Isoflurane-induced neuroinflammation and NKCC1/KCC2 dysregulation result in long-term cognitive disorder in neonatal mice.

BACKGROUND: The inhalational anesthetic isoflurane is commonly utilized in clinical practice, particularly in the field of pediatric anesthesia. Research has demonstrated its capacity to induce neuroinflammation and long-term behavioral disorders; however, the underlying mechanism remains unclear [1]. The cation-chloride cotransporters Na+-K+-2Cl--1 (NKCC1) and K+-2Cl--2 (KCC2) play a pivotal role in regulating neuronal responses to gamma-aminobutyric acid (GABA) [2]. Imbalances in NKCC1/KCC2 can disrupt GABA neurotransmission, potentially leading to neural circuit hyperexcitability and reduced inhibition following neonatal exposure to anesthesia [3]. Therefore, this study postulates that anesthetics have the potential to dysregulate NKCC1 and/or KCC2 during brain development. METHODS: We administered 1.5% isoflurane anesthesia to neonatal rats for a duration of 4 h at postnatal day 7 (PND7). Anxiety levels were assessed using the open field test at PND28, while cognitive function was evaluated using the Morris water maze test between PND31 and PND34. Protein levels of NKCC1, KCC2, BDNF, and phosphorylated ERK (P-ERK) in the hippocampus were measured through Western blotting analysis. Pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α were quantified using ELISA. RESULTS: We observed a decrease in locomotion trajectories within the central region and a significantly shorter total distance in the ISO group compared to CON pups, indicating that isoflurane induces anxiety-like behavior. In the Morris water maze (MWM) test, rats exposed to isoflurane exhibited prolonged escape latency onto the platform. Additionally, isoflurane administration resulted in reduced time spent crossing in the MWM experiment at PND34, suggesting long-term impairment of memory function. Furthermore, we found that isoflurane triggered activation of pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α; downregulated KCC2/BDNF/P-ERK expression; and increased the NKCC1/KCC2 ratio in the hippocampus of PND7 rats. Bumetadine (NKCC1 specific inhibitors) reversed cognitive damage and effective disorder induced by isoflurane in neonatal rats by inhibiting TNF-α activation, normalizing IL-6 and IL-1ß levels, restoring KCC2 expression levels as well as BDNF and ERK signaling pathways. Based on these findings, it can be speculated that BDNF, P-ERK, IL-1ß, IL-6 and TNF - α may act downstream of the NKCC1/KCC2 pathway. CONCLUSIONS: Our findings provide evidence that isoflurane administration in neonatal rats leads to persistent cognitive deficits through dysregulation of the Cation-Chloride Cotransporters NKCC1 and KCC2, BDNF, p-ERK proteins, as well as neuroinflammatory processes.

Construction and verification of a histone deacetylases-related prognostic signature model for colon cancer.

Histone deacetylases (HDACs) contribute significantly to the initiation, progression, and prognosis of colorectal adenocarcinoma (COAD). Additionally, HDACs regulate the tumor microenvironment, immune escape, and tumor stem cells, and are closely linked to COAD prognosis. We developed a prognostic model for COAD that incorporates HDACs to evaluate their specific roles. The COAD dataset containing clinical and mutation data was collected using the TCGA and GEO databases to obtain genes associated with HDAC. LASSO analysis and univariate and multivariate Cox regression analysis were used to determine the presence of prognostic genes. Multivariate Cox analysis was also used to determine risk scores for HDAC-related features. Furthermore, genomic alterations, immune infiltration, and drug response were compared between high- and low-risk groups. Cellular experiments validated the potential regulatory role of BRD3 on COAD proliferation, migration, and apoptosis. The median risk scores, calculated based on the characteristics, demonstrated a more significant prognostic improvement in patients in the low-risk group. Furthermore, HDAC-related features were identified as important independent prognostic factors for patients with COAD. Additionally, genomic mutation status, immune infiltration, and function, as well as response to immunotherapy and chemotherapy, were found to be associated with risk scores. Subgroup analyses indicate that anti-PD-1 therapy may be beneficial for patients in the low-risk group. Additionally, a decrease in risk score was associated with a decrease in immune infiltration. Finally, HCT116 and HT29 cells exhibited inhibition of BRD3 gene proliferation and migration, as well as promotion of apoptosis. In patients with COAD, HDAC-related characteristics may be useful in predicting survival and selecting treatment.

Identifying a possible new target for diagnosis and treatment of postmenopausal osteoporosis through bioinformatics and clinical sample analysis.

BACKGROUND: Postmenopausal osteoporosis, a common yet chronic systemic metabolic disease, has become a major public health problem due to life expectancy increasing around the world. The differentiation of mesenchymal stem cells (MSCs) into osteoblasts, and the differentiation of circulating monocyte cells into osteoclasts, play an important role in the balance of bone metabolism. However, when both undergo pathological changes, it can lead to abnormalities, resulting in osteoporosis. This study aims to explore a new biomarker for postmenopausal osteoporosis, thereby providing a new entry point for bioinformatic research into the clinical diagnosis and treatment of the disease. METHODS: Using the Gene Expression Omnibus (GEO) database, microarray analysis was conducted to identify differentially expressed genes in MSCs and monocytes in both postmenopausal osteoporosis patients and a healthy control group. The Database for Annotation, Visualization and Integrated Discovery (DAVID) database was used to analyze the function and enrichment of the selected genes, and a protein-protein interaction (PPI) network was constructed from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) website and displayed in Cytoscape. To achieve the final results, module analysis of the PPI network was performed by using Molecular Complex Detection (MCODE). RESULTS: We identified 45 high-expression and 26 low-expression genes through the study, all of which underwent pathway enrichment analysis. This enrichment was observed in the cell cycle regulation, osteoclast differentiation, tumor necrosis factor (TNF) signaling pathway, and RNA transport. The top 10 hub genes of the PPI network were SF3B1, SRSF5, FUBP1, SRSF3, TIA1, KHSRP, LUC7L3, PNN, SRC, and ATRX. Comparing the MSCs and monocytes between the postmenopausal osteoporosis patients and the healthy control group, we noted that the expression of the above genes differed greatly. CONCLUSIONS: Through bioinformatic analysis and clinical specimen validation, our study provides a new way for exploring the pathogenesis of postmenopausal osteoporosis. Most importantly, it suggests that the hub genes, SF3B1, SRSF5, FUBP1, KHSRP, and SRC, may become new diagnostic markers and therapeutic targets for diagnosing and treating postmenopausal osteoporosis in the future.

The use of bronchial blockers in patients with aberrant tracheobronchial anatomy: a case report.

Abnormal tracheal bronchus originates from the sidewall of the trachea, and most frequently occurs on the right side, involves subsegmental bronchi and the segmental. The anatomical structure of the airway is of great significance for general anesthesia and lung isolation. Abnormal tracheal bronchus makes lung isolation more complicated. This study presents four rare cases of aberrant tracheobronchial anatomy in the right main bronchus. We review the literature and discuss our solution and propose possible solutions for lung isolation in patients with tracheobronchial abnormalities. Of these, three patients were scheduled for radical resection of lung cancer, and one patient was scheduled for radical resection of middle esophageal cancer. After anesthesia induction, we intubated the right-side double-lumen tube (DLT) using a fiberoptic bronchoscope to guide the intubation. During DLT repositioning, we discovered the tracheobronchial abnormality of the patients. We could not place the DLT appropriately, however we made an effort to achieve lung isolation. We used a bronchus blocker [(BB) Univent tube] to achieve lung isolation for case 1, and the patient had good ventilation and no dyspnea and carbon dioxide retention during the operation. We completed lung isolation for the other three patients with abnormal airways by adjusting the position and replacing the DLT.

Quantitative definitions of pain, CA19-9, and tumor size as high-risk features of resectable pancreatic cancer: a single-center retrospective cohort study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of malignant tumors with the worst prognosis. Surgery and adjuvant chemotherapy are the main treatments for resectable pancreatic cancer. For borderline resectable PDAC, neoadjuvant chemotherapy has been advised. For clearly resectable PDAC, neoadjuvant chemotherapy also might be considered for the patients with high-risk features, but with no precise quantitative criteria to define these features. So, this study aimed to re-evaluate the relationship between high-risk features and prognosis of clearly resectable pancreatic cancer, and to define the precise criteria for these high-risk features. METHODS: Data from 211 patients with clearly resectable pancreatic cancer were reviewed to assess the relationship between overall survival (OS) after surgery and high-risk features, and cut-off values were determined for high-risk features that were associated with poor prognosis of clearly resectable pancreatic cancer. RESULTS: Lymph node metastasis (LNM), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and primary tumor size ≥6 cm were significant variables related to OS. CA19-9 ≥1,000 U/mL was statistically related to prognosis, as was CA19-9 ≥500 U/mL without obstructive jaundice. There was no significant relationship between abdominal and/or back pain and OS, but patients with moderate or severe pain accompanied by tumor size ≥4 cm or 10 times higher CA19-9 levels had worse prognosis. CONCLUSIONS: For clearly resectable pancreatic cancer with R0 resection, the high-risk features were clarified. Abdominal and/or back pain may not be used as a prognostic indicator alone, though combined with CA19-9 or tumor size it may be more valuable for predicting prognosis.

Effect of a Care Bundle Combined with Continuous Positive Airway Pressure in the Postanesthesia Care Unit on Rapid Recovery after Pulmonary Tumor Resection.

Objective: To study the effect of a care bundle combined with continuous positive airway pressure (CPAP) in the postanesthesia care unit (PACU) on rapid recovery after pulmonary tumor resection. Methods: A total of 135 patients requiring anesthesia resuscitation after pulmonary tumor resection in our hospital from June 2020 to February 2021 were selected. They were randomly divided into three groups: the PACU experimental group, PACU control group, and operating room resuscitation (OR) group. Subsequently, their intraoperative clinical symptoms, parameters in monitoring postoperative respiratory status, and follow-up results were compared among the three groups. Results: The PACU experimental group had the highest number of right lesions, while the OR group had the highest intraoperative blood transfusion volume, urine volume, intraoperative colloid volume, intrapulmonary shunt, and intraoperative physician handover rate (P < 0.05). Before surgery, serum potassium (K) in the PACU experimental group was significantly higher than that in the OR group but lower than that in the PACU control group (P < 0.01). During the time in the PACU, blood partial pressure of oxygen (PO2) and oxygen index (OI) levels in the PACU experimental group were significantly higher than those in the other groups (P < 0.01). After surgery, total PACU stay time, time from PACU to extubation, and stay after extubation were markedly reduced in the PACU experimental group (P < 0.05). The highest number of patients with drainage was found in the PACU experimental group, while the highest number of patients without drainage was found in the PACU control group. Conclusion: A care bundle combined with CPAP in the PACU can improve the monitoring time of respiratory status and improve blood gas parameters, thus accelerating the postoperative rehabilitation process of patients undergoing pulmonary tumor resection.

Can anesthetic effects and pain treatment influence the long-term prognosis of early-stage lymph node-negative breast cancer after breast-conserving surgery?

BACKGROUND: Breast cancer is currently the leading cause of women's death. It is crucial to further improve the approach to treatment and the long-term survival rate of breast cancer patients, and to reduce the rates of recurrence and metastasis. It has been reported that the possibility of tumor metastasis depends on the metastatic potential of the tumor and the host defense against tumor metastasis, in which cellular immunity and the function of natural killer (NK) cells are critical to maintaining this balance. Surgical stress response and postoperative pain inhibit perioperative immune function in patients and increase the likelihood of dissemination and metastasis of cancer cells after cancer surgery. The study aims to investigate the effect of anesthetic factors and pain treatment on the long-term prognosis of patients with early stage lymph node negative breast preservation surgery. METHODS: A total of 337 patients with early-stage lymph node negative breast cancer (ASA I-II) who had undergone successful breast-conserving surgery in our hospital were included in this retrospective analysis. Cases were divided into general anesthesia with postoperative analgesia group (GA + PCA), general anesthesia without postoperative analgesia group (GA), epidural anesthesia with postoperative analgesia group (EA + PCA), and epidural anesthesia without postoperative analgesia group (EA). The 5-year survival rate and 5-year disease-free survival were recorded in the 4 groups. RESULTS: The general condition and length of hospital stay of the patients were not statistically different between the 4 groups. However, the 5-year survival rate and 5-year disease-free survival rate of the 4 groups were statistically different. The 5-year survival rate and 5-year disease-free survival rate were the lowest in the GA group, while the EA + PCA group had the highest 5-year disease-free survival rate. The 5-year survival rate and 5-year disease-free survival rate in the GA + PCA group were significantly higher than those in the GA group. The 5-year disease-free survival rate in EA group was significantly higher than GA group. CONCLUSIONS: Epidural anesthesia and postoperative pain treatment maybe beneficial to the long-term prognosis of patients with early-stage lymph node-negative breast cancer.

HNF1A inhibition induces the resistance of pancreatic cancer cells to gemcitabine by targeting ABCB1.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis, and gemcitabine-based chemotherapy remains an effective option for the majority of PDAC patients. Hepatocyte nuclear factor 1α (HNF1A) is a tumor-suppressor in PDAC, but its role in gemcitabine chemoresistance of PDAC has not been clarified. METHODS: The function of HNF1A in gemcitabine was detected by overexpression and knockdown of HNF1A in vitro and in vitro. The regulatory network between HNF1A and ABCB1 was further demonstrated by luciferase assays, deletion/mutation reporter construct assays and CHIP assays. FINDINGS: Here, we found that HNF1A expression is significantly associated with gemcitabine sensitivity in PDAC cell lines. Moreover, we identified that HNF1A overexpression enhanced gemcitabine sensitivity of PDAC both in vitro and in vitro, while inhibition of HNF1A had the opposite effect. Furthermore, by inhibiting and overexpressing HNF1A, we revealed that HNF1A regulates the expression of MDR genes (ABCB1 and ABCC1) in PDAC cells. Mechanistically, we demonstrated that HNF1A regulates ABCB1 expression through binding to its specific promoter region and suppressing its transcription levels. Finally, the survival analyses revealed the clinical value of HNF1A in stratification of gemcitabine sensitive pancreatic cancer patients. INTERPRETATION: Our study paved the road for finding novel treatment combinations using conventional cytotoxic agents with functional restoration of the HNF1A protein, individualized treatment through HNF1A staining and improvement of the prognosis of PDAC patients. FUND: National Natural Science Foundations of China and National Natural Science Foundation of Guangdong Province.