Objective To explore the predictive value of two models based on machine learning algorithms in predicting the initial and subsequent doses of tacrolimus in kidney transplant recipients. Methods A retrospective analysis was conducted on the medical records of 1 013 Chinese kidney transplant recipients at the First Affiliated Hospital of Sun Yat-sen University from January 2015 to April 2019, focusing on the initial and subsequent doses in kidney transplant recipients. Thirty-three variables were collected for the initial dose, and twenty-six variables for the subsequent dose. A genetic algorithm combined with a random-restart hill-climbing algorithm was used to determine a small number of key clinical variables through majority voting, and variables with Lasso regression coefficients less than the optimal variable coefficient threshold were further eliminated. The selected clinical variables were input into a cascaded deep forest (CDF) and TabNet deep neural network for analysis and comparison based on structured tabular data, and the leave-one-subject-out method was used for validation. Results A total of 613 recipients were included in the training set, and 116 recipients were in the external validation set. In the initial dose algorithm of tacrolimus, the clinical variables ultimately included target concentration, time from surgery to target concentration, body weight, gender, type of surgery, time from surgery to first dose, WuZhi capsule, calcium channel blocker, creatinine, hemoglobin and CYP3A5. In the subsequent dose algorithm, the clinical variables ultimately included target concentration, time from surgery to target concentration, WuZhi capsule, creatinine, alanine aminotransferase, aspartate aminotransferase, previous dose, previous dose concentration and time from surgery to previous concentration. Based on the above variables, the TabNet model showed better predictive performance than the CDF model: in the initial dose prediction, the accuracy of the predicted dose within ±20% of the actual dose was 0.801, and the fitting index R² was 0.436; in the subsequent dose prediction, the corresponding accuracy and R² were 0.939 and 0.902, respectively. The results of feature contribution showed that CYP3A5 and target concentration contributed the most to the prediction of initial dose, while previous dose and its corresponding concentration had the greatest impact on subsequent dose prediction. In addition, the results of independent external validation were also satisfactory. Conclusions The optimized TabNet predictive model may provide important reference for drug dose prediction based on machine learning algorithms in clinical practice.

[This corrects the article DOI: 10.1016/j.apsb.2022.07.023.].

OBJECTIVE To elucidate the mechanisms responsible for the inhibitory effects of limonene on the proliferation of non-small cell lung cancer(NSCLC) by non-targeted metabolomics and additional approaches. METHODS The CCK-8 assay was utilized to evaluate the inhibitory effects of limonene on NSCLC A549 cell viability and to ascertain the IC50. In vitro experiments, encompassing colony formation, flow cytometry, iron content assessment, and mitochondrial staining, were conducted to assess the anti-lung cancer and iron-induced cell death effects of limonene. Metabolomic analysis was employed to identify potential pathways influenced by limonene, and Western blotting was carried out to validate pivotal proteins within these pathways. RESULTS In comparison to the control group, the limonene-treated group demonstrated a significant, dose-dependent reduction in A549 cell proliferation and colony formation. Optical microscopy revealed cellular detachment and pronounced changes in cellular morphology following exposure to limonene. Limonene induced apoptosis in A549 cells and arrested them in the G0-G1 phase of the cell cycle. Confocal microscopy unveiled diminished mitochondrial fluorescence and an augmented intracellular iron content, indicative of the classical phenomenon of ferroptosis. Metabolomic investigations unveiled divergent metabolic pathways, including glutathione(GSH) metabolism, arginine biosynthesis, D-glutamine and D-glutamate metabolism, as well as cysteine and methionine metabolism, with many of them intricately linked to intracellular GSH synthesis. Western blotting experiments underscored a marked reduction in the levels of SLC40A1, SLC7A11(xCT), and GPX4 proteins within the cells post-limonene treatment. CONCLUSION Limonene may induce ferroptosis in lung cancer cells by reducing GSH synthesis and increasing Fe2+ levels.

Objective:To evaluate the efficacy and safety of pembrolizumab plus nab-paclitaxel and platinum as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC).Methods:This was a prospective, single-arm, open label, phase 2 clinical study enrolling patients at the Cancer Hospital of the Chinese Academy of Medical Sciences with R/M HNSCC treated with pembrolizumab plus nab-paclitaxel and cisplatin or carboplatin. After six cycles of treatment, patients received pembrolizumab as maintenance therapy until disease progression or intolerable toxicity or completion of 35 cycles of treatment. The primary endpoint was objective response rate, and secondary endpoints included overall survival, progression-free survival, and safety profile. Efficacy was evaluated according to the response evaluation criteria in solid tumors 1.1, survival analysis was performed using the Kaplan-Meier method, and adverse events were assessed using the America National Cancer Institute Common Terminology Criteria for Adverse Events 5.0.Results:A total of 30 patients with R/M HNSCC were enrolled from 23 April 2021 to 22 March 2023, including 28 males and 2 females, with a median age of 67 years. The median follow-up time was 14.5 months, the objective response rate was 70.0%, the disease control rate was 96.7%, and the median progression-free survival and overall survival of all patients were 11.6 months and 18.8 months, respectively. Median duration of response was up to 17.3 months. Grade≥3 treatment-related adverse events were leukopenia (26.7%), neutropenia (26.7%), peripheral neurotoxicity (3.3%), rash (3.3%), hyperalgesia (3.3%), and immune-related pneumonitis (3.3%). The most common immune-related adverse event was hypothyroidism (40.0%).Conclusion:Pembrolizumab combined with nab-paclitaxel and platinum shows encouraging antitumor activity accompanied with a manageable safety profile in untreated R/M HNSCC patients in China.

Objective:To investigate the effects of intra-articular injection of exosomes derived from dental pulp stem cells from hu-man exfoliated deciduous teeth(SHED-EXO)on subchondral bone homeostasis in rat temporomandibular joint osteoarthritis(TMJ OA)process.Methods:36 male SD rats were randomly divided into 3 groups(n=12):control(CON),sodium iodoacetate(MIA)-induced TMJ OA(MIA),and SHED-EXO injection into TMJ OA(SHED-EXO)groups.At 2 and 6 weeks post-treatment,Micro-CT,Double labeling,TRAP staining,and immunohistochemical staining were employed to detect osteoclasts and osteoblasts in the subchondral bone.Additionally,the mRNA expression levels of ADAMTs5,IL-1β,OCN and OPG/RANKL were analyzed by qRT-PCR.Results:The MIA group exhibited significant bone loss and an enlarged bone marrow cavity.In comparison with the CON group,BV/TV and Tb.Th were lower(P＜0.001),while BS/BV,Tb.Sp,and Tb.N were higher(P＜0.01).Additionally,the bone formation rate within 5 days was low-er than that of the control group(P＜0.001).When compared to the MIA group,the SHED-EXO group showed a significant increase in bone morphology and bone mass.BV/TV and Tb.Th were increased(P＜0.01),while BS/BV,Tb.Sp and Tb.N were decreased(P＜0.05).The bone formation rate was higher(P＜0.01).Compared with both the control and treatment groups,the MIA group exhibited a significant increase in the number of osteoclasts in the subchondral bone(P＜0.01),along with a notable decrease in H-type blood vessels and OCN-positive areas(P＜0.01).Conclusion:Intra-articular injection of SHED-EXO can reg-ulate condylar subchondral bone homeostasis in TMJ OA of rats by promoting osteogenesis and inhibiting osteoclasts.

Loganin(LOG),a bioactive compound derived from Cornus officinalis Siebold & Zucc,has been understudied in the context of osteoarthritis(OA)treatment.In this study,we induced an inflammatory response in chondrocytes using lipopolysaccharide(LPS)and subsequently treated these cells with LOG.We employed fluorescence analysis to quantify reactive oxygen species(ROS)levels and measured the expression of NLRP3 and nuclear factor erythropoietin-2-related factor 2(NRF2)using real-time quantitative polymerase chain reaction(qRT-PCR),Western blotting,and immunofluorescence(IF)techniques.Additionally,we developed an OA mouse model by performing medial meniscus destabilization(DMM)surgery and monitored disease progression through micro-com-puted tomography(micro-CT),hematoxylin and eosin(H&E)staining,safranin O and fast green(S&F)staining,and immunohisto-chemical(IHC)analysis.Our results indicate that LOG significantly reduced LPS-induced ROS levels in chondrocytes,inhibited the activation of the NLRP3 inflammasome,and enhanced NRF2/heme oxygenase 1(HO-1)signaling.In vivo,LOG treatment mitigated cartilage degradation and osteophyte formation triggered by DMM surgery,decreased NLRP3 expression,and increased NRF2 expres-sion.These findings suggest that LOG has a protective effect against OA,potentially delaying disease progression by inhibiting the ROS-NLRP3-IL-1β axis and activating the NRF2/HO-1 pathway.

Humans ; Aripiprazole/therapeutic use* ; Schizophrenia/drug therapy* ; Antipsychotic Agents/therapeutic use* ; Risperidone ; China ; Treatment Outcome

As a promising modality for cancer therapy, photodynamic therapy (PDT) still acquired limited success in clinical nowadays due to the extremely serious hypoxia and immunosuppression tumor microenvironment. To ameliorate such a situation, we rationally designed and prepared cascade two-stage re-oxygenation and immune re-sensitization BSA-MHI148@SRF nanoparticles via hydrophilic and hydrophobic self-assembly strategy by using near-infrared photodynamic dye MHI148 chemically modified bovine serum albumin (BSA-MHI148) and multi-kinase inhibitor Sorafenib (SRF) as a novel tumor oxygen and immune microenvironment regulation drug. Benefiting from the accumulation of SRF in tumors, BSA-MHI148@SRF nanoparticles dramatically enhanced the PDT efficacy by promoting cascade two-stage tumor re-oxygenation mechanisms: (i) SRF decreased tumor oxygen consumption via inhibiting mitochondria respiratory. (ii) SRF increased the oxygen supply via inducing tumor vessel normalization. Meanwhile, the immunosuppression micro-environment was also obviously reversed by two-stage immune re-sensitization as follows: (i) Enhanced immunogenic cell death (ICD) production amplified by BSA-MHI148@SRF induced reactive oxygen species (ROS) generation enhanced T cell infiltration and improve its tumor cell killing ability. (ii) BSA-MHI148@SRF amplified tumor vessel normalization by VEGF inhibition also obviously reversed the tumor immune-suppression microenvironment. Finally, the growth of solid tumors was significantly depressed by such well-designed BSA-MHI148@SRF nanoparticles, which could be potential for clinical cancer therapy.

Objective:To investigate the correlation between three-dimensional histogram analysis of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)and Gleason score(GS)in prostate cancer(Pca)from two hospital, and its diagnostic efficacy for discriminating low-grade from high-grade Pca.Methods:A total of 102 pathologically confirmed Pca patients in the First Affiliated Hospital of Zhejiang Chinese Medical University and Hangzhou Traditional Chinese Medical Hospital(TCM Hospital)Affiliated to Zhejiang Chinese Medical University from January 2017 to October 2020 were retrospectively analyzed.The quantitative parameters of Pca, including transport constant(K trans), rate constant(K ep), percent volume of the extravascular extracellular space(V e)and fraction of the Intraplasmic contrast volume(V p), were obtained by manually layer by layer delineating of interested regions of all lesions on the original DCE-MRI imaging.Then the three-dimensional histogram analysis of the above parameters were performed to obtain the minimum, maximum, median, mean, area, 10 thpercentile, 25 thpercentile, 75 thpercentile and 90 thpercentile.The correlations between quantitative parameters and GS, and diagnostic efficiencies were analyzed. Results:102 Pca patients were divided into low-grade prostate cancer group(GS≤3+ 4)(n=44)and high-grade Pca group(GS≥4+ 3)(n=58). There were no statistically significant differences in age and location of lesions between the two groups( P>0.05), but there were statistically significant differences in Gleason score, PSA level and lesion diameter between the two groups( U=0.000, 730.000, 711.000, all P<0.05). The median, mean, 10 thpercentile, 25 thpercentile, 75 thpercentile, 90 thpercentile derived from K trans, and K ep(median, mean, 10%, 25%, 75%, 90%)together with maximum of K transand mean for V e were positively correlated with GS( r=0.405 to 0.583, P<0.05), in which mean of K transhad the highest positive correlation( r=0.583, P=0.000). The histogram parameters derived from V pwere negatively correlated with GS( r=-0.301 to 0.341, P<0.05). The area under ROC of 75th percentile derived from K transwas the highest(0.832). When the cut-off value of 75 thpercentile derived from K transwas ≥0.680/min, its Youden index, sensitivity, and specificity were 0.594, 0.776, 0.818, respectively. Conclusions:The three-dimensional histogram of DCE-MRI quantitative parameters has correlation with GS in Pca patients, can be used to discriminate low-grade from high-grade Pca.

Onodera prognostic nutrition index (OPNI) is a simple and effective parameter. It is calculated by serum albumin level and peripheral blood lymphocyte count. Initially, OPNI is used to assess preoperative nutritional status and surgical risk. In recent years, researchers have found that OPNI is related to the prognosis of many tumors. Simple and accurate prognosis evaluation can help to select treatment methods for digestive system malignant tumors, determine the best pre-operative treatment time and operation time, and improve the survival rate of patients with diges-tive system malignant tumors. The authors review the related literatures at home and abroad, and summarize the research advances in the prognostic value of OPNI for malignant tumors of digestive systems.