Medical ozone alleviates acute lung injury by enhancing phagocytosis targeting NETs via AMPK/SR-A1 axis.

Acute lung injury (ALI) linked to sepsis has a high mortality rate, with limited treatment options available. In recent studies, medical ozone has shown promising results in alleviating inflammation and infection. Here, we aimed to evaluate the therapeutic potential of medical ozone in sepsis-induced ALI using a mouse model, measuring behavioral assessments, lung function, and blood flow. Western blot was used to quantify the levels of protein. In vitro, experiments on BMDM cells examine the impact of AMPK inhibitors and agonists on phagocytic activity. Results indicate that medical ozone can enhance the survival rate, ameliorate lung injury, and improve lung function and limb microcirculation in mice with ALI. Notably, it inhibits NETs formation, a crucial player in ALI development. Medical ozone also counteracts elevated TF, MMP-9, and IL-1ß levels. In ALI mice, the effects of ozone are nullified and BMDMs exhibit impaired engulfment of NETs following Sr-a1 knockout. Under normal physiological conditions, the use of an AMPK antagonist produces similar effects to Sr-a1 knockout, significantly inhibiting the phagocytosis of NETs by BMDMs. On the contrary, AMPK agonists enhance this phagocytic process. In conclusion, medical ozone can alleviate sepsis-induced lung injury via the AMPK/SR-A1 pathway, thereby enhancing phagocytosis of NETs by macrophages.

Urocortin2 attenuates diabetic coronary microvascular dysfunction by regulating macrophage extracellular vesicles.

Diabetic patients develop coronary microvascular dysfunction (CMD) and exhibit high mortality of coronary artery disease. Methylglyoxal (MGO) largely accumulates in the circulation due to diabetes. We addressed whether macrophages exposed to MGO exhibited damaging effect on the coronary artery and whether urocortin2 (UCN2) serve as protecting factors against such diabetes-associated complication. Type 2 diabetes was induced by high-fat diet and a single low-dose streptozotocin in mice. Small extracellular vesicles (sEV) derived from MGO-treated macrophages (MGO-sEV) were used to produce diabetes-like CMD. UCN2 was examined for a protective role against CMD. The involvement of arginase1 and IL-33 was tested by pharmacological inhibitor and IL-33-/- mice. MGO-sEV was capable of causing coronary artery endothelial dysfunction similar to that by diabetes. Immunocytochemistry studies of diabetic coronary arteries supported the transfer of arginase1 from macrophages to endothelial cells. Mechanism studies revealed arginase1 contributed to the impaired endothelium-dependent relaxation of coronary arteries in diabetic and MGO-sEV-treated mice. UCN2 significantly improved coronary artery endothelial function, and prevented MGO elevation in diabetic mice or enrichment of arginase1 in MGO-sEV. Diabetes caused a reduction of IL-33, which was also reversed by UCN2. IL-33-/- mice showed impaired endothelium-dependent relaxation of coronary arteries, which can be mitigated by arginase1 inhibition but can't be improved by UCN2 anymore, indicating the importance of restoring IL-33 for the protection against diabetic CMD by UCN2. Our data suggest that MGO-sEV induces CMD via shuttling arginase1 to coronary arteries. UCN2 is able to protect against diabetic CMD via modulating MGO-altered macrophage sEV cargoes.

UBE3B promotes breast cancer progression by antagonizing HIF-2α degradation.

Mutations in E3 ubiquitin ligase UBE3B have been linked to Kaufman Oculocerebrofacial Syndrome (KOS). Accumulating evidence indicates that UBE3B may play an important role in cancer. However, the precise role of UBE3B in cancer and the underlying mechanism remain largely uncharted. Here, we reported that UBE3B is an E3 ligase for hypoxia-inducible factor 2α (HIF-2α). Mechanically, UBE3B physically interacts with HIF-2α and promotes its lysine 63 (K63)-linked polyubiquitination, thereby inhibiting the Von Hippel-Lindau (VHL) E3 ligase complex-mediated HIF-2α degradation. UBE3B depletion inhibits breast cancer cell proliferation, colony formation, migration, and invasion in vitro and suppresses breast tumor growth and lung metastasis in vivo. We further identified K394, K497, and K503 of HIF-2α as key ubiquitination sites for UBE3B. K394/497/503R mutation of HIF-2α dramatically abolishes UBE3B-mediated breast cancer growth and lung metastasis. Intriguingly, the protein levels of UBE3B are upregulated and positively correlated with HIF-2α protein levels in breast cancer tissues. These findings uncover a critical mechanism underlying the role of UBE3B in HIF-2α regulation and breast cancer progression.

Mechanism of ozone alleviation of malignant ascites in hepatocellular carcinoma through the inhibition of neutrophil extracellular traps.

Malignant ascites in hepatocellular carcinoma is usually a sign of advanced disease and poor prognosis and is also thought to be associated with chronic inflammation mediated by neutrophil extracellular trap (NET) networks. Although ozone, a strong oxidant, has significant antibacterial and anti-inflammatory effects, its effectiveness in treating malignant liver ascites is unclear. We first measured the levels of NETs in the peripheral blood of patients with liver cancer and healthy individuals. Next, we constructed the H22 tumor-bearing mouse model and observed the abdominal girth, body weight, survival rate, and survival time in each group; we marked the proteins associated with NETs in mouse intestinal tissues by immunofluorescence; cf-DNA and cytokines in ascites such as: tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), matrix metalloprotein 9 (MMP-9), and interferon gamma (IFN-γ) levels in ascites were measured by enzyme-linked immunosorbent assay. The expression levels of phosphorylated adenylate-activated protein kinase (P-AMPK) and scavenger receptor-A (SR-A) were detected by immunocytochemistry in the intestinal tissues of each group of mice. We further examined the expression of P-AMPK and SR-A proteins in ascites deposits by Western blotting. The results show, the plasma levels of NETs were higher in patients with hepatocellular carcinoma than in normal subjects (P < 0.01). Abdominal girth and body weight were significantly reduced in the ozone-treated group compared with the model group, while survival and survival time were dose dependently increased (both P < 0.05). NET-associated guanine histone H3 and myeloperoxidase were abundantly expressed at neutrophil aggregates in the intestinal tissues of the model mice, whereas their expression was significantly reduced in the ozone-treated group. The levels of cf-DNA, IL-6, IFN-γ, MMP-9, VEGF, and TNF-α were dose dependently increased in the ascites of H22 tumor-bearing mice in the ozone-treated group compared with the model group (all P < 0.01), while the expression of P-AMPK and SR-A proteins was increased in the ozone-treated group compared with the model group. Ozone showed significant antiperitoneal fluid production properties in H22 tumor-bearing mice, and ozone reduced peritoneal fluid production by activating AMPK and up-regulating SR-A phagocytosis damage-associated molecular patterns to reduce the production of NETs. This suggests that ozone could be used as a new drug for the treatment of malignant ascites in hepatocellular carcinoma.

Comparison of antibody persistency through one year between one-dose and two-dose regimens of Ad5-nCoV vaccine for COVID-19.

This post-hoc analysis compared the receptor-binding domain (RBD)-specific and pseudovirus neutralizing antibodies against the wild-type SARS-CoV-2 strain elicited by one or two doses (56-d interval) of Ad5-nCoV vaccine regimen (NCT04341389 and NCT04566770). Both trials had low-dose and high-dose groups. Propensity score matching was used to adjust the baseline between one- and two-dose regimens. To predict the decrease in antibody titers 1 y after vaccination, half-lives of RBD-binding antibodies and pseudovirus neutralizing antibodies were computed. We obtained 34 and 29 pairs of participants in the low- and high-dose groups based on the propensity score matching. The two-dose regimen of Ad5-nCoV increased the peaking level of neutralizing antibodies compared to the one-dose regimen at day 28, but the responses of the neutralizing antibodies were not consistent with those of the RBD antibodies. Half-lives of the RBD-binding antibodies in the two-dose Ad5-nCoV regimen (202-209 days) were longer than those in the one-dose regimen (136-137 d); half-lives of the pseudovirus neutralizing antibody in the one-dose Ad5-nCoV regimen (177 d) were longer than those in the two-dose regimen (116-131 d). The predicted positive rates of RBD-binding antibodies in the one-dose regimen (34.1%-38.3%) would be lower than those in the two-dose Ad5-nCoV regimen (67.0%-84.0%), while the positive rates of pseudovirus neutralizing antibodies in the one-dose regimen (65.4%-66.7%) would be higher than those in the two-dose regimen (48.3%-58.0%). The two-dose Ad5-nCoV regimen with a 56-d interval had no effect on the persistence of neutralizing antibodies but slowed decay trend of RBD-binding antibodies.

Activation of NLRP2 in Triple-Negative Breast Cancer sensitizes chemotherapeutic therapy through facilitating hnRNPK function.

Nucleotide-binding oligomerization domain (NOD)-like receptor type 2 protein (NLRP2) was reported to inhibit NF-κB in response to inflammatory stimuli, but its role in tumors remains elusive. We screened out NLRP2 from mouse models of breast cancer metastasis. Bioinformatics analysis showed NLRP2 expression was positively correlated with survival rate and negatively correlated with the potential of cancer metastasis. Its significance in Triple-Negative Breast Cancer (TNBC) was investigated by gain- and loss-of-function studies in vivo and vitro. Re-expression of NLRP2 dramatically inhibited the growth and metastasis of the xenograft model of MDA-MB-231 cells. Mechanically, NLRP2 confined hnRNPK within cytoplasm, which in turn blocked vimentin mRNA production. Not only that, NLRP2 further enhanced the H2O2-induced high level of p53&Bax and hence dramatically increased the apoptosis rate (fivefold). Likewise, carboplatin-treated cells showed decreased cell viability, suggesting that patients of TNBC with high level of NLRP2 respond well to chemotherapeutics. Under the stimulus of H2O2, NLRP2-hnRNPK no longer stayed in the cytoplasm, but entered the nucleus to increase the expression of p53 and hence enhanced corresponding apoptosis effect, increasing Bax expression. It suggested that NLRP2 helps p53 enter the nucleus to induce apoptosis. This study revealed a novel function of NLRP2 that modulated oncogenic and anti-oncogenic characteristics of hnRNPK, and provided a new biomarker for TNBC chemotherapy.

[Heavy Metal Concentration, Source, and Pollution Assessment in Topsoil of Chuzhou City].

In order to understand the pollution level and ecological risk of heavy metals in topsoil of Chuzhou City, a total of 4360 soil samples in Chuzhou City were collected, and the concentrations of eight heavy metals including Cr, Zn, Pb, Cu, Ni, Cd, As, and Hg were measured. Correlation analysis, cluster analysis, and principal component analysis were used to analyze the sources of the heavy metals, and the enrichment factor index, single-factor pollution index, pollution load index, geo-accumulation index method, and potential ecological risk index were selected to assess the environmental risk of the eight heavy metals in the topsoil. The results showed that the average values of Cr, Zn, Pb, Cu, Ni, Cd, As, and Hg contents in the surface soil of Chuzhou City were higher than the background value of that in the soil of Yangtze-Huaihe River Basin of Anhui, and Cd, Ni, As, and Hg were significantly different in space and influenced by external disturbance. The eight types of heavy metals could be divided into four categories based on correlation analysis, cluster analysis, and principal component analysis. Cr, Zn, Cu, and Ni were from natural background sources; As and Hg mainly came from sources of industrial and agricultural pollution; Pb mainly came from the sources of transportation pollution and industrial and agricultural pollution; and Cd came from the sources of transportation pollution, natural background, and industrial and agricultural pollution. The overall pollution degree of Chuzhou City was low, and the ecological risk level was at a slight level based on the pollution load index and the potential ecological risk index; however, the ecological risk of Cd and Hg was generally serious, and these two heavy metals should be taken as the objects of priority control. The results provided a scientific basis for soil safety utilization and classification control in Chuzhou City.

Paired-related homeobox 1 induces epithelial-mesenchymal transition in oesophageal squamous cancer.

BACKGROUND: It is unclear that paired-related homeobox 1 (PRRX1) induces epithelial-mesenchymal transition (EMT) in oesophageal cancer and the specific function of PRRX1 in oesophageal cancer metastasis. AIM: To assess the significance of PRRX1 expression and investigate the mechanism of EMT in oesophageal cancer metastasis. METHODS: Detect the expression of PRRX1 by immunohistochemistry in oesophageal tumour tissues and adjacent normal oesophageal tissues; the PRRX1 short hairpin RNA (shRNA) or blank vector lentiviral gene delivery system was transfected into cells; cell proliferation assay, soft agar colony formation assays, cell invasion and migration assays and animal studies were used to observe cells biological characteristics In vitro and in vivo; XAV939 and LiCl were used to alter the activity of Wnt/ß-catenin pathway. Immunofluorescence staining and western blot analysis were used to detect protein expression of EMT markers and Wnt/ß-catenin pathway. RESULTS: PRRX1 is expressed at high levels in oesophageal cancer specimens and is closely related to tumour metastasis in patients with oesophageal cancer. Regulation of PRRX1 expression might exert obvious effects on cell proliferation, especially the migration and invasion of oesophageal cancer cells. Moreover, silencing PRRX1 expression using a shRNA produced the opposite effects. In addition, when PRRX1 was overexpressed, inhibition of the Wnt/ß-catenin pathway with XAV939 negated the effect of PRRX1 on EMT, whereas when PRRX1 was downregulated, activation of the Wnt/ß-catenin pathway with LiCl impaired the effect on EMT. CONCLUSION: PRRX1 is upregulated in oesophageal cancer is closely correlated with cancer metastasis. Additionally, PRRX1 induces EMT in oesophageal cancer metastasis through activation of Wnt/ß-catenin signalling.

Tumor-Intrinsic PD-L1 Exerts an Oncogenic Function through the Activation of the Wnt/ß-Catenin Pathway in Human Non-Small Cell Lung Cancer.

Programmed death ligand 1 (PD-L1) strongly inhibits T cell activation, thereby aiding tumors in escaping the immune response. PD-L1 inhibitors have proven to be effective in the treatment of different types of cancer, including non-small cell lung cancer (NSCLC). Yet, the knowledge regarding the biological function of tumor-intrinsic PD-L1 in lung cancer remains obscure. In our study, we set the goal of determining the function of PD-L1 using overexpression and knockdown strategies. PD-L1 silencing resulted in decreased migratory and invasive ability of tumor cells, together with attenuated colony-forming capacity. Ectopic expression of PD-L1 showed the opposite effects, along with increased activities of MAPK and Wnt/ß-catenin pathways, and the upregulation of Wnt/ß-catenin target genes. Additionally, overexpression of PD-L1 was associated with dysregulated cellular and exosomal miRNAs involved in tumor progression and metastasis. In primary lung tumors, immunohistochemistry revealed that both PD1 and PD-L1 were highly expressed in squamous cell carcinoma (SCC) compared to adenocarcinoma (p = 0.045 and p = 0.036, respectively). In SCC, PD1 expression was significantly associated with tumor grading (p = 0.016). Taken together, our data suggest that PD-L1 may exert an oncogenic function in NSCLC through activating Wnt/ß-catenin signaling, and may act as a potential diagnostic marker for lung SCC.

Schisantherin D from Schisandra chinensis (Turcz.) Baill. exhibits anti-liver fibrosis capacity via modulating ETBR involved signaling, an in vitro and in vivo study.

Excess levels of chemical hepatotoxicants (alcohol, aflatoxin B1), oxidative drugs (acetaminophen) and some cytokines (ET-1, TGF-ß1) can induce chronic or acute liver injury. After these, the severe hepatic disease, especially the liver fibrosis (LF) occurs without taking measures, which brings threat to human health. The dibenzocyclooctadiene lignans of S. chinensis (SCDLs) were found to act as the hepatoprotective components via blocking endothelin B receptor (ETBR). While study on its anti-LF mechanisms especially for its refined compound of schisantherin D (SC-D) is still a lack. So this study aims to investigate the anti-fibrosis effect of SC-D with in vitro and in vivo assays. Bioinformatics analysis revealed the close relations of ETBR to Smad2, Smad3, Nrf2, etc. in LF-related signaling pathways (such as TGF-ß/Smad and Nrf2/ARE). Histopathological staining on livers showed the recovery trend in SC-D treated LF mice. SC-D also modulated expressions of ETBR and fibrosis or anti-oxidative related proteins (such as TIMP1, p-Smad2/3, Nrf2, Smad7, etc.) in LF mice livers. Serum levels of TNF-α, COLI, ALT, AST and LDH in SC-D treated mice were also downregulated compared with LF mice, and upregulated expression of GSH. In vitro studies, SC-D also modulated expressions of LF-related proteins to the normal tendency in LX-2 cell, while weakened its anti- LX-2 proliferation effect by transfections of si-Smad7 or si-Nrf2. Accordingly the anti-LF approach of SC-D showed relations with modulating ETBR linked fibrosis and anti-oxidative related signaling. Also, Smad7 and Nrf2 might be the key factors for SC-D mediated anti-LF effect.

A Risk Model of Eight Immune-Related Genes Predicting Prognostic Response to Immune Therapies for Gastric Cancer.

Immune checkpoint inhibitor (ICI) treatment is considered as an innovative approach for cancers. Since not every patient responded well to ICI therapy, it is imperative to screen out novel signatures to predict prognosis. Based on 407 gastric cancer (GC) samples retrieved from The Cancer Genome Atlas (TCGA), 36 immune-related hub genes were identified by weighted gene co-expression network analysis (WGCNA), and eight of them (RNASE2, CGB5, INHBE, DUSP1, APOA1, CD36, PTGER3, CTLA4) were used to formulate the Cox regression model. The obtained risk score was proven to be significantly correlated with overall survival (OS), consistent with the consequence of the Gene Expression Omnibus (GEO) cohort (n = 433). Then, the relationship between the risk score and clinical, molecular and immune characteristics was further investigated. Results showed that the low-risk subgroup exhibited higher mutation rate, more M1 macrophages, CD8+ and CD4+ T cells infiltrating, more active MHC-I, and bias to "IFN-γ Dominant" immune type, which is consistent with our current understanding of tumor prognostic risk. Furthermore, it is suggested that our model can accurately predict 1-, 2-, and 3-year OS of GC patients, and that it was superior to other canonical models, such as TIDE and TIS. Thus, these eight genes are probably considered as potential signatures to predict prognosis and to distinguish patient benefit from ICI, serving as a guiding individualized immunotherapy.

Acute Mast Cell Leukemia Preceded by Malignant Mediastinal Germ Cell Tumor: A Case Report and Literature Review.

Background: Mast cell leukemia (MCL) is a highly life-threatening and extremely rare subtype of systemic mastocytosis (SM). MCL often genetically contains one or more somatic mutations, particularly activating mutations of KIT. This study reported on an acute MCL patient who had a rare phenotype and genetic mutants with a history of primary malignant mediastinal germ cell tumor (GCT). Case Presentation: A 30-year-old Asian male patient who underwent two rounds of surgery and chemotherapy with a history of primary mediastinal GCT (PM-GCTs) was admitted to our hospital due to persistent chest pain and severe fatigue. The diagnosis of acute MCL was confirmed via morphology analysis and chemical staining of marrow aspirate, as well as via marrow biopsy, with the addition of C-findings that included splenomegaly and cytopenia. The atypical MCs were phenotypically positive for CD117 and CD9 but weakly positive for CD2 and negative for CD25. Next-generation sequencing of the marrow aspirate identified heterozygous mutations in TP53 P301Qfs*44, FLT3 R973X, SETBP1 N272D, and JAK3 I688F, whereas mutations in KIT were not found. Although the initial therapy of corticosteroids, ruxolitinib, and dasatinib-based regimens was effective, he died of acute respiratory distress syndrome after the first cycle of chemotherapy with cladribine and cytarabine. The patient's survival time was 2.4 months after the initial presentation of MCL. Conclusion: In this case, MCL preceded by PM-GCTs had similar clinical symptoms and morphological manifestations but distinctly different genetic profiles than primary MCL. The characteristic morphology of MCL provides the most pivotal evidence that led our diagnosis in the correct direction. A competing hypothesis is that there is a common embryonal cancer stem cell between PM-GCTs and secondary MCL, and the latter is gradually developed in the context of additional "driver mutations".

Folic acid: a potential inhibitor against SARS-CoV-2 nucleocapsid protein.

CONTEXT: Coronavirus disease 2019 is a global pandemic. Studies suggest that folic acid has antiviral effects. Molecular docking shown that folic acid can act on SARS-CoV-2 Nucleocapsid Phosphoprotein (SARS-CoV-2 N). OBJECTIVE: To identify novel molecular therapeutic targets for SARS-CoV-2. MATERIALS AND METHODS: Traditional Chinese medicine targets and virus-related genes were identified with network pharmacology and big data analysis. Folic acid was singled out by molecular docking, and its potential target SARS-CoV-2 N was identified. Inhibition of SARS-CoV-2 N of folic acid was verified at the cellular level. RESULTS: In total, 8355 drug targets were potentially involved in the inhibition of SARS-CoV-2. 113 hub genes were screened by further association analysis between targets and virus-related genes. The hub genes related compounds were analysed and folic acid was screened as a potential new drug. Moreover, molecular docking showed folic acid could target on SARS-CoV-2 N which inhibits host RNA interference (RNAi). Therefore, this study was based on RNAi to verify whether folic acid antagonises SARS-CoV-2 N. Cell-based experiments shown that RNAi decreased mCherry expression by 81.7% (p < 0.001). This effect was decreased by 8.0% in the presence of SARS-CoV-2 N, indicating that SARS-CoV-2 N inhibits RNAi. With increasing of folic acid concentration, mCherry expression decreased, indicating that folic acid antagonises the regulatory effect of SARS-CoV-2 N on host RNAi. DISCUSSION AND CONCLUSIONS: Folic acid may be an antagonist of SARS-CoV-2 N, but its effect on viruses unclear. In future, the mechanisms of action of folic acid against SARS-CoV-2 N should be studied.

Effects of imipenem combined with glutamine in the treatment of severe acute pancreatitis with abdominal infection in mainland China: a meta-analysis.

OBJECTIVE: The aim of this study was to explore the efficacy of imipenem combined with glutamine in the treatment of severe acute pancreatitis with abdominal infection in mainland China using meta-analysis. METHODS: We searched China National Knowledge Network, Wanfang Medical Network, Chinese Science Citation Database, PubMed, and Embase Databases for publications of imipenem combined with glutamine in the treatment of severe acute pancreatitis abdominal infection. The search time limit was from the establishment of the database to April 10, 2021. Stata software version 12.0 was used for statistical analysis; the combined effect size odds ratio and standardized mean difference values were calculated for the count data and measurement data, respectively; and the heterogeneity test was performed in this study. RESULTS: A total of five randomized controlled trials were included. A total of 499 cases were included, with 251 in the observation group and 248 in the control group. Meta-analysis results showed that the efficacy of imipenem combined with glutamine in the treatment of severe acute pancreatitis with abdominal infection was significantly better than that of imipenem alone (odds ratio=0.78, 95%CI 0.71-0.86, p=0.040). CONCLUSION: Imipenem combined with glutamine can significantly improve the efficacy in the treatment of severe acute pancreatitis with abdominal cavity infection.

Long-Term Follow-Up of Combination of B-Cell Maturation Antigen and CD19 Chimeric Antigen Receptor T Cells in Multiple Myeloma.

PURPOSE: A combination of anti-B-cell maturation antigen (BCMA) and anti-CD19 chimeric antigen receptor (CAR) T cells induced high response rates in patients with relapsed or refractory (R/R) multiple myeloma (MM), but long-term outcomes have not been assessed yet. PATIENTS AND METHODS: In this single-arm, phase II trial, patients with R/R MM received a combination of anti-BCMA CAR T cells and anti-CD19 CAR T cells at a dose of 1 × 106 cells/kg, after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. RESULTS: Of 69 enrolled patients, 62 received the combined infusion of anti-BCMA and anti-CD19 CAR T cells with a median follow-up of 21.3 months. The overall response rate was 92% (57/62), and complete response or better was observed in 37 patients (60%). Minimal residual disease-negativity was confirmed in 77% (43/56) of the patients with available minimal residual disease detection. The estimated median duration of response was 20.3 months (95% CI, 9.1 to 31.5). The median progression-free survival was 18.3 months (95% CI, 9.9 to 26.7), and the median overall survival was not reached. Patients with extramedullary disease had significantly inferior survival. Fifty-nine patients (95%) had cytokine release syndrome, with 10% grade 3 or higher. Neurotoxic events occurred in seven patients (11%), including 3% grade 3 or higher. Late adverse effects were rare, except for B-cell aplasia, hypogammaglobulinemia, and infections. CONCLUSION: The combination of anti-BCMA and anti-CD19 CAR T cells induced durable response in patients with R/R MM, with a median progression-free survival of 18.3 months and a manageable long-term safety profile.

Effects of imipenem combined with glutamine in the treatment of severe acute pancreatitis with abdominal infection in mainland China: a meta-analysis

SUMMARY OBJECTIVE: The aim of this study was to explore the efficacy of imipenem combined with glutamine in the treatment of severe acute pancreatitis with abdominal infection in mainland China using meta-analysis. METHODS: We searched China National Knowledge Network, Wanfang Medical Network, Chinese Science Citation Database, PubMed, and Embase Databases for publications of imipenem combined with glutamine in the treatment of severe acute pancreatitis abdominal infection. The search time limit was from the establishment of the database to April 10, 2021. Stata software version 12.0 was used for statistical analysis; the combined effect size odds ratio and standardized mean difference values were calculated for the count data and measurement data, respectively; and the heterogeneity test was performed in this study. RESULTS: A total of five randomized controlled trials were included. A total of 499 cases were included, with 251 in the observation group and 248 in the control group. Meta-analysis results showed that the efficacy of imipenem combined with glutamine in the treatment of severe acute pancreatitis with abdominal infection was significantly better than that of imipenem alone (odds ratio=0.78, 95%CI 0.71-0.86, p=0.040). CONCLUSION: Imipenem combined with glutamine can significantly improve the efficacy in the treatment of severe acute pancreatitis with abdominal cavity infection.

USP5 promotes breast cancer cell proliferation and metastasis by stabilizing HIF2α.

Hypoxia-inducible factor 2α (HIF2α) plays a pivotal role in breast tumor growth and metastasis. However, the regulatory mechanisms of HIF2α protein stability remain poorly understood. The precise role of the deubiquitinase (DUB) ubiquitin-specific peptidase 5 (USP5) in breast cancer and the underlying mechanism remains largely unknown. Here, we identified USP5 as a novel DUB for HIF2α. Physically, USP5 interacts with HIF2α and protects HIF2α from ubiquitin-proteasome degradation, thereby promoting the transcription of HIF2α target genes, such as SLC2A1, PLOD2, P4HA1, and VEGFA. USP5 ablation impairs breast cancer cells proliferation, colony formation, migration, and invasion. Moreover, USP5 is highly expressed in breast cancer, and the protein levels of USP5 are positively correlated with HIF2α protein levels in human breast cancer tissues. Importantly, high levels of USP5 leads to poor clinical outcome in patients with breast cancer. Collectively, USP5 stabilizes HIF2α through its DUB activity and provides a potential therapeutic target for breast cancer.

Clinical Analysis of Single and Double Sacroiliac Screws in the Treatment of Tile C1 Pelvic Fracture.

We investigated the difference between fixation of single and double sacroiliac screws in the treatment of Tile C1 pelvic fractures. The data of 54 patients with Tile C1 pelvic fractures who were admitted to the trauma center of the Red Society Hospital Affiliated to Xi'an Jiaotong University between August 2016 and August 2020 were retrospectively analyzed. All patients with posterior pelvic ring injuries underwent fixation with sacroiliac screws assisted by a percutaneous robotic navigation system. The operative time, amount of intraoperative blood loss, and postoperative follow-up time between the two groups (single sacroiliac and double sacroiliac screw groups) were compared. The Matta and Majeed scores at the last follow-up were compared between the groups to evaluate fracture reduction and functional recovery. Forty-nine patients were followed up for 17.2 (±4.5) months and 16.2 (±3.4) months in the single and double sacroiliac screw groups, respectively. All patients had excellent fracture reduction immediately after surgery, according to the Matta score. All fractures healed without complications. There was no statistically significant difference in preoperative general information, amount intraoperative blood loss, intraoperative anterior ring fixation method, and postoperative follow-up time between the two groups (P > 0.05). The operative time of the single sacroiliac screw group was shorter than that of the double sacroiliac screw group (P < 0.05). At the last follow-up, the Matta score of the double sacroiliac screw group was significantly better than that of the single sacroiliac screw group (P < 0.05), and there was no statistically significant difference in the Majeed functional scores (P > 0.05). For Tile C1 pelvic fractures, double sacroiliac screw fixation of posterior ring injuries can provide a more stable treatment with no statistically significant difference in functional recovery.

NLRP2 inhibits cell proliferation and migration by regulating EMT in lung adenocarcinoma cells.

Nucleotide-binding oligomerization domain-like receptors (NLRs) are crucial types of innate immune sensors and well known for their critical roles in the immune system. However, how NLRP2 functions in the progression of cancer is largely unknown. Here, we identified NLRP2 as an antioncogene in lung adenocarcinoma (LUAD) cells. Gain- and loss-of-function studies revealed that NLRP2 silencing promoted cell proliferation and migration by stimulating NF-kB signaling in the microenvironment, which induced epithelial-to-mesenchymal transition (EMT) phenotype and cytoskeleton reorganization in LUAD cells. The addition of the NF-kB inhibitor rescued the function of NLRP2 on EMT. Moreover, NLRP2 increased the level of cofilin phosphorylation and repressed subsequent F-actin reorganization. Consistently, the in vivo study showed that NLRP2 played an inhibitory role in forming metastasis foci. Taken together, NLRP2 inhibited cell proliferation and migration by regulating EMT in LUAD cells, demonstrating the essential function of NLRP2 in the development of LUAD.

Supervillin Contributes to LPS-induced Inflammatory Response in THP-1 Cell-derived Macrophages.

Supervillin (SVIL) is an actin-binding and membrane-associated protein, which belongs to villin/gelsolin family. It has been reported that SVIL was involved in the regulation of macrophages' movement and lipopolysaccharide (LPS) increased the SVIL mRNA expression in neutrophils, but the underlying mechanisms remain unknown. This work investigated the underlying molecular mechanisms of LPS regulating SVIL expression in macrophages and hence the possible role of SVIL in LPS-induced inflammation. We found that in THP-1-derived macrophages, LPS obviously increased SVIL mRNA and protein expression. Inhibition of TLR4 by Resatorvid (Res) remarkably reversed the LPS-induced SVIL expression. Additionally, inhibition of ERK1/2 signaling pathway (by U0126 or GDC-0994) and NF-κB (by BAY) significantly reduced the LPS-induced SVIL expression. Interestingly, down-regulation of SVIL by SVIL-specific shRNAs significantly attenuated the expression of IL-6, IL-1ß & TNF-α induced by LPS at both mRNA and protein levels. Furthermore, we also observed that SVIL knockdown decreased the proportion of cells in G2/M phase and increased the proportion of cells in S & G0-1 phase of THP-1 derived macrophages, but did not influence the cell viability. Taken together, we demonstrated that LPS induced the expression of SVIL via activating TLR4/NF-κB and ERK1/2 MAPK pathways, and SVIL participated in the inflammatory response of LPS-induced IL-6, IL-1ß and TNF-α upregulation in macrophages.