A Randomized Controlled Trial: Examining the Impact of the Novel Double Setup Endotracheal Tube on the Success Rates of Awake Fiber-Optic Orotracheal Intubation.

BACKGROUND: Advancing the endotracheal tube (ETT) over a flexible bronchoscope (FB) during awake fiber-optic intubation (AFOI) is often impeded. Various maneuvers and tracheal tubes designed to overcome this obstruction may also be unsuccessful or costly. OBJECTIVE: The current study aimed to assess how the novel double configuration ETT affected AFOI success rates on the first attempt. METHODS: A randomized controlled experiment including 40 individuals receiving awake fiber-optic orotracheal intubation was performed in a 1:1 ratio with a single ETT railroaded with its bevel posteriorly (ST) or railroading with a double setup ETT (DT) over a flexible videoscope (FVS) for tracheal intubation. The number of intubation attempts, time spent intubating, and adverse events were examined and compared between the two groups. RESULTS: Twenty patients received a single ETT railroaded with the bevel posteriorly, and 20 patients received railroading with the double setup ETT during AFOI. Intubation on the first attempt was significantly greater in the DT group (90%) than in the ST group (35%). The intubation time was considerably shorter for the DT group (12.8 [7.8-16.9] s) when compared with the ST group (27.9 [16.3-91.0] s). Five patients were intubated by the alternative technique after failure to intubate for several attempts, and 3 cases were found to have a crease in the FVS after intubation in group ST. During topical anesthetic, three individuals in each group experienced transient oxygen desaturation. CONCLUSIONS: Our study discovered that the novel double setup tube could significantly improve the intubation success rate on the first attempt during AFOI for patients with challenging airway when a strategy based on a reduced gap between ETT and FB could not be applied.

A comparative analysis of diagnostic values of high-frequency ultrasound and fiberoptic ductoscopy for pathologic nipple discharge.

BACKGROUND: This study aimed to compare the diagnostic accuracy of high-frequency ultrasound (HFUS) and fiberoptic ductoscopy (FDS) for pathologic nipple discharge (PND). METHODS: HFUS and FDS were conducted in 210 patients with PND (248 lesions) treated at our hospital. The diagnostic accuracy of these two methods was compared using pathological diagnosis as the standard. RESULTS: Among 248 lesions, 16 and 15 of 16 malignant lesions were accurately diagnosed by HFUS and FDS, respectively. Of 232 benign lesions, 183 and 196 cases were accurately diagnosed by HFUS and FDS, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of HFUS in diagnosis of intraductal lesions were 84.36% (95% CI 79.26-88.39%), 60% (95% CI 23.07-92.89%), 96.03% (95% CI 96.55-99.83%), and 7.31% (95% CI 2.52-19.4%) respectively. The sensitivity, specificity, PPV, and NPV of FDS in diagnosis of intraductal lesions were 86.83% (95% CI 82.00-90.52%), 100% (95% CI 56.55-100%), 100% (95% CI 98.21-100%), and 13.51% (95% CI 5.91-27.98%) respectively. Diagnostic accuracy rates of HFUS and FDS were 83.87% (208/248) and 85.08% (211/248), respectively, exhibiting no statistically differences (χ2 = 0.80, P > 0.05). The accuracy of HFUS combined with FDS was 93.14% (231/248), showing statistically differences (χ2 = 10.91, P < 0.05). CONCLUSIONS: Both HFUS and FDS demonstrated high diagnostic values for PND. HFUS has the advantage of non-invasive for nipple discharge with duct ectasia, exhibited good qualitative and localization diagnostic values. It is the preferred evaluation method for patients with nipple discharge. When HFUS cannot identify the cause of PND, FDS can be considered.

COL11A1 serves as a biomarker for poor prognosis and correlates with immune infiltration in breast cancer.

Breast cancer is the malignant tumor with the highest incidence rate at present, and its incidence rate ranks first in the female population. COL11A1 is an important component of collagen XI and is considered to play an important role in a variety of connective tissue diseases. Recent studies have shown that COL11A1 is associated with the occurrence and development of many kinds of malignant tumors. However, its prognostic value in breast cancer and its correlation with immune cell infiltration in tumor tissue are not clear. In this paper, we reveal the prognostic value of COL11A1 in breast cancer and its tumor immune-related function through in-depth bioinformatics analysis. The expression of COL11A1 is abnormally upregulated in breast cancer and is significantly related to the poor prognosis of breast cancer. In the analysis of the clinical characteristics of the patients, we found that the expression level of COLL11A1 was closely related to lymph node metastasis, PAM50 (Prediction Analysis of Microarray 50) expression, clinical stage and so on. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) all suggest that COL11A1 is related to tumor immunity. Further study found that the COL11A1 expression was significantly correlated with the degree of immune infiltration and the expression of a variety of immune cell markers in tumor tissue. More importantly, COL11A1 can affect the prognosis of breast cancer patients by participating in the regulation of tumor immune infiltration. Therefore, we believe that COL11A1 is a very potential target for diagnosis and treatment of breast cancer.

Adenosine Downregulates the Activities of Glutamatergic Neurons in the Paraventricular Hypothalamic Nucleus Required for Sleep.

Adenosine is an endogenous substance that regulates sleep homeostasis. It plays an important role in sleep induction under physiological condition. So far, the neural mechanisms underlying sleep-promoting effects of adenosine are not completely clear. Recent studies have shown that glutamatergic neurons in the paraventricular hypothalamic nucleus (PVH) play an important role in wakefulness. Using whole-cell patch-clamp, we found that adenosine can inhibit glutamatergic neurons in PVH. This inhibition is mainly achieved by activating adenosine type 1 receptors, thereby reducing hyperpolarization-activated cyclic nucleotide-gated cation channels. By recording electroencephalogram (EEG) and electromyography (EMG), it was found that local administration of adenosine type 1 receptor blocker in PVH could significantly reduce the NREM sleep. On the contrary, if adenosine was given, it could increase the NREM sleep. These results suggest that adenosine can promote sleep by reducing the excitability of PVH neurons. This findings reveal a novel mechanism of adenosine regulating sleep homeostasis.

Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer.

BACKGROUND: Although gemcitabine has been considered as the first-line drug for advanced pancreatic cancer (PC), development of resistance to gemcitabine severely limits the effectiveness of this chemotherapy, and the underlying mechanism of gemcitabine resistance remains unclear. Various factors, such as ATP binding cassette (ABC) transporters, microRNAs and their downstream signaling pathways are included in chemoresistance to gemcitabine. This study investigated the potential mechanisms of microRNAs and ABC transporters related signaling pathways for PC resistance to gemcitabine both in vivo and in vitro. METHODS: Immunohistochemistry and Western blotting were applied to detect the expression of ABC transporters. Molecular docking analysis was performed to explore whether gemcitabine interacted with ABC transporters. Gain-of-function and loss-of-function analyses were performed to investigate the functions of hsa-miR-3178 in vitro and in vivo. Bioinformatics analysis, Western blotting and dual-luciferase reporter assay were used to confirm the downstream regulatory mechanisms of hsa-miR-3178. RESULTS: We found that P-gp, BCRP and MRP1 were highly expressed in gemcitabine-resistant PC tissues and cells. Molecular docking analysis revealed that gemcitabine can bind to the ABC transporters. Hsa-miR-3178 was upregulated in gemcitabine resistance PANC-1 cells as compared to its parental PANC-1 cells. Moreover, we found that hsa-miR-3178 promoted gemcitabine resistance in PC cells. These results were also verified by animal experiments. RhoB was down-regulated in gemcitabine-resistant PC cells and it was a downstream target of hsa-miR-3178. Kaplan-Meier survival curve showed that lower RhoB expression was significantly associated with poor overall survival in PC patients. Rescue assays demonstrated that RhoB could reverse hsa-miR-3178-mediated gemcitabine resistance. Interestingly, hsa-miR-3178 promoted gemcitabine resistance in PC by activating the PI3K/Akt pathway-mediated upregulation of ABC transporters. CONCLUSIONS: Our results indicate that hsa-miR-3178 promotes gemcitabine resistance via RhoB/PI3K/Akt signaling pathway-mediated upregulation of ABC transporters. These findings suggest that hsa-miR-3178 could be a novel therapeutic target for overcoming gemcitabine resistance in PC.

Lazertinib improves the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 overexpression cancer cells in vitro, in vivo, and ex vivo.

Multidrug resistance (MDR) is the major cause of chemotherapy failure, which is usually caused by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2. To date, no MDR modulator has been clinically approved. Here, we found that lazertinib (YH25448; a novel third-generation tyrosine kinase inhibitor [TKI]) could enhance the anticancer efficacy of MDR transporter substrate anticancer drugs in vitro，in vivo, and ex vivo. Mechanistically, lazertinib was shown to inhibit the drug efflux activities of ABCB1 and ABCG2 and thus increase the intracellular accumulation of the transporter substrate anticancer drug. Moreover, lazertinib was found to stimulate the ATPase activity of ABCB1/ABCG2 and inhibit the photolabeling of the transporters by 125I-iodoarylazidoprazosin (IAAP). However, lazertinib neither changed the expression or locolization of ABCB1 and ABCG2 nor blocked the signal pathway of Akt or Erk1/2 at a drug concentration effective for MDR reversal. Overall, our results demonstrate that lazertinib effectively reverses ABCB1- or ABCG2-mediated MDR by competitively binding to the ATP-binding site and inhibiting drug efflux function. This is the first report demonstrating the novel combined use of lazertinib and conventional chemotherapeutical drugs to overcome MDR in ABCB1/ABCG2-overexpressing cancer cells.

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression.

Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.

Overexpression of ABCG2 confers resistance to pevonedistat, an NAE inhibitor.

Pevonedistat is a potent, selective, first-in-class NEDD8 activating enzyme inhibitor. It is now under multiple clinical trials that investigate its anticancer effect against solid tumors and leukemia. ATP-binding cassette (ABC) transporters are membrane proteins that are involved in mediating multidrug resistance (MDR). In this article, we reveal that pevonedistat is a substrate of ABCG2 which decreases the therapeutic effect of pevonedistat. The cytotoxicity of pevonedistat was significantly weakened in ABCG2-overexpressing cells, and the drug resistance can be reversed by ABCG2 inhibitors. The ATPase assay suggested that pevonedistat can stimulate ABCG2 ATPase activity in a concentration-dependent manner. Pevonedistat showed little effect on the expression level or subcellular localization of ABCG2 after 72 h treatment. Furthermore, a pevonedistat resistance cell line S1-PR was established and overexpressed ABCG2. Generally, our study provides evidence that ABCG2 can be a prominent factor leading to pevonedistat-resistance. Furthermore, ABCG2 may also be utilized as a biomarker to monitor the development of pevonedistat resistance during cancer treatment.

Anti­proliferative effect of cardamonin on mTOR inhibitor­resistant cancer cells.

A number of mammalian target of rapamycin (mTOR) inhibitors have been approved for the treatment of certain types of cancer or are currently undergoing clinical trials. However, mTOR targeted therapy exerts selective pressure on tumour cells, which leads to the preferential growth of resistant subpopulations. There are two classes of mTOR inhibitors: i) The rapalogs, such as rapamycin, which bind to the 12­kDa FK506­binding protein/rapamycin­binding domain of mTOR; and ii) the ATP­competitive inhibitors, such as AZD8055, which block the mTOR kinase domain. Cardamonin inhibits mTOR by decreasing the expression of regulatory­associated protein of mTOR (Raptor), a mechanism of action which differs from the currently available mTOR inhibitors. The present study investigated the inhibitory effects of cardamonin on mTOR inhibitor­resistant cancer cells. HeLa cervical cancer cells and MCF­7 breast cancer cells were exposed to high concentrations of mTOR inhibitors, until resistant clones emerged. Cytotoxicity was measured using the MTT and colony forming assays. The inhibitory effect of cardamonin on mTOR signalling was assessed by western blotting. The resistant cells were less sensitive to mTOR inhibitors compared with the parental cells. Consistent with the anti­proliferation effect, rapamycin and AZD8055 had no effect on the phosphorylation of rapamycin­sensitive sites on ribosomal protein S6 kinase B1 (S6K1) and AZD8055­sensitive sites on protein kinase B and eukaryotic translation initiation factor 4E binding protein 1 (Thr 37/46), respectively, in rapamycin­ and AZD8055­resistant cells. Cardamonin inhibited cell proliferation and decreased the phosphorylation of mTOR and S6K1, as well as the protein level of raptor, in the mTOR inhibitor­resistant cells. Therefore, cardamonin may serve as a therapeutic agent for patients with cervical and breast cancer resistant to mTOR inhibitors.

Annexin A1, A2, A4 and A5 play important roles in breast cancer, pancreatic cancer and laryngeal carcinoma, alone and/or synergistically.

Annexins are associated with metastasis and infiltration of cancer cells. Proteomic analysis and immunohistochemical staining were used to understand whether several annexins play important roles in cancer alone and/or synergistically. Seven fresh breast cancer samples with 23 paraffin specimens, three fresh pancreatic samples and five fresh laryngeal carcinoma samples with 25 paraffin specimens were obtained from humans, as well as ten golden hamster pancreatic cancer tissue samples, and they were used to observe differential expression of annexins compared with normal tissues using proteomics and immunohistochemical staining. Annexin A2, A4 and A5 were overexpressed in human breast cancer and laryngeal carcinoma tissues and in golden hamster pancreatic cancer tissue samples, respectively, as shown by proteomics and immunohistochemical staining. In addition, annexin A4 and A5 were expressed in breast cancer tissues, while annexin A1 was not expressed. Annexin A1, A2 and A4 were expressed in human laryngeal carcinoma tissues as shown by immunohistochemical staining. Annexin A1, A2, A4 and A5 played important roles in breast cancer, pancreatic cancer and laryngeal carcinoma, alone and/or synergistically, and they may be targets of therapy for malignant tumors. The choice of which annexins to target should depend on their respective biological behaviors.