH6 and PMS2 expressions ( r=0.262, P<0.001; r=0.327, P<0.001); qRT-PCR indicated that downregulated PDCD10 expression caused decreased MSH6 and PMS2 expressions, which disrupted the MMR system. (5) Compared with that by EV-U87 cells, number of neurospheres formed by shPDCD10-U87 cells was significantly increased ( P<0.05); compared with that by EV-U87-RG cells, number of neurospheres formed by shPDCD10-U87-RG cells was significantly increased ( P<0.05). Conclusion:PDCD10 affects the therapeutic sensitivity of GBM to TMZ by arresting cell cycle, disrupting MMR system, and increasing cell stemness.

Objective : To explore the differences of serum inflammatory cytokines and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains⁃2(Tie⁃2) levels between patients with first⁃episode schizophrenia and healthy people , and the correlation with clinical symptoms . Methods : A total of 168 participants were recruited , including 86 patients with first⁃episode schizophrenia (patient group) and 82 healthy people ( control group) . Demographic data , Positive and Negative Symptom Scale (PANSS) and Brief Psychiatric Rating Scale (PANSS) were collected at baseline . Serum inflammatory cytokines and Tie⁃2 levels were determined by MesoScale Discovery (MSD) . Results : Compared with the control group , the levels of serum interleukin (IL) Ⅳ1β and IL⁃4 in the patient group increased (P < 0. 05) , while the level of Tie⁃2 decreased (P < 0. 05) . IL⁃1β level in the patient group was positively correlated with the total score of BPRS , the score of BPRS hostility factor and the score of PANSS positive scale factor (P < 0. 05) . The positive score of PANSS and the total score of BPRS in the patient group had a positive effect on IL⁃1β level (P < 0. 05) . PANSS negative scale factor score , general psychopathological scale factor score and total score of PANSS in patient group also had positive effects on Tie⁃2 level (P < 0. 05) . IL⁃1β level in the patient group could effectively predict the severity of clinical symptoms in patients with first⁃episode schizophrenia at the critical level of 2 127. 076 pg/L , with specificity of 0. 675 and sensitivity of 0. 639 . The AUC of IL⁃1β and Tie⁃2 were 0. 836 1 and 0. 646 2 , respectively . Conclusion The levels of IL⁃1β , IL⁃4 and Tie⁃2 in patients with first⁃episode schizophrenia are different from those in healthy people . IL⁃1β levels in patients with first⁃episode schizophrenia are correlated with part of clinical symptoms . IL⁃1β and Tie⁃2 levels in the patient group may be influencing factors with high sensitivity and specificity in predicting the severity of clinical symptoms in patients with first⁃episode schizophrenia .

Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects. Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials. Previous studies have mainly focused on innate immune cells such as macrophages. In our previous work, we found that T lymphocytes, as adaptive immune cells, are also essential in the osteoinduction procedure. As the most important antigen-presenting cell, whether dendritic cells (DCs) can recognize non-antigen biomaterials and participate in osteoinduction was still unclear. In this study, we found that surgical trauma associated with materials implantation induces necrocytosis, and this causes the release of high mobility group protein-1 (HMGB1), which is adsorbed on the surface of bone substitute materials. Subsequently, HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells, and the inflammatory response was activated. Finally, activated DCs release regeneration-related chemokines, recruit mesenchymal stem cells, and initiate the osteoinduction process. This study sheds light on the immune-regeneration process after bone substitute materials implantation, points out a potential direction for the development of bone substitute materials, and provides guidance for the development of clinical surgical methods.
Biocompatible Materials/metabolism* ; HMGB1 Protein/metabolism* ; Myeloid Differentiation Factor 88/metabolism* ; Bone Substitutes/metabolism* ; Dendritic Cells/metabolism*

OBJECTIVE: To observe the effects of probiotics supplementation on the natural killer T cell (NKT cell) and inflammatory factors in children with sepsis and its protective effect on long-term lung function. METHODS: A total of 100 children with sepsis admitted to the department of pediatric intensive care unit (PICU) of Henan Provincial People's Hospital from March 2021 to May 2022 were selected as the research objects. The children were randomly divided into placebo group and probiotic group, 50 cases in each group. In addition to the conventional treatment, the probiotic group was given oral or nasal administration of 0.5 g probiotics, three times a day for 30 days, and the placebo group received oral placebo. 40 healthy children were selected as the healthy control group. The levels of interleukins (IL-4, IL-10), interferon-γ (IFN-γ) and immunoglobulin E (IgE), percentages of NKT cell in blood and induced sputum, lung function of the two groups of children with sepsis were measured before treatment, 7 days after treatment, and during follow-up. All these data were compared with those of healthy children. Kaplan-Meier analysis was used to compare the incidence of cough varied cough (CVA) between the two septic groups. Multiple linear regression analysis was used to explore the influence of various factors on the proportion of NKT cells in induced sputum. RESULTS: In the placebo group, 2 cases died and 4 cases were lost to follow-up. In the probiotics group, 3 cases died and 5 cases were lost to follow-up. All the inflammatory factors of two groups decreased slowly after 7 day after treatment. There was no significance in the parameters of the two groups, but the levels of probiotic group declined more evidently. During the follow-up, a further decrease of inflammatory factors in probiotic group could be found, the levels of IL-4 and IL-10 were significantly different from those in the placebo group [IL-4 (ng/L): 20.3±9.3 vs. 27.6±11.9, IL-10 (ng/L): 23.1±6.8 vs. 14.4±4.4, both P < 0.05], with a significant decrease in IgE level (μg/L: 53.0±15.6 vs. 64.2±16.9, P < 0.05]. The results of flow cytometry showed that the percentage of NKT cell in peripheral blood in two septic groups decreased gradually, and the proportion of peripheral blood NKT cells in the probiotics group was significantly lower than that in the placebo group after 7 days of treatment [(4.2±0.9)% vs. (5.3±1.2)%, P < 0.05]. In the follow-up, the level of NKT cell in peripheral blood and induced sputum in probiotic group were lower than the placebo group [peripheral blood: (0.024±0.009)% vs. (0.029±0.008)%, induced sputum: (0.025±0.008)% vs. (0.035±0.01)%, both P < 0.05], which were similar to those in the healthy control group. Meanwhile, the percentage of predicted peak expiratory (PEF%) and ratio of forced expiratory volume in one second/forced vital capacity (FEV1/FVC) of probiotic group were higher than those in the placebo group [PEF%: (91.3±4.8)% vs. (85.8±8.6)%, FEV1/FVC ratio: (91.8±4.7)% vs. (87.2±7.4)%, both P < 0.05]. Although there was no significance in the incidence of CVA between two septic groups according to the Kaplan-Meier curve analysis, multiple linear regression analysis showed mechanical ventilation and allergic history were the risk factors for the increase of NKT cells [β values were 0.584, 0.601, 95% confidence interval (95%CI) were 0.069 to 1.099, 0.011 to 1.192, P = 0.027, 0.046], and probiotics was an independent protective factor for the relieve of increase in NKT cells (β value was -0.984,95%CI was -1.378 to -0.591, P = 0.001). CONCLUSIONS Application of probiotics to septic children early could promote the recovery of NKT cell and inflammatory factors, and alleviate the lung function injury induced by them during follow-up, which is helpful to improve the long-term prognosis of the patients.
Child ; Humans ; Interleukin-10 ; Interleukin-4 ; Sepsis ; Probiotics/therapeutic use* ; Lung ; Cough ; Immunoglobulin E

The umbrella trial has received increasing attention in the design of clinical trials for oncology drugs in recent years. This trial design categorizes a single disease into multiple sub-types based on predictive biomarkers or other predictive factors, and simultaneously evaluates the efficacy of multiple targeted therapies. When compared with the traditional drug development model of phase Ⅰ, phaseⅡ, and phase Ⅲ randomized controlled trials, umbrella trials are a more scientifically rigorous trial design that can speed up drug evaluation to address the conflict between numerous untested drugs and diseases with a lack of effective treatment options. This article will focus on the concept, main characteristics, eligibility criteria, design and statistical considerations, ethical considerations, and future directions of umbrella trials, with the aim of providing methodological guidance for the design of clinical trials for oncology drugs.