Characterized the diversity of ABCB1 subtypes in immunogenomic landscape for predicting the drug response in breast cancer.

ABCB1 is an important gene that closely related to analgesic tolerance to opioids, and plays an important role in their postoperative treatment. Recent studies have demonstrated that ABCB1 genotype is significantly associated with the chemico-resistance and chemical sensitivity in breast cancer patients. So, it is become very important to investigate the important role of ABCB1 for predicting drug response in breast cancer patients. In this study, by conducting the Cox proportional hazards regression analysis in breast cancer patients, significant differences were found in prognosis between the ABCB1 high- and low-expression subtypes. Meanwhile, by using immune infiltration profiles as well as transcriptomics datasets, the ABCB1 high subtype was found to be significantly enriched in many immune-related KEGG pathways and biological processes, and was characterized by the high infiltration levels of immune cell types. Furthermore, bioinformatics inference revealed that the ABCB1 subtypes were associated with the therapeutic effect of immunotherapy, which would be important for patient prognosis. In conclusion, these findings may provide useful help for recognizing the diversity between ABCB1 subtypes in tumor immune microenvironment, and may unravel prognosis outcomes and immunotherapy utility for ABCB1 in breast cancer.

Effect of different sedatives on the prognosis of patients with mechanical ventilation: a retrospective cohort study based on MIMIC-IV database.

Aim: To compare the effects of midazolam, propofol, and dexmedetomidine monotherapy and combination therapy on the prognosis of intensive care unit (ICU) patients receiving continuous mechanical ventilation (MV). Methods: 11,491 participants from the Medical Information Mart for Intensive Care (MIMIC)-IV database 2008-2019 was included in this retrospective cohort study. The primary outcome was defined as incidence of ventilator-associated pneumonia (VAP), in-hospital mortality, and duration of MV. Univariate and multivariate logistic regression analyses were utilized to evaluate the association between sedation and the incidence of VAP. Univariate and multivariate Cox analyses were performed to investigate the correlation between sedative therapy and in-hospital mortality. Additionally, univariate and multivariate linear analyses were conducted to explore the relationship between sedation and duration of MV. Results: Compared to patients not receiving these medications, propofol alone, dexmedetomidine alone, combination of midazolam and dexmedetomidine, combination of propofol and dexmedetomidine, combination of midazolam, propofol and dexmedetomidine were all association with an increased risk of VAP; dexmedetomidine alone, combination of midazolam and dexmedetomidine, combination of propofol and dexmedetomidine, combination of midazolam, propofol and dexmedetomidine may be protective factor for in-hospital mortality, while propofol alone was risk factor. There was a positive correlation between all types of tranquilizers and the duration of MV. Taking dexmedetomidine alone as the reference, all other drug groups were found to be associated with an increased risk of in-hospital mortality. The administration of propofol alone, in combination with midazolam and dexmedetomidine, in combination with propofol and dexmedetomidine, in combination with midazolam, propofol and dexmedetomidine were associated with an increased risk of VAP compared to the use of dexmedetomidine alone. Conclusion: Dexmedetomidine alone may present as a favorable prognostic option for ICU patients with mechanical ventilation MV.

Silencing of the integrin-linked kinase gene induces the apoptosis in ovarian carcinoma.

CONTEXT: Integrin-linked kinase (ILK), a multidomain focal adhesion protein serine/threonine kinase, plays an essential role in ovarian carcinoma. There are reports that the expression and activity of ILK are increased in ovarian cancer. OBJECTIVE: To test the hypothesis that ILK pathway mediates the apoptosis of ovarian carcinoma SKOV3 cell influencing the cell survival, we performed these studies. MATERIALS AND METHODS: We applied lentivirus transfection, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT), apoptotic proteins expressions assay, and Hoechst to study our hypothesis. RESULTS: We found that silencing of the ILK increases the cell cytotoxic, growth inhibition, and apoptosis. Moreover, after blocking the activation of ILK with ILK shRNA, up-regulation of pro-apoptotic bax expression and down-regulation of the anti-apoptotic bcl-2 expression were found in ovarian cancer SKOV3 cell line. These were associated with an increasing cleaved caspase-3 activity and chromatin condensation of cell nuclear. Furthermore, the expressions of fas and fas ligand (fasL), belonging to the tumor necrosis factor family and controlling the cell apoptosis, were also enhanced. CONCLUSIONS: Thus, these findings indicate that both the intrinsic pathway and the extrinsic death receptor pathway are involved in the process that silencing of the ILK gene induces the apoptosis in ovarian carcinoma SKOV3 cell.

Mesenchymal Stem Cell-derived Extracellular Vesicle-enclosed microRNA-93 Prevents Hypoxic-ischemic Brain Damage in Rats.

Hypoxic-ischemic brain damage (HIBD) usually induces chronic neurological disorder and even acute death, but effective neuroprotective strategy is still limited. Herein, we performed this study to clarify the mechanism of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) containing microRNA-93 (miR-93) in influencing this damage via regulation of the histone deacetylase 4 (HDAC4)/B-cell lymphoma-2 (Bcl-2) axis. Initially, differentially expressed Bcl-2 was identified in middle cerebral artery occlusion (MCAO), and the upstream regulatory miR-93 and its potential target HDAC4 were also predicted through bioinformatics analysis. HIBD was modeled in vitro by exposing hippocampal neurons to oxygen-glucose deprivation (OGD) and in vivo by MCAO in rats. EVs were isolated from the bone marrow MSCs of well-grown rats. Our experimental data validated that HDAC4 was highly expressed while miR-93 and Bcl-2 were poorly expressed in MCAO rats. Furthermore, HDAC4 overexpression, through inhibiting Bcl-2 via deacetylation, promoted the infarct volume and pathological changes in hippocampal tissues and neuron apoptosis, and impaired neurobehavioral ability of MCAO rats. Of note, miR-93 was found to target HDAC4. Importantly, MSC-derived EVs overexpressing miR-93 suppressed HDAC4 expression and subsequently impeded the apoptosis of OGD-exposed hippocampal neurons in vitro, and also ameliorated HIBD in vivo. Taken together, miR-93 delivered by MSC-derived EVs can ameliorate HIBD by suppressing hippocampal neuron apoptosis through targeting the HDAC4/Bcl-2 axis, a finding which may be of great significance in the treatment of HIBD.

Erratum to dexmedetomidine promotes breast cancer cell migration through Rab11-mediated secretion of exosomal TMPRSS2.

[This corrects the article DOI: 10.21037/atm.2020.04.28.].

Dexmedetomidine promotes breast cancer cell migration through Rab11-mediated secretion of exosomal TMPRSS2.

BACKGROUND: Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, has been reported to increase the malignancy of breast cancer cells in vitro and stimulate tumor growth in mice. Transmembrane protease serine 2 (TMPRSS2) demonstrates proteolytic activity, resulting in degradation of the extracellular matrix (ECM). This study investigated whether and how TMPRSS2 regulates migration of DEX-treated breast cancer cells. METHODS: Breast cancer cell lines MCF-7 and MDA-MB-231 were treated with DEX and scratch assay was performed. Expressions of TMPRSS2, α2-adrenergic receptor, phospho-STAT3Tyr705, Rab11, and ECM components were assessed using real-time polymerase chain reaction (real-time PCR), Western blotting, and immunofluorescence staining. ELISA and ultracentrifugation were used to quantify secreted exosomal proteins. Knockdown assay was used to inhibit the expression of TMPRSS2 and Rab11. RESULTS: DEX significantly increased the migration of MCF-7 and MDA-MB-231, which was accompanied by the upregulation and colocalization of TMPRSS2 and α2-adrenergic receptor. Nuclear phospho-STAT3Tyr705 was increased dramatically following DEX treatment, and TMPRSS2 upregulation was significantly suppressed by the STAT3 inhibitor WP1066. Meanwhile, TMPRSS2 knockdown decreased DEX-induced cellular migration. TMPRSS2 and Rab11 were significantly detected in the media and the isolated exosomes from DEX-treated cells, and their colocalization was also revealed. Rab11 knockdown prevented exosomal TMPRSS2 from increasing in DEX-treated cells. In normal cultured MDA-MB-231, migration was increased by Rab11-positive exosomes isolated from DEX-treated MCF-7. Moreover, transmission electron microscopy showed that Rab11-positive exosomes enriched more components than Rab11-negative exosomes. Additionally, a reduction in ECM components fibronectin, collagen IV, matrix metallopeptidase 16, and Tenascin C was detected after DEX treatment, but was prohibited when TMPRSS2 or Rab11 were knocked down. CONCLUSIONS: This study provides evidence that DEX upregulates TMPRSS2 expression via the activation of α2-adrenergic receptor/STAT3 signaling and promotes TMPRSS2 secretion in exosomes through Rab11, thus resulting in degradation of the ECM, which is responsible for DEX-induced migration of breast cancer cells.

Identification of Potential Long Non-coding RNA Expression Quantitative Trait Methylations in Lung Adenocarcinoma and Lung Squamous Carcinoma.

There are associations between DNA methylation and the expression of long non-coding RNA (lncRNA), also known as lncRNA expression quantitative trait methylations (lnc-eQTMs). Lnc-eQTMs may induce a wide range of carcinogenesis pathways. However, lnc-eQTMs have not been globally identified and studied, and their roles in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) are largely unknown. In the present study, we identified some differential methylation sites located in genes of long intergenic non-coding RNAs (lincRNAs) and other types of lncRNAs in LUAD and LUSC. An integrated pipeline was established to construct two global cancer-specific regulatory networks of lnc-eQTMs in LUAD and LUSC. The associations between eQTMs showed common and specific features between LUAD and LUSC. Some lnc-eQTMs were also related with survival in LUAD- and LUSC-specific regulatory networks. Lnc-eQTMs were associated with cancer-related functions, such as lung epithelium development and vasculogenesis by functional analysis. Drug repurposing analysis revealed that these lnc-eQTMs may mediate the effects of some anesthesia-related drugs in LUAD and LUSC. In summary, the present study elucidates the roles of lnc-eQTMs in LUAD and LUSC, which could improve our understanding of lung cancer pathogenesis and facilitate treatment.

Upregulation of µ-Opioid Receptor in the Rat Spinal Cord Contributes to the α2-Adrenoceptor Agonist Dexmedetomidine-Induced Attenuation of Chronic Morphine Tolerance in Cancer Pain.

BACKGROUND: Sustained morphine treatment for cancer pain has been limited due to analgesic tolerance. Opioid receptor internalization and desensitization mediated by downregulation of mu-opioid receptor (MOR) expression have been confirmed as one of the mechanisms of chronic morphine tolerance. In addition to the opiate system, the α2-adrenergic system is involved in the development of morphine tolerance. Several studies reported that co-administration of α2-adrenoceptor agonist dexmedetomidine inhibits morphine tolerance in normal or neuropathic pain animals. However, the effect of dexmedetomidine on morphine tolerance has not been studied in cancer pain. Therefore, we investigated the effect of intrathecal injection of dexmedetomidine on the development of morphine tolerance in cancer pain and on the expression of MOR in the spinal cord of morphine-tolerant cancer pain rats. METHODS: The model was established using a rat's right hind paw injection of Walker 256 cancer cells. Subcutaneous morphine (10mg/kg) was administrated twice daily for 7 days; meanwhile, the rats received intrathecal α2-adrenoceptor agonist dexmedetomidine (10µ/kg) or antagonist MK-467 (0.25mg/kg) in test groups. Rats receiving drug vehicle served as the control group. Antinociception was detected by von Frey filaments and hot-plate tests. The expression of MOR in the spinal cord was examined through real-time reverse transcription polymerase chain reaction and Western blotting. The data were analyzed via analysis of variance followed by Student t-test with Bonferroni correction. RESULTS: Seven-day chronic morphine administration elicited notable analgesic tolerance in the rats with cancer pain. Co-administration of α2-adrenoceptor agonist dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance, which could be blocked by α2-adrenoceptor antagonist MK-467. Furthermore, pre-treatment of dexmedetomidine significantly upregulated MOR protein expression without a notable change in MOR mRNA expression in the spinal cord. CONCLUSION: Our findings suggest that intrathecal injection of dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance in cancer pain, potentially by upregulating MOR expression in the spinal cord. The α2-adrenoceptor agonist may provide a more versatile analgesia option for morphine treatment for cancer pain.