Pharmacokinetics and Pharmacodynamics of Sacubitril/Valsartan in Maintenance Hemodialysis Patients with Heart Failure.

BACKGROUND: Heart failure (HF) is one of the main comorbidities in patients receiving maintenance hemodialysis (HD). Sacubitril/valsartan (SAC/VAL) is widely used in HF patients with reduced ejection fraction (HFrEF) or HF mid-range ejection fraction (HFmrEF). However, the pharmacokinetic (PK) and pharmacodynamic properties of SAC/VAL in HD patients with HF remain uncertain. OBJECTIVES: This study aimed to analyze the efficacy and PK properties of SAC/VAL in HD patients with HFrEF or HFmrEF. METHODS: HD patients with HFrEF or HFmrEF were treated with SAC/VAL 50 or 100 mg twice a day (BID) and the concentrations of valsartan and LBQ657 (active metabolite of SAC) were determined by high-performance liquid chromatography-tandem mass spectrometry during HD and on the days between HD sessions (interval days). N-terminal-pro B-type natriuretic peptide and high-sensitivity troponin T were measured, and left ventricular ejection fraction (LVEF) was evaluated by echocardiography. RESULTS: The mean maximum plasma concentrations (Cmax) of LBQ657 and VAL on the interval days were 15.46 ± 6.01 and 2.57 ± 1.23 mg/L, respectively. Compared with previous values in patients with severe renal impairment and healthy volunteers, these levels both remained within the safe concentration ranges during treatment with SAC/VAL 100 mg BID. Moreover, SAC/VAL significantly improved LVEF in HD patients with HFrEF or HFmrEF (p < 0.05). CONCLUSIONS: HD did not remove the SAC metabolite LBQ657 or VAL in patients with HF. However, SAC/VAL 100 mg BID was safe and effective in patients undergoing HD.

Systematic Review and Meta-Analysis of -New-Generation Tyrosine Kinase Inhibitors versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia.

BACKGROUNDS: We performed this systematic review and meta-analysis to compare the efficacy of new-generation tyrosine kinase inhibitors (NG-TKIs; including dasatinib, nilotinib, bosutinib, radotinib, and ponatinib) versus imatinib for patients with newly diagnosed chronic myeloid leukemia (CML). SUMMARY: We identified randomized controlled trials comparing the efficacy of NG-TKIs versus imatinib as the first-line treatment for CML patients by searching the PubMed, Cochrane library, and EMBASE databases. Two reviewers independently extracted data and assessed study quality. A meta-analysis was performed to calculate risk ratios and 95% CIs using a fixed-effects model.Our study included 10 trials. Overall, treatment with NG-TKIs significantly improved the major molecular response and MR4.5 at all time points, and early molecular response at 3 months. Importantly, overall survival (OS) was significantly higher with the NG-TKIs at 12 months. Besides, NG-TKI-treated patients showed a significantly lower CML-related death and progression to the accelerated phase/blast crisis. Key Messages: In first-line treatment, NG-TKIs are superior to imatinib regarding OS at 12 months, and because molecular response rates were higher with the NG-TKIs at all time points, the NG-TKIs favor treatment-free remission.

Exosomal miRNA profiling before and after surgery revealed potential diagnostic and prognostic markers for lung adenocarcinoma.

Exosome is a crucial manner for cancer cell to cell communication and circulating exosomes sever as promising diagnostic and prognostic markers for various types of diseases. A predominant type of cargo of exosome is small RNAs, especially miRNAs. Here, we profiled plasma exosomal miRNAs of six lung adenocarcinoma patients before and after surgery, as well as six healthy individuals as normal control. Our profiling revealed 38 upregulated and 37 downregulated exosomal miRNAs in the plasma of lung adenocarcinoma patients. Additionally, we found that most upregulated miRNAs were increased in the lung adenocarcinoma samples of TCGA database. We further evaluated the correlation between the upregulated exosomal miRNAs and overall survival with Kaplan-Meier survival analysis using online databases. Our results suggested that exosomal miR-151a-5p, miR-10b-5p, miR-192-5p, miR-106b-3p, and miR-484 are potential prognostic markers for lung adenocarcinoma. Importantly, we validated candidate miRNAs in lung adenocarcinoma patients before and after surgery as well as in healthy controls and found that miR-484 was significantly increased in the plasma of lung adenocarcinoma patients and strikingly decreased post-surgery. Hence, we provided novel information on lung adenocarcinoma-derived exosomal miRNA and potential non-invasive diagnostic and prognostic markers for lung adenocarcinoma.

Analysis of Influencing Factors of Poststroke Depression: Is Higher Body Mass Index Always a Risk Factor of Poststroke Depression?

Poststroke depression (PSD) is a common complication of stroke. We sought to investigate the influencing factors of PSD and explored the association between body mass index (BMI) and PSD. A total of 397 stroke patients in a hospital in Qiqihar City, China, were included in this study in 2016. The order of independent variable importance was the score of the National Institute of Health Stroke Scale, frequency of stroke, age, BMI, and sleep duration. Sleep duration of 7 hours or more (compared with <7 hours) was negatively associated with the Self-Rating Depression Scale (SDS) score in all quantiles. BMI of 28.0 kg/m or more (compared with 24.0-28.0 kg/m) was negatively associated with SDS score, and the coefficients manifested a continuous increasing trend from P30 to P84.1 in patients aged 65 years or more. In addition, the relationship between BMI and SDS score demonstrated a "U"-shaped curve in patients aged less than 65 years. The National Institute of Health Stroke Scale score, the frequency of stroke, sleep duration, and BMI were the influencing factors of PSD. BMI played different roles in the two age groups.

Percutaneous Myotomy With a Small Needle-Knife and Lipoinjection for Treatment of Glabellar Frown Lines.

BACKGROUND: Glabellar frown lines are a common aesthetic concern, and minimally invasive techniques to treat frown lines have become popular. OBJECTIVES: The authors developed a technique to minimize frown lines by means of percutaneous myotomy with a small needle-knife and lipoinjection. METHODS: Sixty-nine patients underwent treatment of the glabellar frown lines in a prospective study. Percutaneous myotomy of the corrugator supercilii and procerus was conducted with a small needle-knife, and autologous fat was transferred to the glabellar region. Two independent investigators assessed improvement of the glabellar frown lines by applying the Merz Facial Wrinkle Scale preoperatively and 6 months postoperatively. Improvement by ≥1 point was regarded as a response to treatment. Patients also conducted a self-assessment based on the Global Aesthetic Improvement Scale. RESULTS: The mean follow-up period was 8 months. The evaluators determined that the glabellar frown lines of 62 patients (89.9%) responded to treatment. For 4 patients (5.8%), the frown lines were partially improved, and the frown lines did not improve for 3 patients (4.3%). In a self-assessment, 64 patients (92.8%) perceived improvement in their frown lines 6 months postoperatively. No serious complications were recorded. CONCLUSIONS: Treatment of glabellar frown lines by percutaneous myotomy with a small needle-knife and lipoinjection is reliable and minimally invasive. LEVEL OF EVIDENCE: 4.

[Effects and reasons of conversion during video-assisted thoracic surgery lobectomy].

OBJECTIVE: To explore the impact and reasons of conversion during video-assisted thoracic surgery (VATS) lobectomy. METHODS: A total of 374 patients undergoing VATS lobectomy during May 2007 and May 2012 were divided into 2 groups according to whether conversion was necessary. And their clinical data were retrospectively analyzed. RESULTS: Among them, 36 cases (9.6%) converted into thoractomy during VATS lobectomy. Their clinical profiles of age, gender and surgical type were similar. The conversion group had longer operative duration, more blood loss and more benign proportion than VATS group.No inter-group difference existed in postoperative complication, mortality; tube removal time or hospitalization length. The reasons of conversion included hemorrhage (n = 12), vascular adhesion (n = 6), instrumentation complication (n = 5), incomplete fissure (n = 5), uncertain anatomy (n = 3), abnormal blood vessels (n = 3) and insufficient margin (n = 2). CONCLUSION: Conversion during VATS lobectomy may prolong operative duration and increase blood loss.However there is no effect upon patient recovery.

Benefits of remimazolam as an anesthetic sedative for older patients: A review.

Owing to the decreased levels of receptors in the peripheral and central nervous systems, the functions of various organ systems decline in older patients. When administering anesthesia to older patients, it is necessary to consider the effects of medication on the homeostatic balance. Remimazolam, a new benzodiazepine, was recently developed as an anesthetic drug that has shown promise in clinical anesthesia application owing to its molecular structure, targets, pharmacodynamics, and pharmacokinetic characteristics. Remimazolam exhibits a rapid onset and metabolism, with minor effects on liver and kidney functions. Moreover, the drug has a specific antagonist, flumazenil. It is safer to use in older patients than other anesthetic sedatives and has been widely used since its introduction. Comparisons of the pharmacokinetics, metabolic pathways, effects on target organs, and hemodynamics of different drugs with those of commonly used anesthetic sedative drugs are useful to inform clinical practice. This article elaborates on the benefits of remimazolam compared with those of other anesthetic sedatives for sedation in older patients to demonstrate how it offers a new option for anesthetics in older patients. In cases involving older patients with increased clinical complexities or very old patients requiring anesthesia, remimazolam can be selected as the preferred anesthetic sedative, as outlined in this review.

Long-term prognosis in patients with thymoma combined with myasthenia gravis: a propensity score-matching analysis.

Introduction: We aimed to assess the impact of myasthenia gravis (MG) on the long-term prognosis in patients with thymoma after surgery and identify related prognostic factors or predictors. Methods: This retrospective observational study included 509 patients with thymoma (thymoma combined with MG [MG group] and thymoma alone [non-MG group]). Propensity score matching was performed to obtain comparable subsets of 96 patients in each group. A comparative analysis was conducted on various parameters. Results: Before matching, the 10-year survival and recurrence-free survival rates in both groups were 93.8 and 98.4%, and 85.9 and 93.4%, respectively, with no statistically significant difference observed in the survival curves between the groups (p > 0.05). After propensity score matching, 96 matched pairs of patients from both groups were created. The 10-year survival and recurrence-free survival rates in these matched pairs were 96.9 and 97.7%, and 86.9 and 91.1%, respectively, with no statistical significance in the survival curves between the groups (p > 0.05). Univariate analysis of patients with thymoma postoperatively revealed that the World Health Organization histopathological classification, Masaoka-Koga stage, Tumor Node Metastasis stage, resection status, and postoperative adjuvant therapy were potentially associated with tumor recurrence after thymoma surgery. Multivariate analysis demonstrated that the Masaoka-Koga stage and postoperative adjuvant therapy independently predicted the risk of recurrence in patients with thymoma after surgery. Conclusion: There was no difference in prognosis in patients with thymoma with or without MG. The Masaoka-Koga stage has emerged as an independent prognostic factor affecting recurrence-free survival in patients with thymoma, while postoperative adjuvant therapy represents a poor prognostic factor.

Evaluation of the immune responses of biological adjuvant bivalent vaccine with three different insertion modes for ND and IBD.

Infectious bursal disease (IBD) is a widespread problem in the poultry industry, and vaccination is the primary preventive method. However, moderately virulent vaccines may damage the bursa, necessitating the development of a safe and effective vaccine. The Newcastle disease virus (NDV) has been explored as a vector for vaccine development. In this study, reverse genetic technology was used to obtain three recombinant viruses, namely, rClone30-VP2L (P/M)-chGM-CSF (NP), rClone30-chGM-CSF (P/M)-VP2L (NP), and rClone30-VP2L-chGM-CSF (P/M). Animal experiments showed that the three biological adjuvant bivalent vaccines effectively increased anti-NDV and anti-infectious bursal disease virus (IBDV) titres, enhancing both humoral and cellular immune responses in chickens without leading to any harm. Amongst the three biological adjuvant bivalent vaccines, the rClone30-chGM-CSF (P/M)-VP2L (NP) group had higher levels of anti-NDV antibodies at 14 days after the first immunization and stimulated a greater humoral immune response in 7-10 days. While, the rClone30-VP2L (P/M)-chGM-CSF (NP) group was the most effective in producing a higher level of IBDV antibody response. In conclusion, these three vaccines can induce immune responses more rapidly and effectively, streamline production processes, be cost-effective, and provide a new avenue for the development of Newcastle disease (ND) and IBD bivalent vaccines.

Risk of deep vein thrombosis (DVT) in lower extremity after total knee arthroplasty (TKA) in patients over 60 years old.

PURPOSE: There is a significant risk of DVT after TKA. We aim to evaluate the potential risk factors for postoperative DVT in the lower extremities in TKA patients over 60 years of age and provide a reference for the effective prevention of DVT. METHODS: This retrospective study included patients older than 60 who underwent TKA surgery in our hospital from May 2015 to May 2022 and compared and analyzed patients' personal characteristics and clinical data with or without postoperative DVT. Logistic regression analysis was performed to determine the potential risk factors for DVT after TKA. The sensitivity and specificity of each risk factor in the diagnosis of DVT were compared by the ROC curve, and the value of this model in the diagnosis of DVT was further investigated using a multivariable combined diagnosis ROC curve model. RESULTS: A total of 661 patients over 60 who underwent TKA were included. Preoperative Hematocrit (HCT), platelet count, anesthesia mode, postoperative D-dimer, ESR, diabetes mellitus, and other aspects of the DVT group and non-DVT group were statistically significant after TKA (P < 0.05). Multivariate logistics regression analysis showed that preoperative HCT, anesthesia mode, and diabetes were independent risk factors for DVT in patients over 60 years old after TKA. Compared with the univariate ROC model, the multivariable combined ROC curve analysis model has a higher diagnostic value for the diagnosis of DVT. CONCLUSION: DVT is common in patients over 60 years of age after TKA, and there is a multivariable influence on its pathogenesis. For patients over 60 with diabetes, neuraxial anesthesia is recommended for patients with high preoperative HCT levels, which may reduce the incidence of postoperative DVT.

Ginsenoside Rg5 attenuates hypoxia-induced cardiomyocyte apoptosis via regulating the Akt pathway.

Ginsenoside Rg5 has been implicated in a variety of diseases. However, it is unknown whether Ginsenoside Rg5 can protect against hypoxia-induced neonatal rat cardiomyocytes (NRMs). The purpose of this study was to look into the effect of Ginsenoside Rg5 on hypoxia-induced NRMs apoptosis as well as the underlying molecular mechanism. In this study, following isolation and culture of ventricular myocardial cells from neonatal rats, the appropriate concentration of Rg5 was determined using the MTT assay, the effect of Rg5 on apoptosis was assessed employing TUNEL staining and flow cytometry assays. Levels of apoptosis-related proteins and phosphorylated level of Akt (ser 473 and ser 308) were analyzed using the western blot analysis. Finally, the experimental results shown that Ginsenoside Rg5 significantly inhibited hypoxia-induced NRMs apoptosis, decreased the expression pro-apoptotic protein Bax, increased the expression of anti-apoptotic protein Bcl-2 ratio and the level of cleaved caspase 3. Akt signaling activation was found to be the mechanism of Ginsenoside Rg5s protective effect on hypoxia-induced NRMs apoptosis, as an Akt inhibitor eliminated the anti-apoptotic effects of Ginsenoside Rg5. Various analyses were performed and verified, ginsenoside Rg5 suppressed hypoxia-induced apoptosis in NRMs via activation of the Akt signaling.

Development and evaluation of Newcastle disease - avian influenza bivalent vector vaccines in commercial chickens.

Avian influenza (AI) and Newcastle disease (ND) are regarded as the leading viral infectious diseases affecting the global poultry industry. Vaccination is a successful therapeutic intervention to safeguard birds against both ND and AI infections. In this research, ND-AI bivalent vaccines were developed through the incorporation of HA and IRES-GMCSF gene fragments at varying locations of NDV rClone30 vectors. The two constructed vaccines were rClone30-HA-IRES-GMCSF(PM) and rClone30-HA(PM)-IRES-GMCSF(NP). Next, 27-day-old Luhua chickens (the maternal antibody level was reduced to 1.4 log2) were inoculated with the same dose of the vaccines, and humoral and cellular immune responses were assessed at multiple time points. Compared to the commercial vaccine, the levels of anti-NDV antibodies following the administration of the ND-AI vaccines were above the theoretical protection value of 4 log2. The levels of anti-AIV antibodies in the bivalent vaccine group were notably higher than those in the commercial vaccine group. Furthermore, the content of inflammatory factors and transcription levels were significantly increased in chickens administered ND-AI vaccines. The ND-AI vaccines induced stronger proliferative responses of B cells or CD3+, CD8+, and CD4 + T cells. Hematoxylin and eosin staining showed that the tissue damage induced by the two recombinant vaccines was similar to that of commercial vaccines. The outcomes of the study suggest that the two bivalent ND-AI vaccine candidates produced using the reverse genetics approach are both secure and effective. This approach not only enables the multiuse of one vaccine but also provides a new concept for the development of other vaccines against infectious viral diseases.

Epigenetic Alterations of DNA Methylation and miRNA Contribution to Lung Adenocarcinoma.

This study focused on the epigenetic alterations of DNA methylation and miRNAs for lung adenocarcinoma (LUAD) diagnosis and treatment using bioinformatics analyses. DNA methylation data and mRNA and miRNA expression microarray data were obtained from The Cancer Genome Atlas (TCGA) database. The differentially methylated genes (DMGs), differentially expressed genes (DEGs), and differentially expressed miRNAs were analyzed by using the limma package. The DAVID database performed GO and KEGG pathway enrichment analyses. Using STRING and Cytoscape, we constructed the protein-protein interaction (PPI) network and achieved visualization. The online analysis tool CMap was used to identify potential small-molecule drugs for LUAD. In LUAD, 607 high miRNA-targeting downregulated genes and 925 low miRNA-targeting upregulated genes, as well as 284 hypermethylated low-expression genes and 315 hypomethylated high-expression genes, were obtained. They were mainly enriched in terms of pathways in cancer, neuroactive ligand-receptor interaction, cAMP signaling pathway, and cytosolic DNA-sensing pathway. In addition, 40 upregulated and 84 downregulated genes were regulated by both aberrant alternations of DNA methylation and miRNAs. Five small-molecule drugs were identified as a potential treatment for LUAD, and five hub genes (SLC2A1, PAX6, LEP, KLF4, and FGF10) were found in PPI, and two of them (SLC2A1 and KLF4) may be related to the prognosis of LUAD. In summary, our study identified a series of differentially expressed genes associated with epigenetic alterations of DNA methylation and miRNA in LUAD. Five small-molecule drugs and five hub genes may be promising drugs and targets for LUAD treatment.

Risk factors of hospitalization costs and length of stay for tibial plateau fractures.

PURPOSE: This study aimed to analyze the factors influencing the length of stay (LOS) and the cost of hospital stay in patients with tibial plateau fractures (TPFs). METHODS: We enrolled 233 patients with TPFs in this retrospective study. The general conditions, hematological indicators, and imaging data of hospitalized patients were collected. The factors influencing the cost and LOS were determined by a multivariate logistic regression model controlling confounding factors. Receiver operating characteristic (ROC) curve is used to determine the sensitivity and specificity of risk factors. RESULTS: The hospitalization cost of hypoproteinemia was significantly higher than that of the standard group (OR 3.07; 95% CI 1.23-7.69; P = 0.017); Low hemoglobin levels in the male will significantly affect patient hospitalization costs (OR 8.32; 95% CI 2.82-24.57; P = 0.015), will also extend the LOS (OR 3.02; 95% CI 1.15-7.89; P = 0.024). Among Schatzker classification of the tibial plateau, hospitalization costs of type V, VI above fractures were significantly higher than those of class I, II, III, and IV fractures (OR 8.78; 95% CI 3.34-23.09; P < 0.001). CONCLUSION: In this study, hypoproteinemia and the Schatzker classification appeared to be a useful indicator for predicting hospitalization costs for TPFs patients; Male hemoglobin level appears to be an independent risk factor for hospital cost and LOS.

Optimal preoperative timing for prevention of deep vein thrombosis (DVT) in patients over 60 years of age with intertrochanteric fractures.

PURPOSE: To investigate the incidence and risk factors of preoperative DVT in elderly patients with intertrochanteric fracture of the femur and determine the optimal preoperative time. METHODS: Electronic medical records of 358 patients over 60 years of age with intertrochanteric fractures from May 1, 2016, to May 1, 2019, were retrospectively analyzed. The preoperative group was divided into DVT and non-DVT. Univariate analysis was used for preliminary comparison, and multivariate logistic regression analysis was used to identify independent risk factors associated with DVT development. ROC curve was drawn to analyze the specificity and sensitivity of risk factors for DVT diagnosis. The diagnostic value of the model was analyzed by the ROC curve of multivariable combined diagnosis. RESULTS: A total of 358 patients who met the criteria were enrolled. The total prevalence of DVT before surgery was 8.38%. Multivariate logistic regression analysis showed that smoking status, preoperative time, albumin (ALB), D-dimer level, diabetes mellitus, and hypertension were independent risk factors for preoperative DVT. Preoperative time has the best sensitivity and specificity for diagnosing the occurrence of preoperative DVT. The ROC curve analysis model of multivariable combined diagnosis has a better diagnostic value. CONCLUSIONS: In this study, elderly patients with intertrochanteric femur fracture had a higher incidence of deep vein thrombosis before surgery. Early identification of DVT-related risk factors may contribute to individualized risk assessment and preventing adverse outcomes in patients with intertrochanteric fractures.

HMMR associates with immune infiltrates and acts as a prognostic biomaker in lung adenocarcinoma.

BACKGROUND: To explore the expression of hyaluronan mediated motility receptor (HMMR) in lung adenocarcinoma (LUAD) and its relationship with clinicopathological features and tumor-infiltrating is not clear. METHODS: The expression of HMMR in Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA)-LUAD. TCGA was employed to examine the relationship between the clinicopathological characteristics and HMMR expression and the LUAD patients' prognosis. Tumor Immune Estimation Resource (TIMER)database was employed to analyze the relationship between immune infiltration and HMMR. Gene Set Enrichment Analysis was explored through gene enrichment. Gene Expression Omnibus (GEO) data and our hospital data were utilized to confirm the findings. RESULTS: The expression level of HMMR in lung adenocarcinoma tissue and cells was greater than that in the normal group, which was linked to clinical stage, smoking history, and recurrence, and could increase the progression or recurrence of LUAD. Patients in the pathological grade had a significant expression of HMMR in moderately differentiated LUAD tissues. In addition, HMMR has an impact on LUAD patients' overall survival rate [P = 9.5e-06; hazard ratio (HR) = 2]. The level of HMMR expression in LUAD was significantly linked to neutrophils, CD8+T, and CD4+T cells. TMB analysis showed that HMMR could also affect the tumor microenvironment in LUAD. HMMR might be employed as an independent predictive biomarker of LUAD, according to a multivariate COX regression analysis. The findings of GSEA analysis showed that the samples with high HMMR expression levels were rich in cell cycle, cell metabolism, and DNA replication. The analysis results of GSE31210 data are basically consistent with those of TCGA-LUAD. CONCLUSIONS: It is suggested that HMMR has an effect on the occurrence and development of lung adenocarcinoma. Besides, HMMR is also linked to the level of immune infiltration of neutrophils, CD8+T cells, and CD4+T cells and LUAD patients' prognosis. HMMR was suggested to be utilized as a biomarker or therapeutic target to judge the prognosis and immune infiltration of LUAD.

Exosomes from human induced pluripotent stem cells derived mesenchymal stem cells improved myocardial injury caused by severe acute pancreatitis through activating Akt/Nrf2/HO-1 axis.

Human induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) have been believed to be a promising alternative for the stem cell transplantation therapy. The exosomes (Exo) from iMSCs play an important role in several kinds of life activities. The role of exosomes from iMSCs in severe acute pancreatitis (SAP) induced myocardial injury (MI) has not been investigated. The Exo were isolated from iMSCs through differential centrifugation method. The SAP rat model was established with 5% sodium taurocholate injection into the distal end of the bilepancreatic duct. RT-PCR and western blotting were used to measure related gene expression. Masson trichrome and Sirius Red stainings were used to evaluate MI injury. Cardiac function was detected through cardiac ultrasound.Exo promoted cell viability through activating Akt/nuclear factor E2 related factors 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway in vitro. Exo improved MI induced by SAP through activating Akt/Nrf2/HO-1 signaling pathway. Exo improved cardiac function, and suppressed oxidative status in the SAP model. Exo increased the expression of von Willebrand Factor (vWF) and vascular endothelial growth factor (VEGF) through activating Nrf2/HO-1 signaling pathway. Our data indicated that the Exo from iMSCs could improve MI caused by SAP through activating Nrf2/HO-1 axis. These findings firstly unfold the potential application of Exo from iMSCs in treating MI induced by SAP.Abbreviations: LVEF: Left ventricular ejection fraction; LVFS: left ventricular fractional shorten; LVDd: left ventricular end-diastolic diameter; LVDs: left ventricular end-systolic diameter; MI: Myocardial infarction; MSCs: Mesenchymal stem cells; iPSCs: Human-induced pluripotent stem cells; SAP: Severe acute pancreatitis; iMSCs: iPSCs derived VEGF: MSCs; vascular endothelial growth factor; Nrf2: Nuclear factor erythroid 2-related factor; RT-PCR: Real-time polymerase chain reaction; HE: Hematoxylin-eosin; MODS: Multiple organ dysfunction syndrome; PI3K: Phosphatidylinositol 3-kinase; SOD: Superoxide dismutase; FBS: Fetal bovine serum; ECL: Enhanced chemiluminescence; IHC: Immunohistochemistry.

Tumor microenvironment features decipher the outperformance of neoadjuvant immunochemotherapy over chemotherapy in resectable non-small cell lung cancer.

This study evaluated the efficacy of neoadjuvant immunochemotherapy (Io+Chemo) versus chemotherapy alone (Chemo) in resectable non-small cell lung cancer (NSCLC) in a real-world setting. The association of tumor immune microenvironment (TIME) with pathologic response to different neoadjuvant therapies was also explored.Stage I-III NSCLC patients who received Io+Chemo or Chemo alone followed by surgery were included in the study. Tumor tissues collected during surgery were subjected to TIME evaluation using multiplex immunohistochemistry to measure immune cell subsets, including T cells, B cells, NK cells, and macrophages. Fifty-five patients were included, including 24 treated with neoadjuvant Io+Chemo and 31 with Chemo alone. Io+Chemo induced significantly higher major pathologic response (MPR) (75.0% vs. 38.7%, P = 0.0133) and numerically better pathologic complete response (pCR) (33.3% vs. 12.9%, P = 0.1013) than Chemo. Compared with tumors with Chemo, tumors with Io+Chemo demonstrated a significantly higher ratio of M1 macrophage density in the tumor to that in the stroma (P = 0.0446), more abundant CD8+ cells in the stroma (P = 0.0335), and fewer PD-L1+CD68+ cells in both tumor and stroma. pCR/MPR patients displayed significantly higher density of CD3+, CD3+CD4+, CD20+, CD56 bright cell subsets and more tertiary lymphoid structures and significantly lower density of PD-L1+CD68+ and CD3+CD4+Foxp3+cells in the tumor or stroma. This study favored neoadjuvant Io+Chemo over Chemo and revealed the TIME features underlying the outperformance of Io+Chemo over Chemo.

Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer.

Anti-PD-1 treatment has shown unprecedented clinical success in the treatment of non-small-cell lung cancer (NSCLC), but the underlying mechanisms remain incompletely understood. Here, we performed temporal single-cell RNA and paired T-cell receptor sequencing on 47 tumor biopsies from 36 patients with NSCLC following PD-1-based therapies. We observed increased levels of precursor exhausted T (Texp) cells in responsive tumors after treatment, characterized by low expression of coinhibitory molecules and high expression of GZMK. By contrast, nonresponsive tumors failed to accumulate Texp cells. Our data suggested that Texp cells were unlikely to be derived from the reinvigoration of terminally exhausted cells; instead, they were accumulated by (1) local expansion and (2) replenishment by peripheral T cells with both new and pre-existing clonotypes, a phenomenon we named clonal revival. Our study provides insights into mechanisms underlying PD-1-based therapies, implicating clonal revival and expansion of Texp cells as steps to improve NSCLC treatment.

Identification of MicroRNAs as potential biomarkers for detecting ischemic stroke.

BACKGROUND: Increasing epidemic of ischemic stroke (IS) makes it urgent to understand the pathogenesis and regulatory mechanism, previous studies have described microRNAs (miRNAs) is part of the brain's response to ischemia. OBJECTIVE: The aim of this study was to screen potential biomarkers for the prediction and novel treatment of IS. METHODS: Differentially expressed miRNAs were screened from three newly diagnosed IS patients and three controls by RNA sequencing technology. Furthermore, target prediction databases were then used to analysis the target genes of different expressed miRNAs, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database were used to identify the functions and the main biochemical and signal pathways of differentially expressed target genes. RESULTS: Our results revealed that 27 miRNAs were differentially expressed in IS, among which, hsa-miR-659-5p was the most highly increased and was first found to be associated with IS. In addition, KEGG pathway analyses showed that differentially expressed miRNAs were mainly significantly enriched in lysosome pathway, cytokine-cytokine receptor interaction pathway, spliceosome pathway, base excision repair pathway. CONCLUSIONS: miRNAs were involved in IS pathogenesis, and hsa-miR-659-5p, hsa-miR-151a-3p and hsa-miR-29c-5p as the three highest |log2FoldChange| regulation in this study, which may be the biomarkers of IS and need further study.