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 compare the effects of 3 rehydration methods before blood donation on the prevention of on-site and delayed blood donation-related vasovagal response (VVR) . 【Methods】 From January to June 2021, 6 250 whole blood donors in 6 fixed blood donation sites signed informed consent and were divided into 198 clusters according to donor sites and dates, then they were randomly assigned to receive either oral rehydration salts (ORS), sugar water, or water group, and each drank 500 mL of ORS, sugar water or water within 20 minutes before blood donation. The researchers recorded the actual intervention accepted on site, and recorded the immediate VVR and related information. At rest after blood donation, donors submitted an electronic questionnaire containing socio-demographic information. At 48 hours after blood donation, the researchers called back every donor to record delayed VVR and related information. Logistic regression based on intention to treat (ITT) was used to analyze the difference of the incidence of VVR among the three groups, and the average treatment effect on treated (ATT) was calculated. PASS 2021was used to estimate the sample size and R (4.2.0) for statistical analysis. 【Results】 The cumulative incidence of blood donation-related VVR was 2.67% (2.29%-3.11%) among street whole blood donors under the 3 rehydration methods, in which, the incidence of immediate and delayed VVR was 1.02% (0.79%-1.31%) and 1.65% (1.36%-2.01%) respectively. ITT analysis found that ORS were more effective than water in reducing the incidence of delayed VVR【OR=0.59,95% CI[0.37,0.94]】.There was no significant difference in the incidence of immediate VVR between any two groups (P > 0.05), and there was no significant difference in the incidence of delayed VVR in the sugar water group compared with the water group (P > 0.05). There was a difference of -0.013 (【95% CI[-0.022, -0.004]】or -0.008【95% CI[-0.017, -0.000]】in the incidence of delayed VVR in the ORS group compared with water group or sugar water group, the difference was significant (P<0.05). The cumulative VVR of the three groups showed similar results to the delayed VVR. 【Conclusion】 Drinking ORS before blood donation is the most effective rehydration method to prevent delayed VVR. The next step is to establish the predictive model of delayed VVR to screen the susceptible population and provide them with ORS before blood donation, while other population can choose any liquid they like, thus achieving personalized blood donation-related VVR prevention and control.

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.

Objective:To systematically review and evaluate the effect of intraoperative regional cerebral oxygen saturation (rSO 2) monitoring on perioperative neurocognitive disorders (PNDs) in elderly patients undergoing non-cardiac surgery. Methods:China National Knowledge Infrastructure, Wanfang Database, China Biomedical Literature Database, China Science and Technology Journal Database, PubMed, Cochrane Library, Embase and Web of Science databases were searched from inception to October 2022 for randomized controlled trials involving the effects of intraoperative rSO 2 monitoring on PND in elderly patients underwent non-cardiac surgery. The primary outcome measure was the incidence of PND (1-7 days after surgery), and secondary outcome measures were intraoperative minimum rSO 2 (rSO 2min), intraoperative mean rSO 2 (rSO 2mean), maximum percentage of decrease (rSO 2% max) in rSO 2 from baseline (rSO 2baseline), and the Montreal Cognitive Assessment Scale was used to evaluate the quality of references that met the inclusion criteria, and data were extracted for meta-analysis using RevMan5.4 software. Results:Thirteen randomized controlled trials were enrolled, involving 1 134 patients with 557 patients in experimental group (anesthesia under rSO 2 monitoring) and 577 patients in control group. The results of meta-analysis showed that the incidence of PND was significantly lower in experimental group than in control group ( RR=0.32, 95% confidence interval [ CI] 0.25-0.41, P<0.001), the intraoperative rSO 2min was significantly higher in experimental group than in control group ( MD=7.46, 95% CI 5.05-9.86, P<0.001), and the intraoperative rSO 2mean was significantly higher in experimental group than in control group ( MD=5.49, 95% CI 3.97-7.02, P<0.001), the intraoperative rSO 2% max was significantly lower in experimental group than in control group ( MD=-6.55, 95% CI-9.03--4.07, P<0.001), and the postoperative Montreal Cognitive Assessment Scale score was significantly higher in experimental group than in control group ( MD=1.37, 95% CI 0.74-1.99, P<0.001). Conclusions:Intraoperative application of rSO 2 monitoring can reduce the occurrence of PND in elderly patients undergoing non-cardiac surgery.

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*

Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenomenon.We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells(NPCs)in autoprotection against DILI,using acetaminophen(APAP)as a model drug.Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice,followed by a higher dose in a secondary challenge.NPC subsets and dynamic changes were identified in the APAP(hepatotoxicity-sensitive)and APAP-resistant(hepatotoxicity-resistant)groups.A chemokine(C-C motif)ligand 2+endothelial cell subset almost disappeared in the APAP-resistant group,and an R-spondin 3+endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection.Moreover,the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation.DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group.In addition,the natural killer cell subsets NK-3 and NK-4 and the Sca-1-CD62L+natural killer T cell subset may promote autoprotection through interferon-y-dependent pathways.Furthermore,macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity.Overall,this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.

China is stepping up its standardized management of investigator initiated trials(IIT)carried out by medical and health institutions, spotlighting the establishment and improvement of the quality control system of IIT projects than ever before. The authors retrieved official websites of clinical research related units of medical institutions and research institutes at home and abroad, and by means of literature review analyzed the current quality management of IIT projects at home and abroad. They found such setbacks as lack of quality management standards and norms, imperfect quality control mechanism, poor awareness of quality risk, insufficient quality supervision and poor quality control ability of clinical researchers. Based on the above, the paper made the following recommendations for building an IIT project quality control system in China: developing quality management standards and norms, setting up a systematic quality control mechanism(i.e., exploring a three-level quality control mode composed of the project team/department-hospital-national supervision institution/peer review expert team, and implementing the whole process quality control mechanism), strengthening policy guidance and system construction, and strengthening the standardized training of clinical researchers.

Objective:To analyze the clinicopathological features in diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) patients, and provide reference for patients who will receive renal biopsy with diabetes mellitus complicated with chronic kidney disease.Methods:The patients with type 2 diabetes mellitus complicated with chronic kidney disease who underwent renal biopsy were collected through the database at the Nanfang Hospital of Southern Medical University from February 2002 to June 2018. According to the results of renal biopsy, they were divided into DKD group and NDKD group (including DKD+NDKD). The clinical manifestations and pathological types were compared between the two groups.Results:A total of 507 patients were eventually included in the study. There were 114 cases (22.5%) with DKD and 393 cases (77.5%) with NDKD. Pathologically, the most common pathological types of NDKD were membranous nephropathy (30.0%) and IgA nephropathy (19.1%). Among NDKD patients, 5.6% patients had DKD combing with NDKD. In term of the clinical manifestations, DKD patients had a longer history of diabetes (>1 year, 76.3% vs 36.1%, P<0.001), higher quantity of urinary protein [3.69(1.70, 6.74) g/24 h vs 2.21(0.91, 4.97) g/24 h, P<0.001], higher serum creatinine [117.5(85.8, 194.5) μmol/L vs 89.0(68.0, 143.8) μmol/L, P<0.001] than NDKD patients. But the hemoglobin [(105.07±20.85) g/L vs (124.41±25.02) g/L, P=0.002] and cholesterol [(5.69±1.87) mmol/L vs (6.43±2.75) mmol/L, P=0.001] in DKD patients were lower than those in NDKD patients. Logistic regression analysis showed that diabetes mellitus history ( OR=4.162, 95% CI 1.717-10.098, P=0.002) , higer systolic pressure (every 1 mmHg, OR=1.028, 95% CI 1.011-1.045, P=0.001) , history of antihypertensive medication ( OR=3.141, 95% CI 1.496-6.591, P=0.002), diabetic retinopathy ( OR=5.561, 95% CI 2.361-13.100, P<0.001) and higher glycated hemoglobin level (every 1%, OR=1.680, 95% CI 1.333-2.118, P<0.001) were related factors of DKD, while hematuria ( OR=2.781, 95% CI 1.334-5.798, P=0.006) and higher hemoglobin level (every 1 g/L, OR=1.022, 95% CI 1.008-1.037, P=0.002) were related factors of NDKD. Conclusions:There are differences in clinical manifestations and pathological types between DKD and NDKD. The history of diabetes, antihypertensive medication, fundus examination, higher of proteinuria and glycosylated hemoglobin may predict DKD, while hematuria and higher level of hemoglobin may have certain guiding significance for the diagnosis of NDKD. The indication of renal biopsy in patients with diabetes mellitus complicated with chronic kidney disease should include comprehensive clinical manifestations.

The incidence of primary intestinal lymphoma (PIL) in primary gastrointestinal lymphoma (PGIL) is much lower than that of primary gastric lymphoma (PGL). Treatment strategies for PGL have been normalized, but there are still controversies concerning about the diagnosis criteria and optimal treatment of PIL. The lesions are mainly found in intestinal tract, and the most common involvement is ileocecal junction. The pathological types are derived from B-cell and diffuse large B-cell lymphoma (DLBCL) is the most common type, followed by extra-nodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Surgery, chemotherapy, radiotherapy, antibiotics and monoclonal antibody therapy could be used as the monotherapy or different combined therapies, however, the final conclusion has not been reached in the treatment of PIL, accompanied by various influencing factors for prognosis. This review discusses the diagnosis criteria, clinical features, optimal treatment and prognostic factors of PIL. The diagnosis criteria and the optimal treatment will be put more emphasis.

Objective: To investigate the clinical characteristics, treatment regimens, and outcomes of patients with primary breast dif-fuse large B-cell lymphoma (PB-DLBCL). Methods: Between January 2010 and January 2018, 21 patients with PB-DLBCL were diag-nosed, treated, and followed up at the First Affiliated Hospital of Zhengzhou University. All patients were female, with a median age of 49 years (ranging from 21 to 77 years) at presentation. All patients received chemotherapy, of which 17 patients received the CHOP regimen and 4 received the EPOCH regimen. Eight patients received chemotherapy followed by radiotherapy, and 13 received chemo-therapy alone. Six patients received prophylactic intrathecal injections. The incidences of refractory and progressive disease between patients who received different regimens were analyzed using the Chi-square test. The overall survival (OS) and progression-free sur-vival (PFS) rates were calculated using the Kaplan-Meier method, and differences in survival were compared using the Log-rank test. Multivariate analysis was performed with the Cox-regression model for those factors that were confirmed as significant in the univari-ate analysis. Results: The most common presentation was a painless mass. The 5-year OS and PFS rates were 74% and 66%, respective-ly. There was no significant difference in the incidence of refractory or progressive disease between the EPOCH and CHOP groups (P=0.603). Six of those who received prophylactic intrathecal injections had no central nervous system recurrence, and 2 patients who did not receive prophylactic intrathecal injections had central nervous system recurrence. Univariate and multivariate analyses showed that both the level of serum β2 microglobulin [P=0.044, hazard ratio (HR)=0.431, 95% confidence interval (CI): 0.432-0.967] and radio-therapy (P=0.002, HR=0.495, 95% CI: 1.073-2.508) were related to the OS of PB-DLBCL. Conclusions: PB-DLBCL often occurs in women, mostly involving the unilateral breast, which manifests mainly as a painless mass. The level of serum β2 microglobulin is a factor of poor prognosis in PB-DLBCL. The treatment modality of chemotherapy combined with radiotherapy can significantly improve the OS of PB-DLBCL. Prophylactic intrathecal injections may be useful to reduce the incidence of refractory disease or recurrence in the central nervous system.