Effect of esketamine on the ED50 of propofol for successful insertion of ureteroscope in elderly male patients: a randomized controlled trial.

BACKGROUND: Propofol is effective and used as a kind of routine anesthetics in procedure sedative anesthesia (PSA) for ureteroscopy. However, respiratory depression and unconscious physical activity always occur during propofol-based PSA, especially in elderly patients. Esketamine has sedative and analgesic effects but without risk of cardiorespiratory depression. The purpose of this study is to investigate whether esketamine can reduce the propofol median effective dose (ED50) for successful ureteroscope insertion in elderly male patients. MATERIALS AND METHODS: 49 elderly male patients undergoing elective rigid ureteroscopy were randomly divided into two groups: SK Group (0.25 mg/kg esketamine+propofol) and SF Group (0.1 µg/kg sufentanil+propofol). Patients in both two groups received propofol with initial bolus dose of 1.5 mg/kg after sufentanil or esketamine was administered intravenously. The effective dose of propofol was assessed by a modified Dixon's up-and-down method and then was adjusted with 0.1 mg/kg according to the previous patient response. Patients' response to ureteroscope insertion was classified as "movement" or "no movement". The primary outcome was the ED50 of propofol for successful ureteroscope insertion with esketamine or sufentanil. The secondary outcomes were the induction time, adverse events such as hemodynamic changes, hypoxemia and body movement were also measured. RESULT: 49 patients were enrolled and completed this study. The ED50 of propofol for successful ureteroscope insertion in SK Group was 1.356 ± 0.11 mg/kg, which was decreased compared with that in SF Group, 1.442 ± 0.08 mg/kg (P = 0.003). The induction time in SK Group was significantly shorter than in SF Group (P = 0.001). In SK Group, more stable hemodynamic variables were observed than in SF Group. The incidence of AEs between the two groups was not significantly different. CONCLUSION: The ED50 of propofol with esketamine administration for ureteroscope insertion in elderly male patients is 1.356 ± 0.11 mg/kg, significantly decreased in comparsion with sufentanil. TRIAL REGISTRATION: Chinese Clinical Trial Registry, No: ChiCTR2300077170. Registered on 1 November 2023. Prospective registration. http://www.chictr.org.cn .

Effects of individualized positive end-expiratory pressure on intraoperative oxygenation in thoracic surgical patients: study protocol for a prospective randomized controlled trial.

BACKGROUND: Intraoperative hypoxemia and postoperative pulmonary complications (PPCs) often occur in patients with one-lung ventilation (OLV), due to both pulmonary shunt and atelectasis. It has been demonstrated that individualized positive end-expiratory pressure (iPEEP) can effectively improve intraoperative oxygenation, increase lung compliance, and reduce driving pressure, thereby decreasing the risk of developing PPCs. However, its effect during OLV is still unknown. Therefore, we aim to investigate whether iPEEP ventilation during OLV is superior to 5 cmH2O PEEP in terms of intraoperative oxygenation and the occurrence of PPCs. METHODS: This study is a prospective, randomized controlled, single-blind, single-center trial. A total of 112 patients undergoing thoracoscopic pneumonectomy surgery and OLV will be enrolled in the study. They will be randomized into two groups: the static lung compliance guided iPEEP titration group (Cst-iPEEP Group) and the constant 5 cmH2O PEEP group (PEEP 5 Group). The primary outcome will be the oxygenation index at 30 min after OLV and titration. Secondary outcomes are oxygenation index at other operative time points, PPCs, postoperative adverse events, ventilator parameters, vital signs, pH value, inflammatory factors, and economic indicators. DISCUSSION: This trial explores the effect of iPEEP on intraoperative oxygenation during OLV and PPCs. It provides some clinical references for optimizing the lung protective ventilation strategy of OLV, improving patient prognosis, and accelerating postoperative rehabilitation. TRIAL REGISTRATION: www.Chictr.org.cn ChiCTR2300073411 . Registered on 10 July 2023.

Expression of YAP suppresses cell proliferation and elevates the sensitivity of chemotherapy in retinoblastoma cells through lipid-peroxidation induced ferroptosis.

BACKGROUND: Retinoblastoma (RB) is a retinal cancer most commonly occurred in young children. Cisplatin and etoposide had been confirmed as chemotherapy drugs in the treatment of RB, even though the phenomenon of chemotherapeutic resistance has been occurring in clinical treatment frequently. RB has been reported to be a tumor with reduced expression of yes-associated protein (YAP). However, the role of YAP protein and its correlation with the chemotherapy effect in RB still remains unknown. METHODS: Here we used human RB cell lines Y79 and RB3823 to construct YAP over-expression cell lines for exploring the specific role of YAP. In vitro, a series of techniques and methods were used to identify the biological role of YAP in RB, such as Agilent Seahorse assay, lipid peroxidation assay, intracellular reactive oxygen species (ROS) measurement, flow cytometry apoptosis assay, and other basic experimental techniques, among others. RESULTS: The cell growth and cytology experimental results found YAP can inhibit the proliferation of RB cells and promote their apoptosis (Y79 32.71% vs. 3.75%; RB3823 40.32% vs. 6.73%). The mitochondrial fuel flex test, lipid peroxide and ROS measurement confirmed that YAP over-expression could promote mitochondrial fatty-acids ß-oxidation and lipid peroxidation in RB cells. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis for the expression of lipid peroxidation related factors imply that YAP over-expression caused ferroptosis in RB cell lines. In addition, YAP transcription specific activator PY-60 (10 µM) further improved the sensitivity of cisplatin/etoposide. CONCLUSIONS: Our research results found the expression of YAP inhibits cell proliferation and promoted lipid peroxidation induced ferroptosis in RB. Interestingly, the mitochondrial oxidative phosphorylation shows an increased fatty acid dependency and decreased glucose dependency. As a result, this phenomenon improved the sensitivity of RB to cisplatin/etoposide chemotherapy in vitro. Our finding provides a potential therapeutic target for RB chemotherapy.

Biomimetic Epigallocatechin Gallate-Cerium Assemblies for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease that is so far incurable with long-term health risks. The high doses and frequent administration for the available RA drug always lead to adverse side effects. Aiming at the obstacles to achieving effective RA treatment, we prepared macrophage cell membrane-camouflaged nanoparticles (M-EC), which were assembled from epigallocatechin gallate (EGCG) and cerium(IV) ions. Due to its geometrical similarity to the active metal sites of a natural antioxidant enzyme, the EC possessed a high scavenge efficiency to various types of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The macrophage cell membrane assisted M-EC in escaping from the immune system, being uptaken by inflammatory cells, and specifically binding IL-1ß. After tail vein injection to the collagen-induced arthritis (CIA) mouse model, the M-EC accumulated at inflamed joints and effectively repaired the bone erosion and cartilage damage of rheumatoid arthritis by relieving synovial inflammation and cartilage erosion. It is expected that the M-EC can not only pave a new way for designing metal-phenolic networks with better biological activity but also provide a more biocompatible therapeutic strategy for effective treatment of RA.

Retraction notice to "Endogenous production of C-C motif chemokine ligand 2 by nasopharyngeal carcinoma cells drives radioresistance-associated metastasis" [Canc. Lett. 468 (2020) 27-40].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). .

Multi-Locus Sequence Typing and Drug Resistance Analysis of Swine Origin Escherichia coli in Shandong of China and Its Potential Risk on Public Health.

The extensive use of antibiotics has caused antimicrobial resistance and multidrug resistance in Escherichia coli and gradual expands it into a worldwide problem. The resistant E. coli could be transmitted to humans through animal products, thereby creating a problem for bacterial treatment in humans and resulting in a public health issue. This study aims to investigate the molecular typing and drug resistance of swine and human origin E. coli within the same prefecture-level cities of Shandong Province and the potential risk of E. coli on public health. The drug sensitivity results indicated that tetracycline (TE) (97.17%) is a major antibiotic with high drug resistance in 106 swine origin E. coli. There was a significant difference in the drug-resistant genotypes between the two sources, of which the blaTEM positive rate was the highest in the genera of ß-lactams (99% in swines and 100% in humans). Among the 146 E. coli isolates, 98 (91.51% swine origin) and 31 (77.5% human origin) isolates were simultaneously resistant to three or more classes of antibiotics, respectively. The multi-locus sequence typing (MLST) results indicate that the 106 swine origin E. coli isolates are divided into 25 STs with ST1258, ST361, and ST10 being the dominant sequence analysis typing strains. There were 19 MLST genotypes in 40 strains of human E. coli from Tai'an, Shandong Province, with ST1193, ST73, ST648, ST131, ST10, and ST1668 being the dominant strains. Moreover, the cluster analysis showed that CCl0 and CC23 were the common clonal complexes (CCs) from the two sources. Our results provide a theoretical basis for guiding the rational use of antibiotics and preventing the spread of drug-resistant bacteria, and also provide epidemiological data for the risk analysis of foodborne bacteria and antimicrobial resistance in swine farms in Shandong Province.

Mutational landscape of primary pulmonary salivary gland-type tumors through targeted next-generation sequencing.

OBJECTIVES: Primary pulmonary salivary gland-type tumors (PSGTs) mainly comprise of mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC), which are rare and molecularly poorly understood. This study aimed to profile the molecular alterations of PSGTs via targeted next-generation sequencing (NGS). MATERIAL AND METHODS: Immunohistochemistry was used to screen PSGTs in 32 patients and MAML2 and MYB rearrangements were detected using fluorescence in situ hybridization. 1021-Genepanel of targeted NGS was conducted to profile genomic mutations in all the PSGT patients. RESULTS: Among the 32 patients, 25 had MEC and 7 had ACC. MAML2 and MYB rearrangements were detected in 80.0% (20/25) of the MEC and 71.4% (5/7) of the ACC patients. Among the MEC patients, 10 (40.0%) had ≥1 mutation, and 6 of them had 11 isolated mutations with abundance >5%, namely NFE2L2, MYOD1, INPP4B, CCND2, SNTG1, HSPD1, TGFBR1, RBM10, NOTCH4, ASXL1, and PTPRD mutations. The remaining 4 patients had 9 mutations with abundance <5%, namely KMT2A, PDCD11, FLT1, BRCA2, APC, SLX4, FOXP1, FGFR1, and HRAS mutations. All the ACC patients had mutations, which were enriched in 5 pathways including the PI3K and NOTCH pathways, chromatin and cytoskeleton remodeling, and DNA damage. These results explain PSGTs harbor distinct driver features of MAML2 or MYB rearrangement, accompanied with wide mutational diversity with very low rate of somatic mutation. Several important pathways, including the NOTCH and PI3K pathways, and chromatin remodeling could be targeted to improve the survival in patients with ACC.

Radioresistant Nasopharyngeal Carcinoma Cells Exhibited Decreased Cisplatin Sensitivity by Inducing SLC1A6 Expression.

Cisplatin-based regimens are commonly used for the treatment of nasopharyngeal carcinoma (NPC) in patients who receive concurrent chemoradiotherapy. The sensitivity of NPC cells to cisplatin is closely associated with the efficacy of radiation therapy. In this study, we established two radioresistant NPC cell lines, HONE1-IR and CNE2-IR, and found that both cell lines showed reduced sensitivity to cisplatin. RNA-sequence analysis showed that SLC1A6 was upregulated in both HONE1-IR and CNE2-IR cell lines. Downregulation of SLC1A6 enhanced cisplatin sensitivity in these two radioresistant NPC cell lines. It was also found that the expression of SLC1A6 was induced during radiation treatment and correlated with poor prognosis of NPC patients. Notably, we observed that upregulation of SLC1A6 led to elevating level of glutamate and the expression of drug-resistant genes, resulted in reduced cisplatin sensitivity. Our findings provide a rationale for developing a novel therapeutic target for NPC patients with cisplatin resistance.

Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson's Disease Mice Model Revealed by Transcriptome.

Parkinson's disease (PD) is a neurodegenerative disease caused by a variety of unclear complex pathogenic factors. The 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced progressive PD mice is a well-recognized classic model for studying PD, but the molecular toxicology of this model is still unclear. Here, for the first time, we report gradual neurodegenerative processes in MPTP/p-induced progressive PD mice model using RNA-seq. Transcriptional responses are orchestrated to regulate the expression of many genes in substantia nigra, such as Ntf3, Pitx3, Th, and Drd2, leading to the degeneration of dopaminergic neurons at last. We proposed that the established model could be divided into three phases based on their molecular toxicological features: "the stress response phase" which maintained the microenvironment homeostasis, "the pre-neurodegenerative phase" which demonstrated observed MPTP/p cytotoxicity and gradual degeneration of dopaminergic neurons, and "the neurodegenerative phase" which reflected distinct damage and dopaminergic neuron apoptotic process. Glia cells exhibited a certain protective effect on dopaminergic neurons in 3rd and 6th MPTP/p-induced cytotoxicity. But in 10th MPTP/p injection, glia cells play a promoting role in PD and tissue damages caused by oxidative stress. This study also indicated that the substantia nigra of PD mice showed unique patterns of changes at each stage. Moreover, neurotrophic signaling pathway, ECM-receptor interaction, oxidative phosphorylation, apoptosis and necroptosis were enriched at 3rd and 6th MPTP/p injection, which might be associated with the PD progress. This study provided an extensive data set of molecular toxicology for elucidating of PD progression and offered comprehensive theoretical knowledge for the development of new therapy.

Pharmacokinetics and tissue distribution study of obtusifolin in rats by liquid chromatography-tandem mass spectrometry.

This paper reports the validation of an assay for obtusifolin based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application to a preclinical pharmacokinetic study in rats. After sample preparation of plasma and tissue homogenates by protein precipitation, the analyte and internal standard (IS) were separated by a reversed-phase chromatographic system in a run time of 5.0 min and detected by negative ion electrospray ionization followed by selected reaction monitoring of the precursor-to-product ion transitions at m/z 283.0-268.1 for obtusifolin and m/z 329.0-314.1 for IS. The assay was linear in the concentration range 1.0-500 ng/ml with the LLOQ of 1.0 ng/ml. In the pharmacokinetic study of an intragastric administration of 1.3 mg/kg obtusifolin, the maximum plasma concentration of obtusifolin was 152.5 ± 62.3 ng/ml, reached at 0.39 ± 0.17 h. The AUC0-t and AUC0-∞ were 491.8 ± 256.7 and 501.7 ± 256.7 ng × h/ml, respectively, with an elimination half-life of 3.1 ± 0.7 h. Obtusifolin was rapidly distributed into tissues, with the highest distribution in the liver and less in the brain. These results will give some insights for further pharmacological investigation of obtusifolin.

Breast-conserving therapy is safe both within BRCA1/2 mutation carriers and noncarriers with breast cancer in the Chinese population.

BACKGROUND: BRCA1/2 mutation is associated with a high risk of breast cancer, which may preclude breast cancer patients with BRCA1/2 mutation from breast-conserving therapy (BCT) [breast-conserving surgery (BCS), followed by radiotherapy, BCT]. It is debatable whether BCT could be a rational choice for Chinese breast cancer patients with a BRCA1/2 mutation. METHODS: The study comprised a cohort of women with invasive breast cancer either receiving BCT or mastectomy following the criteria for the germline BRCA1/2 mutation test. Germline DNA for BRCA1/2 testing was derived from blood samples. Survival analyses were performed. The correlations were analyzed between survival and distinct types of surgery. To compare the survival between different surgical management, Kaplan-Meier univariate analysis and multivariate Cox regression was used. RESULTS: In BRCA1/2 mutation carriers (N=176) and noncarriers (N=293), 25% and 27.3% of the patients received BCT, respectively (P=0.675). Patients receiving mastectomy (without radiotherapy or followed by radiotherapy) have larger tumor size (P<0.05 both in BRCA1/2 mutation carriers and noncarriers), prognostically worse tumor characteristics including significantly more advanced TNM stage (P=0.017 and P<0.0001 respectively) and more positive lymph nodes (P=0.008 and P<0.0001, respectively) both in BRCA1/2 mutation carriers and noncarriers. Still, more often received systemic therapy has also been observed. After adjustment for clinical-pathological characteristics and systemic treatment, patients who received BCT had a similar breast cancer disease-free survival compared with patients who received mastectomy, both in BRCA1/2 mutation carriers and noncarriers [HR BRCA1/2 =1.17, confidence interval (CI): 0.57-2.39, P=0.68; HRnoncarriers =0.91, CI: 0.47-1.77, P=0.79, respectively). The recurrence free survival after BCT did not differ from mastectomy in BRCA1/2 mutation carriers [BCT, 5-year cumulative recurrence-free survival (RFS) =0.95, CI: 0.89-1.00; mastectomy, 5-year cumulative RFS =0.93, CI: 0.85-1.00], even better for BCT in noncarriers (BCT, 5-year cumulative RFS =0.67, CI: 0.42-0.89; mastectomy, 5-year cumulative RFS =0.83, CI: 0.71-0.95). CONCLUSIONS: Thus, BCT may be a safe and rational choice for Chinese female breast cancer patients with a BRCA1/2 mutation. However, tumor size, the TNM stage, the number of positive lymph nodes, might be taken into consideration when choosing surgical management.

Endogenous production of C-C motif chemokine ligand 2 by nasopharyngeal carcinoma cells drives radioresistance-associated metastasis.

Patients with recurrent nasopharyngeal carcinoma (NPC) have more co-existing distant metastasis than those of no-recurrence and are more likely to suffer distant metastasis after re-irradiation than patients with newly diagnosed NPC. However, the relationship between radioresistance and distant metastasis and the mechanisms involved in radioresistance-associated metastasis are still unclear. In this study, we proved that C-C motif chemokine ligand 2 (CCL2) expression was significantly elevated in HONE1-IR cells and recurrent NPC tumour. Inhibition of CCL2 enhanced sensitivity to radiotherapy in NPC cells. Moreover, autocrine CCL2 promoted NPC cell adaptive radioresistance, metastasis and epithelial-mesenchymal transition. Additionally, p53 activated CCL2 transcription. High CCL2 expression was highly associated with poorer locoregional recurrence free survival, progression free survival and overall survival in patients with newly diagnosed NPC. Notably, high CCL2 expression was an independent prognostic factor for distant metastasis free survival in recurrent NPC patients. Our results provide insights into the autocrine signalling mechanisms of CCL2 and suggest that inhibition of autocrine CCL2 may be a candidate treatment strategy for management of radioresistant NPC.

[Lentivirus-mediated LOX-1-RNA interference attenuates oxidative stress-induced apoptosis in myocardial cells].

OBJECTIVE: To construct a lectin-like oxidized low-density lipoprotein receptor (LOX-1) RNA interference (RNAi) lentivirus and explore the role of LOX-1 in H(2)O(2)-induced apoptosis of rat myocardial cells. METHODS: LOX-1 shRNA sequence was synthesized and cloned into pLentiLox3.7 (pLL3.7) lentiviral vector to construct the lentiviral vector pLL3.7-LOX1. The lentiviral vectors (pLL3.7 and pLL3.7-LOX1) and the packaging vectors dR8.9 and VSVG were co-transfected into 293FT cells for packaging the lentivirus. H9C2 myocardial cells were infected by the lentiviruses to observe the inhibitory rate of LOX-1 on H(2)O(2)-induced apoptosis of H9C2 cells by RT-PCR, CCK-8, and Hochest33258 staining. RESULTS: Double restriction enzyme digestion and DNA sequencing confirmed correct insertion of the sequence. Suppression of LOX-1 by the lentivirus attenuated H(2)O(2)-induced cell viability reduction and apoptosis in the myocardial cells (P<0.01). CONCLUSION: LOX-1 activation may play an important role in H(2)O(2)-induced apoptosis of rat myocardial cells.