Central memory CD4+ T cells play a protective role against immune checkpoint inhibitor-associated myocarditis.

AIMS: The widespread use of immune checkpoint inhibitors (ICIs) has demonstrated significant survival benefits for cancer patients and also carry the risk of immune-related adverse events (irAEs). ICIs-associated myocarditis is a rare and serious adverse event with a high mortality rate. Here, we explored the mechanism underlying ICIs-associated myocarditis. METHODS AND RESULTS: Using the peripheral blood of patients with ICIs therapy and ICIs treated mice with transplanted tumors, we dissect the immune cell subsets and inflammatory factors associated with myocarditis. Compared to the control group, patients with myocarditis after ICIs therapy showed an increase in NK cells and myeloid cells in peripheral blood, while T cells significantly decreased. Among T cells, there was an imbalance of CD4/CD8 ratio in the peripheral blood of myocarditis patients, with a significant decrease in central memory CD4+ T (CD4+ TCM) cells. RNA-Seq revealed that CD4+ TCM cells in myocarditis patients were an immunosuppressive cell subset, which highly express the immunosuppressive factor IL4I1. To elucidate the potential mechanism of the decrease in CD4+ TCM cells, protein array was performed and revealed that several inflammatory factors gradually increased with the severity of myocarditis in the myocarditis group, such as IL-1B/CXCL13/CXCL9, while the myocardial protective factor IL-15 decreased. Correlation analysis indicated a positive correlation between IL-15 and CD4+ TCM cells, with high expression of IL-15 receptor IL15RA. Furthermore, in vivo studies using an anti-PDL1 antibody in a mouse tumor model indicated a reduction in CD4+ TCM cells and an increase in CD8+ TEMRA cells, alongside evidence of cardiac fibrosis. Conversely, combining anti-PDL1 antibody treatment with IL-15 led to a resurgence of CD4+ TCM cells, a reduction in CD8+ TEMRA cells, and a mitigated risk of cardiac fibrosis. CONCLUSIONS: Our data highlight CD4+ TCM cells as a crucial role in cardiac protection during ICIs therapy. IL-15, IL4I1 and CD4+ TCM cells can serve as therapeutic targets to reduce ICIs-associated myocarditis in cancer patients.

Dual-level strategy for quantitative kinetics for the reaction between ethylene and hydroxyl radical.

The atmospheric reactions are mainly initiated by hydroxyl radical (OH). Here, we choose the C2H4 + OH reaction as a model reaction for other reactions of OH with alkenes. We use the GMM(P).L//CCSD(T)-F12a/cc-pVTZ-F12 theoretical method as the benchmark results close to the approximation of CCSDTQ(P)/CBS accuracy to investigate the C2H4 + OH reaction. The rate constants for the C2H4 + OH reaction at high-pressure limit were calculated by using the dual-level strategy. It integrates the transition state theory rate constant calculated by GMM(P).L//CCSD(T)-F12a/cc-pVTZ-F12 with the canonical variational transition state theory containing small-curvature tunneling (CVT/SCT) calculated by using the M11-L functional method with the MG3S basis set. The rate constants of C2H4 + OH at different pressures were obtained by using both the system-specific quantum Rice-Ramsperger-Kassel (SS-QRRK) theory and master equation method. The calculated results uncover that both the calculated rate constants at different pressures and temperatures are quantitatively consistent with the values obtained by the experimental measurements in the C2H4 + OH reaction. We find that the post-CCSD(T) contributions to the barrier height for the C2H4 + OH reaction are significant with the calculated value of -0.38 kcal/mol. We also find that the rate determining step is only dominated by the tight transition state under atmospheric conditions, whereas previous investigations indicated that the rate constants were controlled by both the loose and tight transition states in the C2H4 + OH reaction. The present findings unravel that it is an important factor for the effect of torsional anharmonicity on quantitative kinetics.

Exploration of factors affecting hemodynamic stability following pheochromocytoma resection - cohort study.

Purpose: Surgery is the only way to cure pheochromocytoma; however, postoperative hemodynamic instability is one of the main causes of serious complications and even death. This study's findings provide some guidance for improved clinical management. Patients and methods: This study was to investigate the factors leading to postoperative hemodynamic instability in the postoperative pathology indicated pheochromocytoma from May 2016 to May 2022. They were divided into two groups according to whether vasoactive drugs were used for a median number of days or more postoperatively. The factors affecting the postoperative hemodynamics in the perioperative period (preoperative, intraoperative, and postoperative) were then evaluated. Results: The median number of days requiring vasoactive drug support postoperatively was three in 234 patients, while 118 (50.4%) patients required vasoactive drug support for three days or more postoperatively. The results of the multivariate analysis indicated more preoperative colloid use (odds ratio [OR]=1.834, confidence interval [CI]:1.265-2.659, P=0.001), intraoperative use of vasoactive drug (OR=4.174, CI:1.882-9.258, P<0.001), and more postoperative crystalloid solution input per unit of body weight per day (ml/kg/d) (OR=1.087, CI:1.062-1.112, P<0.001) were risk factors for predicting postoperative hemodynamic instability. The optimal cutoff point of postoperative crystalloid use were 42.37 ml/kg/d. Conclusion: Hemodynamic instability is a key issue for consideration in the perioperative period of pheochromocytoma. The amount of preoperative colloid use, the need for intraoperative vasoactive drugs, and postoperative crystalloid solution are risk factors for predicting postoperative hemodynamic instability (registration number: ChiCT2300071166).

Association of immune checkpoint inhibitors therapy with arterial thromboembolic events in cancer patients: A retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have emerged as a standard treatment for various malignancies. However, research indicates blocking the immune checkpoint pathway may exacerbate atherosclerotic lesions. OBJECTIVES: We aimed to investigate whether ICI therapy increases the risk of arterial thromboembolic events (ATEs). METHODS: A retrospective cohort study was conducted on patients with histologically confirmed cancer at our institution between 2018 and 2021, using the propensity score matching method. The primary endpoint was ATEs occurrence, comprising acute coronary syndrome, stroke/transient ischemic attack, and peripheral arterial thromboembolism. Subgroup analyses assessed whether the ICI treatment effect on ATEs varied over time by limiting the maximum follow-up duration. Logistic regression analysis identified ATE risk factors in ICI-treated patients. RESULTS: Overall, the ICI group (n = 2877) demonstrated an ATEs risk 2.01 times higher than the non-ICI group (RR, 2.01 [95% CI (1.61-2.51)]; p < 0.001). Subgroup analysis revealed no significant increase in ATEs risk for ICI-treated patients within 1 year (Limited to a max 9-month follow-up, p = 0.075). However, ATEs risk in the ICI group rose by 41% at 1 year (p = 0.010) and 97% at 4 years (p ≤ 0.001). Age, diabetes, hypertension, peripheral atherosclerosis, atrial fibrillation, chronic ischemic heart disease, distant cancer metastasis, and ICI treatment cycles contributed to ATEs risk elevation in ICI-treated patients. CONCLUSION: ICI-treated patients may exhibit a higher risk of ATEs, especially after 1 year of treatment.

Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress.

BACKGROUND & AIMS: Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC. METHODS: Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine. RESULTS: Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes ring finger protein 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice. CONCLUSIONS: Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

Pre-anesthesia ultrasound monitoring of subclavian vein diameter changes induced by modified passive leg raising can predict the occurrence of hypotension after general anesthesia: a prospective observational study.

BACKGROUND: Perioperative hypotension increases postoperative complication rates and prolongs postoperative recovery time. Whether Passive Leg Raising test (PLR) and Subclavian Vein Diameter (DSCV) can effectively predict post-anesthesia hypotension remains to be tested. This study aimed to identify specific predictors of General Anesthesia (GA)induced hypotension by measuring DSCV in the supine versus PLR position. METHODS: A total of 110 patients who underwent elective gynecological laparoscopic surgery under general anesthesia, were enrolled in this study. Before anesthesia, DSCV and theCollapsibility Index of DSCV(DSCV-CI) were measured by ultrasound, and the difference in maximal values of DSCV between supine and PLR positions was calculated, expressed as ΔDSCV. Hypotension was defined as Mean Blood Pressure (MBP) below 60mmhg or more than 30% below the baseline. Patients were divided into two groups according to the presence (Group H) or absence (Group N) of postanesthesia hypotension. The area under the receiver operating characteristic curve (ROC) and logistic regression analyses were used to evaluate the predictability of DSCV and other parameters for predicting preincision hypotension. RESULTS: Three patients were excluded due to unclear ultrasound scans, resulting in a total of 107 patients studied. Twenty-seven (25.2%) patients experienced hypotension. Area under the ROC curve of ΔDSCV was 0.75 (P < 0.001) with 95% confidence interval (0.63-0.87), while DSCV and DSCV-CI were less than 0.7. The odds ratio (OR)of ΔDSCV was 1.18 (P < 0.001, 95%CI 1.09-1.27) for predicting the development of hypotension. ΔDSCV is predictive of hypotension following induction of general anesthesia. CONCLUSIONS: ΔDSCV has predictive value for hypotension after general anesthesia. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry on 04/10/2021.

Diagnostic value of circN4BP2L2 in type I and type II epithelial ovarian cancer.

BACKGROUND: CircN4BP2L2 was previously identified to be significantly decreased in epithelial ovarian cancer (EOC) and was associated with disease progression. The aim of this study was to evaluate the diagnostic value of plasma circN4BP2L2 using the unifying model of type I and type II EOC. METHODS: A total of 540 plasma samples were obtained from 180 EOC patients, 180 benign ovarian cyst patients, and 180 healthy volunteers. CircN4BP2L2 was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) were assessed using enzyme-linked immunosorbent assay (ELISA). Receiver operating curve (ROC), the area under the curve (AUC), sensitivity and specificity were estimated. RESULTS: Low level of circN4BP2L2 was associated with advanced tumor stage (p < 0.01) in type I EOC. Decreased circN4BP2L2 was associated with lymph node metastasis (LNM) (p = 0.04) in type II EOC. The expression level of circN4BP2L2 in type I was similar to that in type II. CircN4BP2L2 could significantly separate type I or type II from benign or normal cohort (p < 0.01). Early-stage type I or type II EOC vs. benign or normal cohort could also be distinguished by circN4BP2L2 (p < 0.01). CONCLUSION: CircN4BP2L2 might serve as a promising diagnostic biomarker for both type I and type II EOC. The diagnostic safety for circN4BP2L2 in early-stage type I or type II EOC is also acceptable. Further large-scale well-designed studies are warranted to investigate whether circN4BP2L2 is specific for all histologic subgroups.

Identification of Immune-Related lncRNAs for Predicting Prognosis and Immune Landscape Characteristics of Uveal Melanoma.

Immune-related genes and long noncoding RNAs (lncRNAs) have a significant impact on the prognostic value and immunotherapeutic response of uveal melanoma (UM). Therefore, we tried to develop a prognostic model on the basis of irlncRNAs for predicting prognosis and response on immunotherapy of UM patients. We identified 1,664 immune-related genes and 2,216 immune-related lncRNAs (irlncRNAs) and structured a prognostic model with 3 prognostic irlncRNAs by co-expression analysis, univariable Cox, LASSO, and multivariate Cox regression analyses. The Kaplan-Meier analysis indicated that patients in the high-risk group had a shorter survival time than patients in the low-risk group. The ROC curves demonstrated the high sensitivity and specificity of the signature for survival prediction, and the one-, three-, and five-year AUC values, respectively, were 0.974, 0.929, and 0.941 in the entire set. Cox regression analysis, C-index, DCA, PCA analysis, and nomogram were also applied to assess the validity and accuracy of the risk model. The GO and KEGG enrichment analyses indicated that this signature is significantly related to immune-related pathways and molecules. Finally, we investigated the immunological characteristics and immunotherapy of the model and identified various novel potential compounds in the model for UM. In summary, we constructed a new model on the basis of irlncRNAs that can accurately predict prognosis and response on immunotherapy of UM patients, which may provide valuable clinical applications in antitumor immunotherapy.

A Pan-Cancer Analysis Reveals CLEC5A as a Biomarker for Cancer Immunity and Prognosis.

Background: CLEC5A is a member of the C-type lectin superfamily. It can activate macrophages and lead to a series of immune-inflammation reactions. Previous studies reveal the role of CLEC5A in infection and inflammation diseases. Method: We acquire and analyze data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) database, and other comprehensive databases via GSCALite, cBioPortal, and TIMER 2.0 platforms or software. Single-cell sequencing analysis was performed for quantifying the tumor microenvironment of several types of cancers. Results: CLEC5A is differentially expressed in a few cancer types, of which overexpression accompanies low overall survival of patients. DNA methylation mainly negatively correlates with CLEC5A expression. Moreover, CLEC5A is positively related to immune infiltration, including macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs). Immune checkpoint genes are significantly associated with CLEC5A expression in diverse cancers. In addition, CLEC5A expression correlates with mismatch repair (MMR) in several cancers. Tumor mutation burden (TMB), microsatellite instability (MSI), and neoantigens show a positive association with CLEC5A expression in several cancers. Furthermore, CLEC5A in cancer correlates with signal transduction, the immune system, EMT, and apoptosis process. The drug sensitivity analysis screens out potential therapeutic agents associated with CLEC5A expression, including FR-180204, Tivozanib, OSI-930, Linifanib, AC220, VNLG/124, Bexarotene, omacetaxine mepesuccinate, narciclasine, leptomycin B, PHA-793887, LRRK2-IN-1, and CR-1-31B. Conclusion: CLEC5A overexpresses in multiple cancers in contrast to normal tissues, and high CLEC5A expression predicts poor prognosis of patients and immune infiltration. CLEC5A is a potential prognostic biomarker of diverse cancers and a target for anti-tumor therapy.

Forkhead Box S1 mediates epithelial-mesenchymal transition through the Wnt/ß-catenin signaling pathway to regulate colorectal cancer progression.

BACKGROUND: Recent studies have shown that the fox family plays a vital role in tumorigenesis and progression. Forkhead Box S1 (FOXS1), as a newly identified subfamily of the FOX family, is overexpressed in certain types of malignant tumors and closely associated with patient's prognosis. However, the role and mechanism of the FOXS1 in colorectal cancer (CRC) remain unclear. METHOD: FOXS1 level in CRC tissues and cell lines was analyzed by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry (IHC) was used to detect the relationship between FOXS1 expression and clinicopathological features in 136 patients in our unit. The expression of FOXS1 was knocked down in CRC cells using small interfering RNA (siRNA) technology. Cell proliferation was assessed by CCK8 assay, colony formation, and 5-Ethynyl-20-deoxyuridine (EdU) incorporation assay. Flow cytometry detected apoptosis and wound healing, and Transwell assays determined cell migration and invasion. Western blotting was used to detect the levels of proteins associated with the Wnt/ß-catenin signaling pathway. Then, we used short hairpin RNA (shRNA) to knock down FOXS1 to see the effect of FOXS1 on the proliferation, migration, invasion, and metastasis of CRC cells in vivo. Finally, we investigated the impact of Wnt activator LiCl on the proliferation, migration, invasion, and metastasis of CRC cells after FOXS1 knockdown. RESULT: Compared to those in normal groups, FOXS1 overexpressed in CRC tissues and CRC cells (P < 0.05). Upregulation of FOXS1 association with poor prognosis of CRC patients. si-FOXS1 induced apoptosis and inhibited proliferation, migration, invasion, the epithelial-mesenchymal transition (EMT), and the Wnt/ß-catenin signaling pathway in vitro; sh-FOXS1 inhibited the volume and weight of subcutaneous xenografts and the number of lung metastases in vivo. LiCl, an activator of Wnt signaling, partially reversed the effect of FOXS1 overexpression on CRC cells. CONCLUSION: FOXS1 could function as an oncogene and promote CRC cell proliferation, migration, invasion and metastasis through the Wnt/ßcatenin signaling pathway, FOXS1 may be a potential target for CRC treatment.

Characteristics and Predictors of Venous Thromboembolism Among Lymphoma Patients Undergoing Chemotherapy: A Cohort Study in China.

Background: Venous thromboembolism (VTE) is a potential complication among lymphoma patients. We evaluated the incidence rate and predictors of VTE in lymphoma patients undergoing chemotherapy. Methods: The present study retrospectively studied 1,069 patients with lymphoma who were treated with chemotherapy from 2018 to 2020. We investigated clinical predictors of VTE among all patients. The follow-up results were obtained via telephone communication and from inpatient and outpatient records. Results: A total of 1,069 patients underwent chemotherapy for lymphoma. During a mean follow-up of 23.1 months, 52 (4.9%) patients developed VTE. According to a multivariate analysis, the five variables found to be independently associated with VTE were male sex (HR 2.273, 95% CI 1.197-4.316, p = 0.012), age >64-years-old (HR 2.256, 95% CI 1.017-5.005, p = 0.045), the number of cycles of chemotherapy (HR 4.579, 95% CI 1.173-17.883, p = 0.029), platelet count ≥350 × 109/L (HR 2.533, 95% CI 1.187-5.406, p = 0.016), and D-dimer >0.5 mg/L (HR 4.367, 95% CI 2.124-8.981, p < 0.001). Conclusion: This population-based study confirms the risk factors for VTE among patients with lymphoma who underwent chemotherapy and confirms that targeted thromboprophylaxis may reduce the burden of VTE in this population.

Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.

The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti-Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line-derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor-expressing T cells based on the novel anti-uPAR effectively kill DGC patient-derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner.

Development and Validation of a Risk Prediction Model for Venous Thromboembolism in Lung Cancer Patients Using Machine Learning.

Background: There is currently a lack of model for predicting the occurrence of venous thromboembolism (VTE) in patients with lung cancer. Machine learning (ML) techniques are being increasingly adapted for use in the medical field because of their capabilities of intelligent analysis and scalability. This study aimed to develop and validate ML models to predict the incidence of VTE among lung cancer patients. Methods: Data of lung cancer patients from a Grade 3A cancer hospital in China with and without VTE were included. Patient characteristics and clinical predictors related to VTE were collected. The primary endpoint was the diagnosis of VTE during index hospitalization. We calculated and compared the area under the receiver operating characteristic curve (AUROC) using the selected best-performed model (Random Forest model) through multiple model comparison, as well as investigated feature contributions during the training process with both permutation importance scores and the impurity-based feature importance scores in random forest model. Results: In total, 3,398 patients were included in our study, 125 of whom experienced VTE during their hospital stay. The ROC curve and precision-recall curve (PRC) for Random Forest Model showed an AUROC of 0.91 (95% CI: 0.893-0.926) and an AUPRC of 0.43 (95% CI: 0.363-0.500). For the simplified model, five most relevant features were selected: Karnofsky Performance Status (KPS), a history of VTE, recombinant human endostatin, EGFR-TKI, and platelet count. We re-trained a random forest classifier with results of the AUROC of 0.87 (95% CI: 0.802-0.917) and AUPRC of 0.30 (95% CI: 0.265-0.358), respectively. Conclusion: According to the study results, there was no conspicuous decrease in the model's performance when use fewer features to predict, we concluded that our simplified model would be more applicable in real-life clinical settings. The developed model using ML algorithms in our study has the potential to improve the early detection and prediction of the incidence of VTE in patients with lung cancer.

General anesthesia bullies the gut: a toxic relationship with dysbiosis and cognitive dysfunction.

Perioperative neurocognitive disorder (PND) is a common surgery outcome affecting up to a third of the elderly patients, and it is associated with high morbidity and increased risk for Alzheimer's disease development. PND is characterized by cognitive impairment that can manifest acutely in the form of postoperative delirium (POD) or after hospital discharge as postoperative cognitive dysfunction (POCD). Although POD and POCD are clinically distinct, their development seems to be mediated by a systemic inflammatory reaction triggered by surgical trauma that leads to dysfunction of the blood-brain barrier and facilitates the occurrence of neuroinflammation. Recent studies have suggested that the gut microbiota composition may play a pivotal role in the PND development by modulating the risk of neuroinflammation establishment. In fact, modulation of gut microbiome composition with pre- and probiotics seems to be effective for the prevention and treatment of PND in animals. Interestingly, general anesthetics seem to have major responsibility on the gut microbiota composition changes following surgery and, consequently, can be an important element in the process of PND initiation. This concept represents an important milestone for the understanding of PND pathogenesis and may unveil new opportunities for the development of preventive or mitigatory strategies against the development of these conditions. The aim of this review is to discuss how anesthetics used in general anesthesia can interact and alter the gut microbiome composition and contribute to PND development by favoring the emergence of neuroinflammation.

The Effect of Improving Preoperative Sleep Quality on Perioperative Pain by Zolpidem in Patients Undergoing Laparoscopic Colorectal Surgery: A Prospective, Randomized Study.

METHODS: A prospective, randomized study was conducted with 88 patients undergoing laparoscopic colorectal surgery. The experimental group (S group, n = 44) was given 10 mg of zolpidem tartrate one night before the surgical procedure, while no medication was given to the control group (C group, n = 44). The primary outcome was the intraoperative remifentanil consumption. Sufentanil consumption, average patient-controlled analgesia (PCA) effective press times, the visual analog scale (VAS) scores, and incidences of postoperative nausea and vomiting (PONV) were recorded at 6 h (T1), 12 h (T2), and 24 h (T3) postoperatively. RESULTS: The intraoperative remifentanil consumption was significantly lower in the S group than that in the C group (p < 0.01). Sufentanil consumption at 6 h and 12 h postoperatively was significantly lower in the S group than that in the C group (p < 0.05); average PCA effective press times and VAS scores, at 6 h and 12 h postoperatively, were significantly lower in the S group than those in the C group (p < 0.01); differences between groups 24 h postoperatively were not significant. No significant between-group difference was noted in the incidence of nausea and vomiting. CONCLUSION: Improving patients' sleep quality the night before surgical procedure by zolpidem can decrease the usage of intraoperative analgesics and reduce postoperative pain.

Mitigation of acute radiation-induced brain injury in a mouse model using anlotinib.

BACKGROUND: With the development of radiological technologies, radiotherapy has been gradually widely used in the clinic to intracranial tumours and become standardised. However, the related central nervous system disorders are still the most obvious complications after radiotherapy. This study aims to quantify the effectiveness of anlotinib, a small molecule inhibitor of multiple receptor tyrosine kinases, in mitigating acute phase of radiation-induced brain injury (RBI) in a mouse model. METHODS: The onset and progression of RBI were investigated in vivo. All mice, (except for the sham group) were irradiated at a single-fraction of 20 Gy and treated with different doses of anlotinib (0, 0.2 and 0.8 mg/kg, respectively). The expression levels of glial fibrillary acidic protein (GFAP), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and phosphorylated vascular endothelial growth factor receptor-2 (p-VEGFR2) were assessed by western blot. Histological changes were identified by luxol fast blue (LFB) staining. RESULTS: The expression levels of GFAP, HIF-1α, and VEGF were downregulated following treatment with anlotinib. However, anlotinib failed to inhibit the development of demyelination. Cerebral edema [as measured by brain water content (BWC)] was also mitigated following treatment with anlotinib. CONCLUSIONS: In summary, treatment with anlotinib significantly mitigated the adverse effects of acute RBI in a dose-dependent manner by downregulating the activation of astrocytes, improving brain hypoxia, and alleviating cerebral edema.

A novel UBE2T inhibitor suppresses Wnt/ß-catenin signaling hyperactivation and gastric cancer progression by blocking RACK1 ubiquitination.

Dysregulation of the Wnt/ß-catenin signaling pathway is critically involved in gastric cancer (GC) progression. However, current Wnt pathway inhibitors being studied in preclinical or clinical settings for other cancers such as colorectal and pancreatic cancers are either too cytotoxic or insufficiently efficacious for GC. Thus, we screened new potent targets from ß-catenin destruction complex associated with GC progression from clinical samples, and found that scaffolding protein RACK1 deficiency plays a significant role in GC progression, but not APC, AXIN, and GSK3ß. Then, we identified its upstream regulator UBE2T which promotes GC progression via hyperactivating the Wnt/ß-catenin signaling pathway through the ubiquitination and degradation of RACK1 at the lysine K172, K225, and K257 residues independent of an E3 ligase. Indeed, UBE2T protein level is negatively associated with prognosis in GC patients, suggesting that UBE2T is a promising target for GC therapy. Furthermore, we identified a novel UBE2T inhibitor, M435-1279, and suggested that M435-1279 acts inhibit the Wnt/ß-catenin signaling pathway hyperactivation through blocking UBE2T-mediated degradation of RACK1, resulting in suppression of GC progression with lower cytotoxicity in the meantime. Overall, we found that increased UBE2T levels promote GC progression via the ubiquitination of RACK1 and identified a novel potent inhibitor providing a balance between growth inhibition and cytotoxicity as well, which offer a new opportunity for the specific GC patients with aberrant Wnt/ß-catenin signaling.

Identification of the Risk Factors of Postoperative Pulmonary Complications in Elderly Patients Undergoing Elective Colorectal Surgery.

OBJECTIVE: This study was to identify the perioperative related risk factors of postoperative pulmonary complications (PPCs) in elderly patients undergoing elective colorectal surgery, which will provide new insight for better prevention and intervention of PPCs in elderly patients. METHODS: A retrospective study involving 445 patients (age ≥65), who registered in Shengjing Hospital affiliated to China Medical University for elective colorectal surgery from October 2014 to March 2017, was conducted. Clinical data, including demographic information, medical history, preoperative examination, and surgery-related factors, were analyzed and compared between the patient group with PPCs and the group without PPCs. t-test or χ2 test was performed for statistical analysis between the 2 groups. Binary logistic regression analysis was further employed to identify the potential independent risk factors of PPCs. RESULTS: Among the 445 patients enrolled in the study, 49 (11%) had PPCs, while 396 (89%) did not. The main risk factors of PPC occurrence in the elderly patients undergoing elective colorectal surgery included older age (age ≥75 years), ASA >II, hypertension, myocardial ischemia, basic pulmonary diseases, laparotomy, blood transfusion, preoperative hemoglobin <100 g/L, and albumin <35 g/L. Laparotomy (compared with laparoscope) and ASA >II were independent risk factors for the increased incidence of PPCs. CONCLUSION: More attention should be paid to patients with older age and ASA >II in elective colorectal surgery. Choice of laparoscopic operation, proper treatment of hypertension, myocardial ischemia, basic pulmonary diseases, and correction of anemia and nutritional status can effectively reduce the incidence of PPCs. An adequate and comprehensive evaluation of the potential risk factors related to PPCs is required before surgery.

Analgesic Effect of Serratus Anterior Plane Block After Thoracoscopic Surgery: A Randomized Controlled Double-Blinded Study.

PURPOSE: Fast-track surgery is a developing trend in medical care. It is a core challenge for clinical anesthesia to reasonably reduce the dosage of opioids and relieve postoperative pain. Serratus anterior plane block (SAPB) is a novel analgesic technique with such advantages as easy operation, good safety, and few side effects. PATIENTS AND METHODS: In total, 60 patients aged 18 to 65 years who were diagnosed with lung cancer and scheduled for thoracoscopic resection were randomly assigned to receive SABP or local infiltration anesthesia. We analyzed the time within 48 hrs after operation to visual analogue scale (VAS) pain score of 4 or higher and the number of patients requiring additional analgesics at 6 hrs and 12 hrs after operation. RESULTS: The estimated median time to VAS ≥4 was 4 hrs (1.32 to 6.68) in the control group and 11 hrs (6.71 to 15.29) in the SAPB group (log-rank test: P=0.008). The number of patients requiring additional analgesics at 6- and 12 hrs after operation was significantly lower in the SAPB group than that in the control group (P<0.05). CONCLUSION: Compared with local infiltration, SAPB provided extended postoperative analgesia after thoracoscopic surgery with reduced consumption of additional analgesics in the early postoperative stage.