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.

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 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.

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.

Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via regulation of TFRC-dependent ferroptosis

The clinical utilization of doxorubicin (Dox) in various malignancies is restrained by its major adverse effect: irreversible cardiomyopathy. Extensive studies have been done to explore the prevention of Dox cardiomyopathy. Currently, ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy. Sorting Nexin 3 (SNX3), the retromer-associated cargo binding protein with important physiological functions, was identified as a potent therapeutic target for cardiac hypertrophy in our previous study. However, few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy. In this study, a decreased level of SNX3 in Dox-induced cardiomyopathy was observed. Cardiac-specific Snx3 knockout (Snx3-cKO) significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly. SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro, and cardiac-specific Snx3 transgenic (Snx3-cTg) mice were more susceptible to Dox-induced ferroptosis and cardiomyopathy. Mechanistically, SNX3 facilitated the recycling of transferrin 1 receptor (TFRC) via direct interaction, disrupting iron homeostasis, increasing the accumulation of iron, triggering ferroptosis, and eventually exacerbating Dox-induced cardiomyopathy. Overall, these findings established a direct SNX3-TFRC-ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRC-dependent ferroptosis.

Macrophage-camouflaged epigenetic nanoinducers enhance chemoimmunotherapy in triple negative breast cancer

Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer (TNBC), but the clinical outcomes remain unsatisfied. Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion, which is a critical factor for the poor response to chemoimmunotherapy in TNBC. Herein, macrophage-camouflaged nanoinducers co-loaded with paclitaxel (PTX) and decitabine (DAC) (P/D-mMSNs) were prepared in combination with PD-1 blockade therapy, hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue. Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties. First, DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX. Subsequently, PTX induces immunogenic death of tumor cells, promotes phagocytosis of dead cells by dendritic cells, and recruits cytotoxic T cells to infiltrate tumors. Finally, DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy. P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.

Pathological features and immune microenvironment in HER-2 intratumoral heterogeneous breast cancers / 中华肿瘤杂志

Objective: To observe the clinical pathology features, and immune microenvironment of HER-2 intratumoral heterogeneity breast cancer. Methods: Thirty cases of HER-2 intratumoral heterogeneous breast cancer were retrospectively analyzed in Tianjin Medical University Cancer Institute and Hospital from November 2017 to June 2020. HER-2 expression was detected by immunohistochemistry and verified by dual color silver-enhanced in-situ hybridization (D-SISH). HER-2 intratumoral positive and negative regions were divided. The pathological characteristics, subtype, and the level of tumor infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) were evaluated respectively. Results: The proportion of HER-2 positive cells of the breast cancer ranged from 10% to 90%. The pathological type was mainly invasive non-special typecarcinoma. Six cases presented different pathological types between HER-2 positive and negative regions. The HER-2-positive areas included 2 cases of carcinoma with apocrine differentiation, and the negative areas included 2 cases of invasive micropapillary carcinoma, 1 case of invasive papillary carcinoma, and 1 case of carcinoma with apocrine differentiation. In HER-2 positive regions, 17 cases were Luminal B and 13 cases were HER-2 overexpressed types. There were 22 cases of Luminal B and 8 cases of triple negative tumors in the HER-2 negative areas. The levels of TILs in HER-2 positive and negative areas accounted for 53.3% (16/30) and 26.7% (8/30), respectively, with a statistically significant difference (P=0.035). The positive expression of PD-L1 in HER-2 positive area and HER-2 negative area were 6 cases and 9 cases, respectively. Among 8 cases with HER-2 negative regions containing triple negative components, 4 cases were positive for PD-L1 expression. Conclusions: In the case of HER-2 intratumoral heterogeneity, it is necessary to pay attention to both HER-2 positive and negative regions, and evaluate subtype separately as far as possible. For HER-2 intratumoral heterogeneous breast cancer containing triple negative components, the treatment mode can be optimized by refining the intratumoral expression of PD-L1.

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.

Research progress of cell death in radiation protection and radiosensitization / 中国辐射卫生

@#The rapid advances in technology and medicine have greatly facilitated the application of ionizing radiation. Clinically, radiotherapy is one of the major treatments for malignant tumors. However, besides killing tumor cells, ionizing radiation inevitably leads to radiation damage and even death of normal cells. How ionizing radiation causes cell death and the forms of cell death have always been important research topics in this field. Recently, several forms of cell death induced by irradiation have been discovered. Apart from apoptosis, pyroptosis, necroptosis, ferroptosis, autophagic cell death, and methuosis have gradually become research hotspots, and provide new targets for the development of radioprotective drugs and radiosensitizers. In this review, we summarize various forms of ionizing radiation-induced cell death and related molecular mechanisms. We also introduce the latest progress in radiation protection and radiosensitization based on these cell death mechanisms. This review will provide a reference for the research and development of radioprotective drugs and radiosensitizers in the future.

Role of gasdermin D in the pathological progression of liver diseases / 临床肝胆病杂志

As a novel star molecule, gasdermin D (GSDMD) plays an important role in the amplification of immune inflammatory response and the process of pyroptosis. After being cleaved and activated by caspase-1, the N-terminal of GSDMD is rapidly released, which anchors on the cell membrane and forms pores, thereby leading to pyroptosis, accompanied by the release of a large amount of the strong proinflammatory factors IL-1β and IL-18. Acute/chronic liver inflammatory response and cell death are the common pathological features of liver diseases such as viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, liver failure, and hepatocellular carcinoma. This article summarizes the basic structural characteristics of GSDMD and elaborates on its important role in the pathological progression of various liver diseases. In addition, it is proposed that prevention and treatment strategies with GSDMD as a potential therapeutic target can provide new ideas for further studies on the clinical prevention and treatment of liver diseases.

A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy

The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8+ T lymphocytes with considerable metabolic flexibility toward a highly activated, long-lived, and memory-like phenotype. Such an idea intervenes both metabolite (lactate) and cellular metabolic pathway, which essentially alters overall cell fates toward the desired situation. Collectively, the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.

PD-1 inhibitor plus anlotinib for metastatic castration-resistant prostate cancer: a real-world study / 亚洲男科学杂志(英文版)

Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.

Short-term efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy for the treatment of non-small cell lung cancer / 中国胸心血管外科临床杂志

@#Objective    To explore the short-term efficacy and safety of pembrolizumab combined with chemotherapy in the neoadjuvant treatment of non-small cell lung cancer. Methods    The clinical data of 11 male patients with non-small cell lung cancer who underwent pembrolizumab combined with neoadjuvant chemotherapy in the Department of Thoracic Surgery, the First Affiliated Hospital of Xi'an Jiaotong University from December 2019 to June 2021 were retrospectively analyzed. The average age of the patients was 52.0-79.0 (62.0±6.9) years. The imaging data and pathological changes before and after neoadjuvant treatment were compared, and adverse reactions during neoadjuvant treatment were recorded. Objective remission rate (ORR) and main pathological remission rate (MPR) and pathological complete remission rate (pCR) were the main observation endpoints. Results    After preoperative neoadjuvant therapy with pembrolizumab combined with platinum or paclitaxel, all patients successfully underwent thoracoscopic radical resection of lung cancer. The ORR was 72.7%, and the MPR was 81.8%. Among them, 45.5% of patients achieved pCR. The main adverse reactions were hypoalbuminemia, decreased appetite and nausea. The mortality rate within 30 days after surgery was 0, and no tumor metastasis was observed. Conclusion    Pembrolizumab combined with neoadjuvant chemotherapy is safe and feasible to treat non-small cell lung cancer, and the short-term efficacy is beneficial.

Study on the mechanism of VEGF inducing tolerogenic dendritic cells in oral squamous cell carcinoma / 口腔医学

Objective@#To investigate the mechanism of vascular endothelial growth factor(VEGF) inducing tolerogenic dendritic cells(DCs) in oral squamous cell carcinoma (OSCC).@*Methods@#The DCs were divided into four groups: Control group (DC), VEGF group (VEGF added into DC), Co-culture group (DC co-cultured with SCC7) and Anti-VEGF group (anti-VEGF antibody added into DC co-cultured with SCC7). Flow cytometry (FCM) was used to detect DC surface markers. To detect the effect of DC on proliferation activity of T lymphocyte, the experiment included five groups: Nc group (T lymphocyte), Control group (T lymphocyte added into DC), VEGF group (T lymphocyte + DC + VEGF), Co-culture group (T lymphocyte + DC + supernatant of SCC7) and Anti-VEGF group (T lymphocyte + DC + supernatant of SCC7 + anti-VEGF antibody). Subsequently, the mixed lymphocyte reaction(MLR) was conducted. The expression levels of indole-2, 3-doxygenase(IDO)and programmed cell death 1 ligand 1(PD-L1)in DC were detected by western blot, real time PCR and FCM respectively. For the cytotoxic lymphocyte (CTL) assay, SCC7 cells and CTLs were mixed and CTL-mediated SCC7 cells cytotoxicity was tested. The experiment included four groups: Control group (T lymphocyte + DC), IDO inhibition group (T lymphocyte + DC + IDO inhibitor), Anti-PD-L1 antibody group (T lymphocyte + DC + anti-PD-L1 antibody) and Combination group (T lymphocyte + DC + IDO inhibitor + anti-PD-L1 antibody). The SCC7 tumor-bearing mice treated with IDO inhibitor and the anti-PD-L1 antibody were sacrificed and the tumor inhibition rate and the spleen index were determined. @*Results@#Compared with Control group, exogenous VEGF or SCC7 co-culture inhibited the relative number of DC expressing CD11C, CD80, CD86, CD40 and MHC Ⅱ. The positive DCs were increased in the Anti-VEGF group compared with VEGF or Co-culture group. In VEGF or Co-culture group, the number of T cells stimulated by SCC7-pulsed DCs was decreased compared with Control group. However, the ability of Anti-VEGF group to induce T cell proliferation was significantly increased compared with VEGF or Co-culture group. Significantly increased expression of IDO and PD-L1 were observed in VEGF and Co-culture group. However, this was partially reversed by addition of anti-VEGF antibody into the co-culture system. Compared with Control group, the expressions of CD11C and CD86 in DC in both the IDO inhibition group and Anti-PD-L1 antibody group were increased, and were significantly higher in the Combination group compared with the single drug groups. The similar results were exhibited in MLR and CTL assay. In vivo, the results revealed that the tumors obtained from the mice in three experimental groups were smaller than those in the control group. Furthermore, the tumor volume of the Combination group was the smallest. The spleen index of each group was calculated and the results showed the spleen index of the three experimental groups was significantly higher than that of Control group.@*Conclusion@#VEGF in OSCC micro-environment inhibits the maturation and function of DC that are transformed into tolerogenic DC by high expression of IDO and PD-L1.

Advances on mechanisms of regulated cell death in neurotoxicity of aluminum / 环境与职业医学

Aluminum is a light metal which is rich in the earth's crust and widely used. Recently, the adverse health effects of environmental and occupational aluminum exposure on human have attracted more and more attention. Aluminum exposure has toxic effects on the central nervous system and is believed to be closely related to the development and progression of Alzheimer's disease. The neurotoxic mechanism of aluminum is complex, especially the role of regulated cell death (RCD) in aluminum-induced neuronal death remains to be further studied. RCD refers to all modes of cell death regulated by multiple intracellular signal transduction pathways under physiological and pathological conditions, including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. This review summarized the morphological characteristics and mechanisms of each RCD mode in the process of aluminum-induced neuronal death, and discussed the relationship and transformation between different RCD modes, providing a new scientific basis for future studies on the treatment and intervention of neurotoxicity induced by aluminum exposure.