Comparing a novel Catfish flow restoration device and the Solitaire stent retriever for thrombectomy revascularisation in emergent largevessel occlusion stroke: a prospective randomised controlled study.

BACKGROUND: The Catfish stent retriever is a newly developed mechanical thrombectomy device for rapid recanalisation in emergent large vessel occlusion (ELVO) stroke. The current trial aimed to assess whether the Catfish stent retriever is non-inferior to the Solitaire stent retriever in terms of outcomes in ELVO stroke. METHODS: This was a randomised, prospective, parallel-group, multicentre, open-label, non-inferiority study conducted at 18 sites in China. The primary outcome was the proportion of cases with successful recanalisation (modified thrombolysis in cerebral infarction score of 2b or 3) following the procedure. Secondary efficacy outcomes included the National Institutes of Health Stroke Scale scores at 24 hours and 7 days or discharge if earlier, time from artery puncture to successful recanalisation and good clinical outcome (modified Rankin scale score ≤2) at 90 days. Safety outcomes included symptomatic intracranial haemorrhage, all cause-death and severe adverse events at 90 days. RESULTS: Between 3 March 2019 and 5 June 2021, 118 and 120 patients were randomly allocated to the Catfish and Solitaire groups, respectively. The primary endpoint after all endovascular procedures was non-inferior in the Catfish group (88.5%, 100/113) than in the Solitaire group (87.7%, 100/114), with a rate difference (RD) of 0.78% (95% CI -7.64 to -9.20; p=0.001). Sensitivity analysis only considering the per-protocol set also yielded similar results, with an RD of 0.83% (95% CI -7.03 to -8.70; p<0.001). Additionally, the proportions of cases with good clinical outcomes (47.8% vs 50.0%, p=0.739) and all-cause death rates (17.7% vs 18.8%, p=0.700) were similar in both groups at 90 days. CONCLUSIONS: The Catfish stent retriever is an effective and safe device for endovascular recanalisation in ELVO stroke. TRIAL REGISTRATION NUMBER: NCT03820882.

Traditional Chinese medicines and capecitabine-based chemotherapy for colorectal cancer treatment: A meta-analysis.

This meta-analysis was conducted to evaluate the efficacy and safety of the addition of Traditional Chinese Medicine (TCMs) to capecitabine-based regimens for colorectal cancer (CRC) in term of tumor. The eight electronic databases including Cochrane Library, PubMed, Web of Science (WOS), Excerpt Medica Database (Embase), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals (CQVIP), and Wanfang Database were systematically searched for eligible studies from their inception to March 2021. Thirty-nine randomized controlled trials were involved in this study, and all the data were analyzed by Review Manager 5.3 (Nordic Cochran Centre, Copenhagen, Denmark) and R 4.0.5 software. The meta-analyses suggested that TCMs in combination with capecitabine-based regimens increased objective response rate (ORR) in the palliative treatment of CRC (risk ratio [RR], 1.35 [1.17, 1.55], I2  = 0%), disease control rate (DCR) (RR, 1.22 [1.12, 1.32], I2  = 3%), and quality of life (QOL) (RR, 1.71 [1.44, 2.03], I2  = 0%), with decreased risks of myelosuppression, anemia, thrombocytopenia, liver/renal dysfunction, neurotoxicity, nausea/vomiting, neutropenia, diarrhea, leukopenia, improved the peripheral lymphocyte, reduced the expression of tumor markers, and related factors. Further sensitivity analysis of specific plant-based TCMs found that dangshen, fuling, and gancao had significantly higher contributions to the results of the RR. The results show that capecitabine-based chemotherapy combined with TCM in the treatment of CRC increases the efficiency of ORR and DCR, reduces chemotherapeutic agents-associated adverse reactions, and improves their life quality as compared with chemotherapy alone, but further randomized and large sample of studies are needed.

Development and validation of prognostic models for colon adenocarcinoma based on combined immune-and metabolism-related genes.

Background: The heterogeneity of tumor tissue is one of the reasons for the poor effect of tumor treatment, which is mainly affected by the tumor immune microenvironment and metabolic reprogramming. But more research is needed to find out how the tumor microenvironment (TME) and metabolic features of colon adenocarcinoma (COAD) are related. Methods: We obtained the transcriptomic and clinical data information of COAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering analysis was used to identify different molecular subtypes, identify differentially expressed genes (DEGs) associated with immune-and metabolism-related genes (IMRGs) prognosis. Univariate and multivariable Cox regression analysis and Lasso regression analysis were applied to construct the prognostic models based on the IMRG risk score. The correlations between risk scores and TME, immune cell infiltration, and immune checkpoint genes were investigated. Lastly, potential appropriate drugs related to the risk score were screened by drug sensitivity analysis. Results: By consensus clustering analysis, we identified two distinct molecular subtypes. It was also found that the multilayered IMRG subtypes were associated with the patient's clinicopathological characteristics, prognosis, and TME cell infiltration characteristics. Meanwhile, a prognostic model based on the risk score of IMRGs was constructed and its predictive power was verified internally and externally. Clinicopathological analysis and nomogram give it better clinical guidance. The IMRG risk score plays a key role in immune microenvironment infiltration. Patients in the high-risk groups of microsatellite instability (MSI) and tumor mutational burden (TMB) were found to, although with poor prognosis, actively respond to immunotherapy. Furthermore, IMRG risk scores were significantly associated with immune checkpoint gene expression. The potential drug sensitivity study helps come up with and choose a chemotherapy treatment plan. Conclusion: Our comprehensive analysis of IMRG signatures revealed a broad range of regulatory mechanisms affecting the tumor immune microenvironment (TIME), immune landscape, clinicopathological features, and prognosis. And to explore the potential drugs for immunotherapy. It will help to better understand the molecular mechanisms of COAD and provide new directions for disease treatment.

Micro-vesicles from mesenchymal stem cells over-expressing miR-34a inhibit transforming growth factor-ß1-induced epithelial-mesenchymal transition in renal tubular epithelial cells in vitro.

BACKGROUND: The use of microRNAs in the therapy of kidney disease is hampered by the difficulties in their effective delivery. Micro-vesicles (MVs) are known as natural carriers of small RNAs. Our prior research has demonstrated that MVs isolated from mesenchymal stem cells (MSCs) are capable of attenuating kidney injuries induced by unilateral ureteral obstruction and 5/6 sub-total nephrectomy in mice. The present study aimed to evaluate the effects of miR-34a-5p (miR-34a)-modified MSC-MVs on transforming growth factor (TGF)-ß1-induced fibrosis and apoptosis in vitro. METHODS: Bone marrow MSCs were modified by lentiviruses over-expressing miR-34a, from which MVs were collected for the treatment of human Kidney-2 (HK-2) renal tubular cells exposed to TGF-ß1 (6 ng/mL). The survival of HK-2 cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and Annexin V-Light 650/propidium iodide (PI) assays. The expression levels of epithelial markers (tight junction protein 1 [TJP1] and E-cadherin) and mesenchymal markers (smooth muscle actin alpha (α-SMA) and fibronectin) in HK-2 cells were measured using Western blot analysis and an immunofluorescence assay. In addition, changes in Notch-1/Jagged-1 signaling were analyzed using Western blotting. Data were analyzed using a Student's t test or one-way analysis of variance. RESULTS: MiR-34a expression increased three-fold in MVs generated by miR-34a-modified MSCs compared with that expressed in control MVs (P < 0.01, t = 16.55). In HK-2 cells, TJP1 and E-cadherin levels decreased to 31% and 37% after treatment with TGF-ß1, respectively, and were restored to 62% and 70% by miR-34a-enriched MSC-MVs, respectively. The expression of α-SMA and fibronectin increased by 3.9- and 5.0-fold following TGF-ß1 treatment, and decreased to 2.0- and 1.7-fold after treatment of HK-2 cells with miR-34a-enriched MSC-MVs. The effects of miR-34a-enriched MSC-MVs on epithelial-mesenchymal transition (EMT) markers were stronger than control MSC-MVs. The effects of miR-34a-enriched MSC-MVs on these EMT markers were stronger than control MSC-MVs. Notch-1 receptor and Jagged-1 ligand, two major molecules of Notch signaling pathway, are predicted targets of miR-34a. It was further observed that elevation of Notch-1 and Jagged-1 induced by TGF-ß1 was inhibited by miR-34a-enriched MSC-MVs. In addition, TGF-ß1 exposure also induced apoptosis in HK-2 cells. Although miR-34a-mofidied MSC-MVs were able to inhibit TGF-ß1-triggered apoptosis in HK-2 cells, the effects were less significant than control MSC-MVs (control:TGF-ß1: miR-nc-MV:miR-34a-MV = 1.3:0.6:1.1:0.9 for MTT assay, 1.8%:23.3%:9.4%:17.4% for apoptosis assay). This phenomenon may be the result of the pro-apoptotic effects of miR-34a. CONCLUSIONS: The present study demonstrated that miR-34a-over-expressing MSC-MVs inhibit EMT induced by pro-fibrotic TGF-ß1 in renal tubular epithelial cells, possibly through inhibition of the Jagged-1/Notch-1 pathway. Genetic modification of MSC-MVs with an anti-fibrotic molecule may represent a novel strategy for the treatment of renal injuries.

Effects of inactivated Bordetella pertussis on phosphodiesterase in the lung of ovalbumin sensitized and challenged rats.

This paper indicated that inactivated Bordetella pertussis (iBp) can enhance the lung airway hyperreactivity of the rats sensitized and challenged with OVA. The mechanisms were involved in the upregulation of cAMP-PDE activity and PDE4A, PDE4D, and PDE3 gene expression in the lungs. But only PDE4 activity was different between the OVA and OVA+iBp groups, and PDE4D expression was significantly increased in iBp rats alone. So, our data suggested that cosensitization with OVA and iBp affects lung airway reactivity by modulating the lung cAMP-PDE activity and PDE4D gene expression.

Up-regulation of Slc39A2(Zip2) mRNA in peripheral blood mononuclear cells from patients with pulmonary tuberculosis.

Zinc is the most common trace mineral after iron in the human body. In organisms, zinc transporters help zinc influx and efflux from cells. A previous study has reported that Zip2 was up-regulated over 27-fold in human monocytic THP-1 cells, when intracellular zinc was depleted by TPEN. Our study found Zip2 was over-expressed in leukocytes of asthmatic infants, especially those in which the serum zinc level was lower than those in healthy infants. Pulmonary tuberculosis (PTB) patients have significantly low serum zinc levels. Here we investigated whether Zip2 level was changed in the patients with PTB. Zip2 mRNA and protein levels in peripheral blood mononuclear cells (PBMC) from PTB (n1=23) and healthy controls (n2=42) were detected by quantitative real-time PCR and western blot, respectively. mRNA expression levels of another four zinc transporters, Zip1, Zip6, Zip8 and ZnT1, were detected by quantitative real-time PCR. Zip2 mRNA level was significantly up-regulated in PTB patients (P=0.001), and Zip8 mRNA level was significantly down-regulated compared with control individuals (P<0.001). In contrast, there were no significant changes in mRNA levels of Zip1, Zip6 and ZnT1 in either group (P>0.05). Zip2 protein expression levels increased in PTB patients compared with control individuals. Our study found that knockdown of ZIP2 with siRNA caused a decrease in Zip2 levels in PBMC of PTB patients, while reducing the expression of INF-γ (P<0.01) and increasing the expression of IL-6(P<0.01). These data provide evidence that increased expression of Zip2 gene is closely associated with immunity of PTB patients, suggesting that the Zip2 gene may play a key role in the initial infection control of the human body, by promoting and maintaining the immune response of adaptive T cells.

Zl-n-91, a selective phosphodiesterase 4 inhibitor, suppresses inflammatory response in a COPD-like rat model.

Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by poorly reversible airflow limitation induced by cigarette smoking and/or other noxious particle and gases. Phosphodiesterase (PDE) 4 inhibitors are known to elevated cAMP concentrations in inflammatory cells, leading to inhibition of inflammatory response, relaxation of smooth muscle in the airway, and modulation of sensory nerves in the lung as well. To investigate whether Zl-n-91, a new selective PDE4 inhibitor, could decrease inflammation and improve lung function in a COPD-like rat model, male Sprague-Dawley rats are used to challenge with lipopolysaccharide (LPS) and cigarette smoking (CS) exposure to induce COPD-like animal model. Administration of Zl-n-91 at different dosages results in decreases of inflammatory cell in bronchoalveolar lavage fluid (BALF) as compared with vehicle treatment. Zl-n-91 at 0.03, 0.3 or 3mg/kg not only dose-dependently inhibited PDE4 activity, but also decreased MMP-9 level in lungs and improved dynamic compliance (C(dyn)) as compared with vehicle treatment. Therefore, Zl-n-91 could inhibit inflammatory responses in rats after cigarette smoking exposure and LPS challenge, and it could be of some therapeutic potential as an alternative medicine in treatment of pulmonary diseases such as COPD.