Non-small cell lung cancer (NSCLC), as the predominant histological subtype of lung cancer, accounts for approximately 85% of all lung cancer cases. In recent years, immune checkpoint inhibitors (ICIs), represented by programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors, have achieved breakthrough advancements in patients with driver gene-negative NSCLC. They have been established as a key component of first-line treatment regimens and have significantly improved clinical outcomes. However, limited clinical evidence has emerged showing the phenomenon of histological transformation from NSCLC to small cell lung cancer (SCLC) in patients experiencing disease progression after ICIs monotherapy or combination therapy. Systematic research data on the clinical characteristics, molecular biological basis, and subsequent treatment strategies for such transformation events are currently lacking. This article reports a case of SCLC transformation occurring in a patient with KRAS-mutated lung adenocarcinoma after 16 months of ICIs combination therapy and provides a systematic review of 22 similar published cases. The study demonstrates that small cell transformation is a critical mechanism of immunotherapy resistance, and transformed patients exhibit poor prognosis. The research emphasizes the importance of dynamic monitoring of neuron-specific enolase (NSE) and standardized repeat biopsies during treatment, providing a basis for clinical practice. This aids in enhancing the recognition and management capabilities for this rare histological transformation, ultimately improving patient outcomes.
Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Lung Neoplasms/immunology* ; Carcinoma, Non-Small-Cell Lung/immunology* ; Small Cell Lung Carcinoma/genetics* ; Male ; Middle Aged ; Female

Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound RP20, which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning RP20 as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be elucidated. Serum creatinine (SCr) and blood urea nitrogen (BUN) were detected through pathological evaluation after CTD (1.5 mg/kg) oral gavage in mice in 3 days. Kidney lipidomics based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate lipids disorder after CTD exposure in mice. Then, spatial metabolomics based on matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to detect the kidney spatial distribution of lipids. Integrative analysis was performed to reveal the spatial lipid disorder mechanism and verify key lipids in vitro. The results showed that the levels of SCr and BUN were increased, and tubular necrosis was observed in mouse kidneys, resulting in acute tubular necrosis (ATN) in CTD-induced AKI. Then, lipidomics results revealed that after CTD exposure, 232 differential lipid metabolites and 11 pathways including glycerophospholipid (GP) and sphingolipid (SL) metabolism were disrupted. Spatial metabolomics revealed that 55 spatial differential lipid metabolites and nine metabolic pathways were disturbed. Subsequently, integrative analysis found that GP metabolism was stimulated in the renal cortex and medulla, whereas SL metabolism was inhibited in the renal cortex. Up-regulated lysophosphatidylcholine (LysoPC) (18:2(9Z,12Z)), LysoPC (16:0/0:0), glycerophosphocholine, and down-regulated sphingomyelin (SM) (d18:0/16:0), SM (d18:1/24:0), and SM (d42:1) were key differential lipids. Among them, LysoPC (16:0/0:0) was increased in the CTD group at 1.1196 μg/mL, which aggravated CTD-induced ATN in human kidney-2 (HK-2) cells. LysoPC acyltransferase was inhibited and choline phosphotransferase 1 (CEPT1) was activated after CTD intervention in mice and in HK-2 cells. CTD induces ATN, resulting in AKI, by activating GP metabolism and inhibiting SL metabolism in the renal cortex and medulla, LysoPC (16:0/0:0), LysoPC acyltransferase, and CEPT1 may be the therapeutic targets.

Objective To investigate the role and mechanism of silent information regulator 1(SIRT1)-NOD-like receptor protein 3(NLRP3)axis in the effect of remifentanil against ischemia-reperfusion injury(IRI)in rat livers.SD rats were randomly divided into sham operation group(sham group),IRI group,IRI+remifentanil pretreatment group(IRI+RPC group),IRI+SIRT1 inhibitor EX-527 group(IRI+EX-527 group)and IRI+RPC+EX-527 group,with 8 rats in each group.The levels of serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),lactate dehydrogenase(LDH),interleukin(IL)-1β and IL-18 of rats in each group were detected.The liver tissue pathology was observed.The apoptosis rate of hepatocytes in rats was detected.The expressions of SIRT1,NLRP3,cleaved cysteinyl aspartate specific proteinase-1(Cleaved Caspase-1)and Gasdermin D(GSDMD)proteins in rat liver tissue were detected.Results Compared with the sham group,the liver tissue pathological score and hepatocyte apoptosis rate of rats in the IRI group were increased,the serum ALT,AST,LDH,IL-1β,and IL-18 levels were increased,the relative expression of SIRT1 protein in liver tissue was decreased,and the relative expression of NLRP3,Cleaved Caspase-1,and GSDMD proteins were increased(all P<0.05).Compared with the IRI group,the liver tissue pathological score and hepatocyte apoptosis rate of rats in the IRI+RPC group were decreased,the serum ALT,AST,LDH,IL-1β,and IL-18 levels were decreased,the relative expression of SIRT1 protein in liver tissue was increased,and the relative expression of NLRP3,Cleaved Caspase-1,and GSDMD proteins were decreased;the liver tissue pathological score and hepatocyte apoptosis rate of rats in the IRI+EX-527 group were increased,the ALT,AST,LDH,IL-1β,and IL-18 levels were increased,the relative expression of SIRT1 protein in liver tissue was decreased,and the relative expression of NLRP3,Cleaved Caspase-1,and GSDMD proteins were increased(all P<0.05).Compared with the IRI+RPC group,the liver tissue pathological score and hepatocyte apoptosis rate in the IRI+RPC+EX-527 group were increased,the levels of ALT,AST,LDH,IL-1β,and IL-18 were increased,the relative expression of SIRT1 protein in liver tissue was decreased,and the relative expression of NLRP3,Cleaved Caspase-1,and GSDMD proteins were increased(all P<0.05).Conclusions SIRT1 may participate in the regulation of remifentanil against rat liver IRI by inhibiting NLRP3 mediated cell pyroptosis.

OBJECTIVE: To explore the toxicological mechanism of drug-induced liver injury(DILI) in rats induced by cantharidin(CTD). METHODS: SD rats were exposed to different doses of CTD(0.061 4, 0.092 1, 0.184 1 mg·kg−1) by oral gavage for 28 d. Liver index and serum liver function indictors were detected. HE staining was used to evaluate the pathological changes of liver. Then the proteins in endoplasmic reticulum stress(ERS), autophagy, and apoptosis-pathway were detected by Western blotting. RESULTS: The liver index was increased in CTD groups. The ALT, AST, LDH, ALP and T-Bil were increased by CTD with a dose-dependent manner. Disrupted hepatic architecture and dilatation of central vein were observed after CTD intervention. The protein expression levels of GRP78, CHOP, ATF4, Beclin-1, LC3, Caspase-3, Caspase-8, and Bax/Bcl-2 were increased after CTD intervention. Molecular docking results revealed that GRP78, ATF4, and Beclin-1 could directly interconnect with CTD. CONCLUSION CTD can activate ERS, autophagy and synergistically inducing downstream apoptosis in rat, providing a novel insight into the mechanism of CTD-induced DILI.

Nosocomial infection poses a significant threat to patient safety and increase their disease burden. Outbreaks of nosocomial infection are the main harmfulness associated with nosocomial infection, which making them socially sensitive issues. Nosocomial infection surveillance and warning are core contents of nosocomial infection management. Accurate early warning technology for nosocomial infection outbreaks can reflect the management capability of infection prevention and control. This study designed an early warning system based on a multi-dimensional and multi-scale comprehensive information surveillance mode for nosocomial infection outbreaks which was launched in March 2023. This system extracted the process-related indicators of nosocomial infection from various hospital information systems into the nosocomial infection database center. Under the multi-dimensional and multi-scale surveillance mode, the process-related data were stratified according to the predefined dimensions and scales, then generating time-series datasets of numerous subgroups. The system conducted weekly for all time-series datasets of subgroups based on warning rules, and subsequently sent out warning signals to managers. These warning signals could be verified by managers through data check, case verification and epidemiological investigation. Once a nosocomial infection outbreak was confirmed, intervention measures could be implemented promptly. In practical application, the system generated warning signals for nosocomial infection clusters in 12 departments on August 7th, 2023. The traditional nosocomial infection case report system ultimately reported 54 nosocomial infection cases, which distributed across 13 departments, with clusters(more than 3 cases) observed in 6 departments. All these 6 departments received warning signals generated from our system. It has been demonstrated that our system could predicted the nosocomial infection clusters 5.3 days earlier than the traditional nosocomial infection case report system on average, with warning sensitivity of 100.0% and positive predictive value of 50.0%. Early warning under the multi-dimensional and multi-scale comprehensive information surveillance mode was able to transform the work pattern of nosocomial infection outbreaks control and management from passive to active. Particularly it has advantages in early detection for occult outbreaks, providing a valuable support for improving nosocomial infection management capability.

Multiple myeloma(MM)is a malignant proliferative disease of plasma cells,ranking as the second most common hematologic tu-mor.Although the use of proteasome inhibitors and immunotherapeutic regimens has improved the prognosis of patients with MM,it re-mains incurable in most patients,mainly because of the eventual development of drug resistance in MM cells.Myeloid-derived suppressor cells(MDSCs)are a heterogeneous group of cells causing significant suppression of the T-cell immune response.They arise from bone mar-row myeloid progenitor cells that are blocked from differentiation and promote MM development by resisting immune destruction.Recent studies indicate that MDSCs stimulate MM cell proliferation,inducing drug resistance and metastasis.In this paper,we review multiple mechanisms exhibited by MDSCs in MM pathogenesis and discuss the feasibility and challenges of current therapeutic strategies targeting MDSCs,aiming to provide pertinent references regarding MM treatment.

Objective:An artificial intelligence(AI)model based on deep learning algorithms was constructed using clinical data to evaluate the feasibility of predicting the efficacy of neoadjuvant immunotherapy combined with chemotherapy for non-small cell lung cancer(NSCLC).Methods:Clinical and pathological data of 132 patients with NSCLC who were diagnosed and treated with neoadjuvant immunotherapy combined with chemotherapy between January 2020 and January 2024 at Beijing Chest Hospital/Beijing Tuberculosis and Thoracic Tumor Research Institute were collected.Statistical analysis was conducted to identify the main factors affecting the efficacy of neoadjuvant im-munotherapy combined with chemotherapy.Variables were selected based on statistical results and relevant literature,and a variable data-set was constructed.A deep learning model was established using a multi-layer perceptron(MLP)algorithm with 5-fold cross-validation,and the performance of the model was evaluated using receiver operating characteristic curve(ROC).Results:Among the 132 patients,univari-ate analysis demonstrated statistically significant differences in sex(P=0.020),smoking history(P=0.004),carcinoembryonic antigen(CEA)(P=0.038)and programmed death-ligand 1(PD-L1)≥1%(P=0.038)between the major pathological response(MPR)and non-MPR groups.Patients in the complete pathological response(pCR)group and non-pCR groups showed statistical differences in tumor size(P=0.007)and CEA levels(P=0.010).After 5-fold cross-validation,the average area under the curve(AUC)of the MPR prediction model in the validation and test sets was 0.72 and 0.71,respectively.Conclusions:The deep learning model can effectively predict the efficacy of neoadjuvant chemoim-munotherapy in patients with NSCLC.

Objective To design and test the reliability and validity of patient admission nursing assessment sheet of integrated Chinese and westem medicine ward.Methods On the basis of literature research,with traditional Chinese medicine"look,hear,ask and pulse-taking"as the basic framework,physical discrimination as the evaluation outcome,combined with the general nursing evaluation points of patients admitted to hospital,we designed the patient admission nursing assessment sheet of integrated Chinese and westem medicine ward,and then we adopted the Delphi method to conduct an inquiry on the draft of the admission sheet.In April 2022,3 clinical nurses were selected to evaluate 160 admitted patients from Integrated Traditional Chinese and Western Medicine Department of a tertiary A comprehensive hospital in Hubei Province,and Fleiss'Kappa coefficient and content validity coefficient were used to test the reliability and validity.Results The recovery rates of the 2 rounds of expert correspondence questionnaires were 95.45％and 100％.The authority coefficients were 0.931 and 0.957;the Kendall harmony coefficients were 0.101 and 0.106(P＜0.01);the importance scores of articles were 4.13～4.82;the coefficient of variation was 0.07～0.19 in 2nd round of expert correspondence.The final nursing assessment list for inpatients in the integrated Chinese and Western medicine ward included 3 parts:general demographic data assessment,four-Chinese medicine diagnosis assessment/physical discrimination,and nursing risk assessment,and there are 32 evaluation contents in the assessment sheet.The Fleiss'Kappa coefficient of this assessment sheet was 0.602(P＜0.001);the item content validity index was 0.857～1.000,and the overall content validity index was 0.920.Conclusion The admission nursing assessment sheet for inpatients in integrated Chinese and Westem medicine wards has good reliability and validity,and it is suitable for the integrated Chinese and Westem medicine wards.