Research advances in traditional Chinese medicine regulation of programmed cell death in intervening against hepatic fibrosis / 临床肝胆病杂志

Hepatic fibrosis （HF） is a pathological process of abnormal repair of liver tissue structure caused by chronic liver injury， and its pathogenesis has not been fully clarified. Related studies have shown that programmed cell death may be associated with the onset of HF， and traditional Chinese medicine （TCM） has a significant effect in regulating programmed cell death to intervene against HF. This article reviews the main mechanism of the influence of programmed cell death on HF and discusses the possible mechanism of TCM regulation of programmed cell death in improving HF， which provides new ideas for TCM prevention and treatment of HF.

Construction and self-activation detection of yeast two-hybrid bait plasmid of human programmed cell death ligand 1 immunoglobulin variable region domain gene / 中国生物制品学杂志

@#Objective To construct a yeast two-hybrid recombinant bait plasmid of human programmed cell death ligand 1(PD-L1)immunoglobulin variable region(IgV)domain gene,detect its expression in yeast and detect the cytotoxicity and self-activation of PD-L1 IgV protein as well as the interaction between PD-L1 IgV and human thioredoxin(hTrx).Methods Human PD-L1 was analyzed by bioinformatics method,and primers were designed to amplify PD-L1 IgV domain based on the coding region of PD-L1 gene registered in NCBI GenBank database. PCR amplification was carried out with pENTERPD-L1 plasmid as template,and then cloned into yeast two-hybrid bait vector pGBKT7. The recombinant bait plasmid and pGBKT7 empty vector were transformed into Y2HGold yeast cells respectively,and the PD-L1 IgV gene and its expression were detected by PCR and Western blot;Meanwhile,the protein toxicity and self-activation of PD-L1 IgV were detected,and the interaction between PD-L1 IgV and hTrx was detected by drip plate method.Results The bioinformatics analysis results of PD-L1 were consistent with related reports. The recombinant bait plasmid pGBKT7-PD-L1 IgV was correctly constructed,and Y2HGold positive clone was obtained,in which PD-L1 IgV was stably expressed. The empty vector pGBKT7 and recombinant bait plasmid pGBKT7-PD-L1 IgV grew well on SD/-Trp and SD/-Trp/X-α-Gal plates with the same colony size and number and white colony,but they did not grow on SD/-Trp/X-α-Gal/AbA plates,which indicated that PD-L1 IgV protein had no toxicity and no self-activation effect on yeast. The results of drip plates test showed that all experimental groups grew well on SD/-Trp/-Leu plate,while only positive control group grew on SD/-Trp/-Leu/X-α-Gal/AbA plate and showed blue color,which indicated that bait protein PD-L1 IgV and hTrx did not self-activate,and there was no interaction between them.Conclusion Recombinant human PD-L1 IgV bait plasmid was successfully constructed. PD-L1 IgV protein showed no toxicity and self-activation effect on yeast cells,and there was no interaction between PD-L1 IgV and hTrx. Subsequently,hTrx can be used to construct a peptide aptamer library,from which peptide aptamers that specifically bind to PD-L1 IgV can be screened.

Quercetin Alleviates Lipopolysaccharide-Induced Cardiac Inflammation via Inhibiting Autophagy and Programmed Cell Death / 生物医学与环境科学（英文）

OBJECTIVE@#The aim of this study is to explore the potential modulatory role of quercetin against Endotoxin or lipopolysaccharide (LPS) induced septic cardiac dysfunction.@*METHODS@#Specific pathogen-free chicken embryos ( n = 120) were allocated untreated control, phosphate buffer solution (PBS) vehicle, PBS with ethanol vehicle, LPS (500 ng/egg), LPS with quercetin treatment (10, 20, or 40 nmol/egg, respectively), Quercetin groups (10, 20, or 40 nmol/egg). Fifteen-day-old embryonated eggs were inoculated with abovementioned solutions via the allantoic cavity. At embryonic day 19, the hearts of the embryos were collected for histopathological examination, RNA extraction, real-time polymerase chain reaction, immunohistochemical investigations, and Western blotting.@*RESULTS@#They demonstrated that the heart presented inflammatory responses after LPS induction. The LPS-induced higher mRNA expressions of inflammation-related factors (TLR4, TNFα, MYD88, NF-κB1, IFNγ, IL-1β, IL-8, IL-6, IL-10, p38, MMP3, and MMP9) were blocked by quercetin with three dosages. Quercetin significantly decreased immunopositivity to TLR4 and MMP9 in the treatment group when compared with the LPS group. Quercetin significantly decreased protein expressions of TLR4, IFNγ, MMP3, and MMP9 when compared with the LPS group. Quercetin treatment prevented LPS-induced increase in the mRNA expression of Claudin 1 and ZO-1, and significantly decreased protein expression of claudin 1 when compared with the LPS group. Quercetin significantly downregulated autophagy-related gene expressions (PPARα, SGLT1, APOA4, AMPKα1, AMPKα2, ATG5, ATG7, Beclin-1, and LC3B) and programmed cell death (Fas, Bcl-2, CASP1, CASP12, CASP3, and RIPK1) after LPS induction. Quercetin significantly decreased immunopositivity to APOA4, AMPKα2, and LC3-II/LC3-I in the treatment group when compared with the LPS group. Quercetin significantly decreased protein expressions of AMPKα1, LC3-I, and LC3-II. Quercetin significantly decreased the protein expression to CASP1 and CASP3 by immunohistochemical investigation or Western blotting in treatment group when compared with LPS group.@*CONCLUSION@#Quercetin alleviates cardiac inflammation induced by LPS through modulating autophagy, programmed cell death, and myocardiocytes permeability.

Research progress in RIPK3 and its inhibitors / 中国药理学通报

Receptor-interacting serine/threonine-protein kinase 3(RIPK3),a member of the RIP kinase family,plays an important role in cell death,especially in necroptosis. In addition,RIPK3 is also involved in apoptosis and pyroptosis,suggesting that RIPK3 may be the intersection of multiple cell death and it possesses the potential to be a target for precise regulation of cell death. According to the kinase binding mode,current RIPK3 inhibitors can be classified into type ,type Ⅱ and other types. This review summarizes the research progress in the role of RIPK3 in cell death and its inhibitors,which is of great significance in seeking drugs for the treatment of injury-related diseases.

Research progress in ferroptosis pathways and ubiquitination modification of ferroptosis-related molecules / 中国药理学通报

Ferroptosis is an iron-dependent cell death caused by phospholipid peroxidation damage of polyunsaturated fatty acids on cell membranes and involves several pathways, including the iron homeostasis regulatory pathway, the cystine glutamate reverse transporter (system Xc) pathway and the voltage-dependent anion channel (VDAC) pathway. Ferroptosis is involved in the development of several diseases (e. g. myocardial infarction, stroke, cancer and degenerative diseases). The ubiquitination is an important post-translational modification of various protein molecules in the organism. Studies have shown that regulating the ubiquitination of ferroptosis pathway-related molecules can control cellular ferroptosis. Targeting the ubiquitination of ferroptosis pathway-related molecules can effectively promote or inhibit ferroptosis, which is expected to be a new strategy for the treatment of cancer or cardiovascular diseases. In this paper we review the progress of the ferroptosis pathways and the ubiquitination modification of ferroptosis-related molecules.

Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses

Radiotherapy (RT) can potentially induce systemic immune responses by initiating immunogenic cell death (ICD) of tumor cells. However, RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases. Herein, we construct multifunctional self-sufficient nanoparticles (MARS) with dual-enzyme activity (GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse. In addition to limiting the Warburg effect to actualize starvation therapy, MARS catalyzes glucose to produce hydrogen peroxide (H2O2), which is then used in the Cu+-mediated Fenton-like reaction and RT sensitization. RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms, which have a robust ICD impact on mobilizing the immune system. Thus, when MARS is combined with RT, potent systemic antitumor immunity can be generated by activating antigen-presenting cells, promoting dendritic cells maturation, increasing the infiltration of cytotoxic T lymphocytes, and reprogramming the immunosuppressive tumor microenvironment. Furthermore, the synergistic therapy of RT and MARS effectively suppresses local tumor growth, increases mouse longevity, and results in a 90% reduction in lung metastasis and postoperative recurrence. Overall, we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Histopathological examination of the protective effect of intense exercise in apoptotic germ cell damage due to diabetes

Purpose: The aim of this study was to determine the protective and antioxidative effects of intensive exercise on streptozotocin (STZ)-induced testicular damage, apoptotic spermatognial cells death, and oxidative stress. Methods: 36 male Sprague Dawley rats were divided into three groups: control, diabetes, and diabetes+intensive exercise (IE) groups. Testicular tissues were examined histopathologically and antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) activity, as well as serum testosterone level, were measured. Results: Seminiferous tubules and germ cells were found to be better in the testis tissue of the intense exercise group than in the diabetes group. Diabetes suppressed antioxidant enzymes CAT, SOD, GPx and testosterone levels were significantly decreased, and increased MDA level in the diabetic group compared to diabetes+IE group (p < 0.001). Following four weeks of treatment, intensive exercise improved the antioxidant defense, significantly decreased MDA activity, and increased testosterone levels in testicular tissue in the diabetic group compared to diabetes+IE group (p < 0.01). Conclusion: STZ-induced diabetes causes damage to the testis tissue. In order to prevent these damages, exercise practice has become very popular nowadays. In present study, our intensive exercise protocol, histological, and biochemical analysis of the effect of diabetes on the testicular tissues is shown.

Supervivencia extendida con pembrolizumab en un paciente con cáncer de pulmón no microcítico estadio IV: Reporte de caso / Extendedsurvival with pembrolizumab in a patient with stage IV non-small cell lung cancer:A case report

Introducción:La inmunoterapia con pembrolizumab ha mejorado el pronóstico del cáncer de pulmón metastásico. En el presente caso se presenta la supervivencia extendidad y evolución de un paciente específico.Caso clínico:Hombre de 66 años, fumador. Diagnosticado de masa pulmonar en lóbulo infe-rior izquierdo de dimensiones 9 x 8 cm, con metástasis supra e infratentoriales intraaxiliares. Taller diagnóstico: Establecida como neoplasia de pulmón en estadio IVc, se comprobó el estado de PDL1 que positivo en un 80 % de la muestra de masa pulmonar. Debuta con me-tástasis cerebrales.Evolución: Se inció inmunoterapia con Pembrolizumab, el cual se mantubo hasta la presencia de un efecto secundario atribuido al pembrolizumab, cumpliendo 30meses de supervivencia hasta el cierre de esta observación no se reportó la muerte del paciente.Conclusiones:En el presente reporte, la determinación del biomarcador histológico PDL1 po-sitivo en cáncer de pulmón ayudo a prescribir un tratamiento con inmunoterpia dirigida, lo que demostró aumentar la supervivencia más allá que el tratamiento convencional con quimiote-rapia

Introduction: Immunotherapy with pembrolizumab has improved the prognosis of metastatic lung cancer. A specific patient's extended survival and evolution is presented in the present case.Clinical case: 66-year-old man, smoker. Diagnosed with a lung mass in the left lower lobe measuring 9 x 8 cm, with supra and infratentorial intra-axial metastases.Diagnostic workshop: To establisha stage IVc lung neoplasm, 80% of the lung mass sample was confirmed to be positive for PDL1.Evolution: Immunotherapy was started with Pembrolizumab, which was maintained until the presence of a side effect attributed to pembrolizumab, completing 30 months of survival until the closure of this observation, the patient's death was not reported.Conclusions: In the present report, the determination of the positive histological biomarker PDL1 in lung cancer helped prescribe treatment with targeted immunotherapy, which was shown to increase survival beyond conventional treatment with chemotherapy

Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy

Abstract Programmed Cell Death-1 (PCD-1) is a key immune checkpoint receptor, which mainly expresses on activated T, B, Dendritic (DC), Natural Killer (NK), and Treg cells. On the surface of activated T-cells, PCD-1 expression is upregulated after the recognition of peripherals antigens by T cells; subsequently, the elevated binding of PD-1 to Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2) becomes a key step for downstream inhibitory signaling. Although the role of PD-L1 has been evaluated more thoroughly by clinical research, and PD-L1 has also been used more widely in the clinical setting, PD-L2 also plays an important role in the negative regulation of T-cells, one of the necessary conditions that lead to immune tolerance. Expression of PD-L1 either in tumors or in infiltrating immune cells has been verified predominantly by Immunohistochemistry (IHC) in a variety of tumors, suggesting a role for the PD-1/PD-L1 axis as a prognostic trait and therapeutic target across multiple histotypes. The complex interplay between these factors plays a major role in the diffusion and clinical application of PD-L1 IHC assays as predictive biomarkers of response to PD-1/PD-L1 inhibitors. Checkpoint blockades are registered for the treatment of various cancers, including gynecological malignancies.

Ferroptosis: a potential treatment scheme for glioblastoma / 肿瘤研究与临床

Glioblastoma (GBM) is a clinically common type of glioma with a very poor prognosis and complex drug resistance mechanisms, high mortality, short survival time; invasiveness and recurrence are the main obstacles to treatment. Ferroptosis is an iron-dependent regulated cell death associated with massive lipid peroxidation that is related with the development and treatment response of various types of tumors. Cancer cells rely on their strong antioxidant capacity to avoid ferroptosis, therefore, exploring ferroptosis may be an effective strategy to prevent tumor proliferation and invasion. This article mainly reviews the mechanism of ferroptosis in GBM, as well as the research status and progress of ferroptosis as a potential therapeutic target.

Clinical value of a cuproptosis-related differential long non-coding RNA scoring formula in clear cell renal cell carcinoma / 肿瘤研究与临床

Objective:To investigate the value of a cuproptosis-related differential long non-coding RNA (lncRNA) scoring formula related to the prognosis of clear cell renal cell carcinoma (ccRCC) patients in the clinical diagnosis, prognosis prediction and treatment options based on bioinformatics.Methods:Gene matrix and clinical data of ccRCC patients were obtained from the Cancer Genome Atlas (TCGA) database (update to 29 March, 2022). The expression data of 539 ccRCC tissues and 72 paracancerous normal tissues were collected from gene matrix; the data of 530 ccRCC were collected from clinical data. Pearson correlation analysis, Wilcoxon signed rank test and univariate Cox proportional risk model were used to analyze the screened cuproptosis-related differential lncRNA related to the prognosis. R software was used to randomly divide 530 ccRCC patients with survival data into training set (266 cases) and validation set (264 cases) according to approximate 1∶1 ratio. LASSO regression analysis was used to construct a cuproptosis-related differential lncRNA scoring formula and cross-validation was performed. Receiver operating characteristic (ROC) curve analysis was used to evaluate the specificity and sensitivity of cuproptosis-related differential lncRNA scoring formula, and the area of the curve (AUC) was calculated. According to the median risk value, all patients were divided into the low-risk group and high-risk group; Kaplan-Meier method was used to analyze the difference in the overall survival (OS) of patients in the low-risk group and high-risk group. T test was used to detect the differences in the risk value of patients with different clinicopathological characteristics. R package rms was used to construct the nomogram for predicting 1-year, 3-year, 5-year OS rates of ccRCC patients, R package pRRophetic was used to predict the half-inhibitory concentration ( IC50) of common targeted drugs such as sorafenib and sunitinib in clinical treatment of ccRCC patients, and IC50 value of patients in low-risk group and high-risk group was compared by using Wilcoxon signed rank test. Tissue samples of 20 ccRCC patients who underwent radical nephrectomy and were diagnosed with pathology and the matched paracancerous normal tissues were collected from the First Hospital of Shanxi Medical University between June 2021 and December 2021. Real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of key lncRNA in ccRCC tissues. Results:Based on the expression matrix of 10 cuproptosis genes (FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1, PDHB, MTF1, GLS, CDKN2A) of ccRCC patients in TCGA database, 153 cuproptosis-related differential lncRNA related to the prognosis were identified. According to LASSO regression analysis, a scoring formula of 4 cuproptosis-related differential lncRNA related to the prognosis was obtained, risk value was calculated as 0.020×AC015912.3+0.011×AC026401.3+0.063×AC103706.1+(-0.076)×EPB41L4A-DT. All patients were divided into high-risk group (≥0.76) and low-risk group (<0.76) based on the median value (0.76). ROC curve analysis showed that the scoring formula had good prediction accuracy in 1-year, 3-year, 5-year OS rates. In training set, validation set, the total cohort, the OS of patients in the high-risk group was worse than that in the low-risk group (all P < 0.001). The age, pathological degree, tumor staging, risk value calculated by cuproptosis-related differential lncRNA were independent influencing factors of OS (all P < 0.001). There were statistically significant differences in the risk value calculated by cuproptosis-related differential lncRNA scoring formula among patients with different pathological degree, tumor staging, T staging, N staging, M staging (all P < 0.01), while there were no statistically significant differences among patients with different gender and age (all P > 0.05). The established nomogram had good prediction accuracy in the 1-year, 3-year, 5-year OS rates. Sunitinib and sirolimus showed higher sensitivity in the high-risk group; axitinib, sorafenib and pazopanib showed higher sensitivity in the low-risk group. qRT-PCR results showed that relative expression level of AC015912.3 in ccRCC tissues was up-regulated compared with paracancerous tissues (1.00±0.04 vs. 0.68±0.24, t = 6.37, P < 0.01); the relative expression level of AC026401.3 in ccRCC tissues was up-regulated compared with paracancerous tissues (1.00±0.05 vs. 0.64±0.22, t = 7.29, P < 0.01); the relative expression level of AC103706.1 in ccRCC tissues was up-regulated compared with paracancerous tissues (1.00±0.04 vs. 0.64±0.21, t = 7.49, P < 0.01); the relative expression level of EPB41L4A-DT in ccRCC tissues was up-regulated compared with paracancerous tissues (1.00±0.06 vs. 0.73±0.10, t = 10.68, P < 0.01). Conclusions:Cuproptosis-related differential lncRNA scoring formula based on TCGA database can be used as a new marker for clinical diagnosis and prognosis prediction of ccRCC patients, which can help guide the clinical drug treatment of patients and facilitate accurate diagnosis and treatment.

Correlation of KRAS gene mutation and programmed death receptor ligand 1 expression with prognosis of first-line concurrent chemoradiotherapy in patients with locally advanced non-small cell lung cancer / 肿瘤研究与临床

Objective:To investigate the relationship between KRAS gene mutation, programmed death receptor ligand 1 (PD-L1) expression and prognosis of first-line concurrent chemoradiotherapy in patients with locally advanced non-small cell lung cancer.Methods:The clinical data of 50 patients with locally advanced non-small cell lung cancer who were admitted to Nanping First Hospital from January 2018 to December 2021 were retrospectively analyzed. All patients were treated with first-line concurrent chemoradiotherapy. Tissue samples of patients were obtained and paraffin embedded before treatment. Real-time fluorescence quantitative polymerase chain reaction was used to detect the type of KRAS gene mutation in tissues before treatment, and the expression of PD-L1 was determined by immunohistochemistry (the percentage of positive cells in tumor cells ≥1% was positive), and the relationship between KRAS gene status, PD-L1 expression and clinical characteristics and short-term efficacy of patients was analyzed. Patients were followed up for 1 year, and progression-free survival (PFS) curves were plotted by Kaplan-Meier method, and log-rank test was used for comparison. Univariate and multivariate Cox proportional hazards models were used to analyze the influencing factors of PFS.Results:Among the 50 patients, 11 (22.00%) were KRAS mutant, and 36 (72.00%) were PD-L1 positive. Among the 11 patients with KRAS mutation, there were 2 cases of codon 13 mutation and 9 cases of codon 12 mutation in exon 2. The objective response rate (ORR) and clinical control rate (DCR) were 76.00% (38/50) and 86.00% (43/50). There were no significant differences in patients' age, pathological type, TNM stage, ORR and DCR between KRAS mutant group and KRAS wild type group (all P > 0.05). The proportions of male patients [72.73% (8/11) vs. 38.46% (15/39)], patients with smoking history [90.91% (10/11) vs. 20.51% (8/39)] and patients with PD-L1 positive expression [100.00% (11/11) vs. 64.10% (25/39)] in KRAS mutant group were higher than those in KRAS wild type group (all P < 0.05). There were no significant differences in patients' age, pathological type, gender, smoking history, TNM stage, ORR and DCR between PD-L1 positive group and PD-L1 negative group (all P > 0.05). The median PFS time of patients in KRAS mutant group and wild type group was 8.75 and 11.32 months, and the difference in PFS between the two groups was statistically significant ( P = 0.039). The median PFS time of patients with PD-L1 positive and negative was 10.19 and 11.16 months, and there was no statistical significance in PFS between the two ( P = 0.116). Multivariate Cox regression analysis showed that KRAS gene mutation was an independent risk factor for PFS in patients with locally advanced NSCLC after first-line concurrent chemoradiotherapy ( HR = 1.449, 95% CI 1.071-1.196, P = 0.017). PD-L1 expression, smoking history and gender were not independent influencing factors for PFS (all P > 0.05). Conclusions:KRAS gene status is closely related to the prognosis of patients with locally advanced non-small cell lung cancer treated with first-line concurrent chemoradiotherapy, while PD-L1 expression is not.

Construction and validation of a prognostic nomogram model of programmed death receptor 1 inhibitors in treatment of hepatitis B-related hepatocellular carcinoma / 肿瘤研究与临床

Objective:To investigate the factors influencing the prognosis of hepatitis B-related hepatocellular carcinoma treated with programmed death receptor 1 (PD-1) inhibitors, and to construct a prognostic nomogram model for these patients and evaluate its clinical significances.Methods:The clinical data of 121 patients with hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors at the First Affiliated Hospital of Xinxiang Medical College from July 2018 to July 2021 were retrospectively analyzed. Follow-up was performed from the beginning of PD-1 inhibitor use, and the Kaplan-Meier method was used to analyze the overall survival of patients. The variables screened by the univariate Cox proportional hazards model analysis and variables clinically believed to be related to the prognosis were included in the multivariate Cox proportional hazards model for overall survival, and the stepwise regression method was used to screen the independent factors influencing overall survival. Based on the independent influencing factors of overall survival, R 3.5.1 software was used to construct a prognostic nomogram model for overall survival of hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors. Calibration curve was used to the consistency of model prediction and practice. The Harrell consistency index and receiver operating characteristic (ROC) curve (with imaging diagnosis as the gold standard) were used to analyze the efficacy of model in predicting the 1-year and 2-year overall survival rates.Results:The median follow-up time of 121 patients was 12.40 months, and the median overall survival time was 14.30 months, with overall survival rates of 82.60% and 62.30% at 6 and 12 months. Multivariate Cox regression analysis showed that albumin (ALB) ( HR = 0.946, 95% CI 0.901-0.992), international normalized ratio (INR) ( HR = 32.034, 95% CI 5.046-203.362), aspartate aminotransferase (AST) ( HR = 1.010, 95% CI 1.007-1.012) were independent influencing factors for overall survival of patients. According to the three factors, a prognostic nomogram model for hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors was constructed. The slope of the calibration curve of the model predicting 1-year and 2-year overall survival rates was close to 1. The Harrell consistency index of the nomogram model was 0.809 (95% CI 0.760-0.858). ROC curve analysis showed that the area under the curve (AUC) of the nomogram model predicting 1-year and 2-year overall survival rates of patients was 0.794 (95% CI 0.744-0.887, P < 0.001) and 0.791 (95% CI 0.708-0.860, P = 0.002). Conclusions:ALB, INR and AST are the influencing factors of prognosis of hepatitis B-related hepatocellular carcinoma patients treated with PD-1 inhibitors, and the nomogram model constructed based on prognostic influencing factors has a good effect on predicting the 1-year and 2-year overall survival rates of patients, which can be used to screen the population suitable for immunotherapy and is conducive to the clinical formulation of individualized and precise treatment plans.

Programmed cell death induced by Klebsiella pneumoniae infection / 中华微生物学和免疫学杂志

Klebsiella pneumoniae can cause a variety of infectious diseases, especially in immunocompromised population. The emergence of multidrug-resistant hypervirulent Klebsiella pneumoniae has greatly limited the choice of treatment for Klebsiella pneumoniae infection, and the exploration of new treatment strategies is imminent. In the process of infection, there is a complex interaction between the programmed cell death of host cells and the invasion of Klebsiella pneumoniae. This paper mainly reviewed the research progress in several mechanisms of programmed cell death such as pyroptosis, apoptosis, necroptosis and autophagy caused by Klebsiella pneumoniae.

Roles of PD-1/PD-L1 immune checkpoint in thyroid diseases / 中华核医学与分子影像杂志

Programmed cell death receptor 1 (PD-1)/PD-1 ligand (PD-L1) maintains immune tolerance of normal tissues and mediates immune escape of tumors. For autoimmune thyroiditis, thyroid follicular epithelial cells inhibit the damage of T cells by up-regulating PD-L1 expression. With the application of immune checkpoint inhibitors (ICIs) in the field of cancer therapy, the incidence of immune-related thyroid disorders caused by ICIs has increased. Thyroid function should be monitored during and after ICIs treatment to promptly diagnose primary and (or) secondary thyroid disorders. The PD-1/PD-L1 signaling directly stimulates thyroid cancer cells, and exerts inhibitory effects on tumor-infiltrating immune cells. Combination of ICIs targeting PD-1/PD-L1 with chemo-radiotherapy or targeted therapy is a promising therapeutic strategy in the treatment of refractory thyroid cancers.

Prognostic value of pretreatment 18F-FDG PET/CT in patients with metastatic melanoma treated with anti-PD1 immunotherapy / 中华核医学与分子影像杂志

Objective:To assess the prognostic value of pretreatment 18F-FDG PET/CT metabolic parameters in patients with metastatic malignant melanoma treated with anti-programmed cell death-1 (PD1) immunotherapy. Methods:A retrospective analysis of 29 patients (15 males, 14 females, age (59.1±13.0) years) with pathologically diagnosed metastatic malignant melanoma in Nanjing Drum Tower Hospital between June 2017 and October 2020 was conducted. Anti-PD1 immunotherapy were performed in all patients after 18F-FDG PET/CT imaging. 18F-FDG PET/CT parameters including SUV max, bone marrow-to-liver SUV max ratio (BLR), spleen-to-liver SUV max ratio (SLR) were obtained. Total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) of primary lesions were measured automatically using the thresholds of 40%SUV max. The median value of each PET parameter was regarded as the threshold value and was used to divide patients into 2 groups (≥ and < the median value, respectively). Kaplan-Meier survival curve and Cox proportional risk model were used to analyze the overall survival (OS) differences between groups. Results:The median follow-up time was 15.0 months and 13 patients died. The median OS was 26.0(95% CI: 20.4-31.6) months. The median SUV max, TMTV, TLG, BLR and SLR were 6.2, 8.2 cm 3, 38.6 g, 0.82 and 0.84 respectively. Kaplan-Meier method and log-rank test showed that differences of OS between SUV max≥6.2 and <6.2 groups, TLG≥38.6 g and <38.6 g groups, BLR≥0.82 and <0.82 groups, SLR≥0.84 and <0.84 groups were not significant ( χ2 values: 0.01-0.35, P values: 0.061-0.929), while patients with TMTV≥8.2 cm 3 suffered from poorer OS compared with those with TMTV<8.2 cm 3 ( χ2=5.90, P=0.015). Cox multivariate analysis showed that TMTV (hazard risk ( HR)=6.347, 95% CI: 1.039-38.789) was a significant predictor of OS ( P=0.045). Conclusion:18F-FDG PET/CT parameter TMTV is the independent predictive factor of OS in metastatic melanoma treated with anti-PD1 immunotherapy.

Research progress on the relationship between Ferroptosis and renal ischemia-reperfusion injury / 中国医师杂志

Ferroptosis is a new type of programmed cell death, which is different from apoptosis, pyrodeath, necrosis and autophagy. It is characterized by the imbalance of cell iron homeostasis, which leads to the accumulation of reactive oxygen species and lipid peroxides, which exceeds the antioxidant capacity of cells and eventually leads to oxidative death of cells. Studies have shown that ferroptosis plays an important role in acute renal injury induced by renal ischemia-reperfusion and inhibition of ferroptosis can effectively alleviate renal ischemia-reperfusion injury. It is of great significance to study the relationship and mechanism of ferroptosis and renal ischemia-reperfusion injury to prevent acute renal function injury caused by renal ischemia-reperfusion injury in clinical work .

Evaluation value of serum soluble programmed cell death protein 1, soluble B7 homolog 5 molecules combined with trefoil factor 2 on disease severity and death risk in patients with acute pancreatitis / 中国医师进修杂志

Objective:To investigate the value of serum soluble programmed cell death protein 1 (sPD-1), soluble B7 homolog 5 (sB7-H5) and trefoil factor 2 (TFF2) in evaluating the severity of disease and the risk of death in patients with acute pancreatitis (AP).Methods:A prospective research method was adopted. Three hundred and twenty-eight patients with AP (AP group) from February 2020 to February 2021 in Xiangyang Central Hospital were selected, including 124 patients with mild AP (MAP), 106 patients with moderately severe AP (MSAP) and 98 patients with severe AP (SAP). The serum levels of sPD-1, sB7-H5 and TFF2 were measured by enzyme-linked immunosorbent assay and compared with 60 healthy people (healthy control group). The patients with AP were followed up for 90 d, 284 patients survived and 44 died. The amylase, C-reactive protein (CRP), procalcitonin (PCT), acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ), sequential organ failure assessment (SOFA), modified CT severity index (MCTSI), sPD-1, sB7-H5 and TFF2 were compared between the two groups. Pearson method was used for correlation analysis. Multivariate Logistic regression was used to analyze the independent risk factors of death in patients with AP. The efficacy of sPD-1, sB7-H5 and TFF2 in predicting the death in patients with AP was evaluated using the receiver operating characteristics (ROC) curve.Results:The sPD-1, sB7-H5 and TFF2 in AP group were significantly higher than those in healthy control group: (177.99 ± 17.81) ng/L vs. (50.20 ± 10.81) ng/L, (2.69 ± 0.72) μg/L vs. (1.40 ± 0.35) μg/L and (569.97 ± 38.91) μg/L vs. (94.59 ± 11.98) μg/L, and there were statistical differences ( P<0.01). The amylase, sPD-1, sB7-H5 and TFF2 in patients with MSAP and SAP were significantly higher than those in patients with MAP: (639.36 ± 91.67) and (835.24 ± 109.30) U/L vs. (575.24 ± 89.78) U/L, (180.13 ± 20.61) and (221.17 ± 15.70) ng/L vs. (142.03 ± 16.76) ng/L, (2.85 ± 0.74) and (3.34 ± 0.82) μg/L vs. (2.05 ± 0.52) μg/L, (539.66 ± 36.58) and (763.55 ± 40.08) μg/L vs. (442.90 ± 35.79) μg/L, the indexes in patients with SAP were significantly higher than those in patients with MSAP, and there were statistical differences ( P<0.01). Pearson correlation analysis result showed that sPD-1 was positively correlated with sB7-H5 and TFF2 in patients with AP ( r = 0.552 and 0.641, P<0.01), and the sB7-H5 was positively correlated with TFF2 ( r = 0.610, P<0.01). The amylase, CRP, PCT, APACHE Ⅱ, SOFA, MCTSI, sPD-1, sB7-H5 and TFF2 in the dead patients were significantly higher than those in the living patients: (1 098 ± 105) U/L vs. (641 ± 93) U/L, (235.60 ± 40.17) mg/L vs. (118.04 ± 32.90) mg/L, (4.32 ± 0.52) μg/L vs. (3.14 ± 0.44) μg/L, (19.39 ± 3.14) scores vs. (11.18 ± 2.53) scores, (12.13 ± 2.78) scores vs. (7.40 ± 2.15) scores, (7.12 ± 1.73) scores vs. (4.31 ± 1.52) scores, (222.23 ± 22.30) ng/L vs. (171.14 ± 18.50) ng/L, (3.37 ± 0.89) μg/L vs. (2.59 ± 0.59) μg/L and (629.27 ± 39.63) μg/L vs. (560.78 ± 30.45) μg/L, and there were statistical differences ( P<0.01). Multivariate Logistic regression analysis result showed that CRP, PCT, APACHE Ⅱ, SOFA, sPD-1, sB7-H5 and TFF2 were independent risk factors death of in patients with AP ( OR = 1.339, 1.416, 1.285, 1.327, 1.092, 1.171 and 1.080; 95% CI 1.145 to 1.566, 1.146 to 1.751, 1.132 to 1.460, 1.150 to 1.531, 1.024 to 1.164, 1.072 to 1.280 and 1.031 to 1.131; P<0.01). The ROC curve analysis result showed that the area under the curve of sPD-1, sB7-H5 and TFF2 combined detection to predict the death in patients with AP was larger than that of sPD-1, sB7-H5, and TFF2 alone detection (0.870 vs. 0.771, 0.734 and 0.685). Conclusions:The increase of serum sPD-1, sB7-H5 and TFF2 levels in patients with AP is related to the severity of disease of patients with AP. The combined detection of the indexes can assist in evaluating the risk of death in patients with AP.

Research progress on ferroptosis in the treatment of oral cancer / 口腔疾病防治

@#Ferroptosis is a newly discovered method of programmed cell death. Current studies have shown that activation of ferroptosis-related pathways can inhibit the growth and proliferation of tumor cells and reverse their drug resistance. Oral cancer is a common malignant tumor with a high recurrence rate and high drug resistance. Inducing ferroptosis is a potential treatment strategy. There are still many uncertainties in the application of ferroptosis in the treatment of oral cancer, which need to be further explored. This article systematically introduces the mechanism of ferroptosis and its recent progress in oral cancer treatment to provide new mechanisms and methods for the clinical treatment of oral cancer. Current research shows that the mechanism of ferroptosis is mainly related to amino acid metabolism, Fe2+ metabolism, and lipid metabolism. Ferroptosis in oral cancer cells can reverse drug resistance in cancer cells and improve the activity of immune cells. New drugs, such as curcumin analogs and triptolide, can induce ferroptosis in oral cancer, and the development of nanomaterials has improved the utilization rate of drugs. Inhibiting the expression of the ferroptosis-related factors SLC7A11, NF-E2-related factor 2 (Nrf2), and ferritin heavy chain 1 (FTH1) can promote ferroptosis in oral cancer cells. It is a potential target for the clinical treatment of oral cancer, but its translation into clinical practice still needs further research.