Exosomal miR-21 determines lung-to-brain metastasis specificity through the DGKB/ERK axis within the tumor microenvironment.

BACKGROUND: Brain metastasis affects 20-40 % of lung cancer patients, severely diminishing their quality of life. This research focuses on miR-21, overexpressed in these patients and inversely associated with DGKB in the ERK/STAT3 pathway, suggesting a dysregulated pathway with therapeutic potential. AIMS: The objective was to investigate miR-21's role in lung cancer patients with brain metastases and whether targeting this pathway could improve treatment outcomes. We also examined the miR-21 content in tumor spheres-derived extracellular vesicles (EVs) and their influence on ERK/STAT3 signaling and metastasis. MATERIALS AND METHODS: Tumor spheres were created from metastatic lung cancer cells. We studied miR-21 levels in these spheres, their impact on macrophage polarization, and the transition of nonmetastatic lung cancer cells. Furthermore, we analyzed miR-21 content in EVs derived from these spheres and their effect on ERK/STAT3 signaling and metastasis potential. KEY FINDINGS: We found tumor spheres had high miR-21 levels, promoting macrophage polarization and, epithelial-mesenchymal transition. These spheres-derived EVs, enriched with miR-21, accelerated ERK/STAT3 signaling and metastasis. Silencing miR-21 and inhibiting ERK signaling with ulixertinib notably mitigated these effects. Moreover, ulixertinib reduced brain metastasis incidence and increased survival in a mouse model and led to reduced tumor sphere generation and miR-21 levels in EVs. SIGNIFICANCE: Our study highlights the exacerbation of lung-to-brain metastasis via miR-21-rich EV secretion. This underlines the therapeutic promise of targeting the miR-21/ERK/STAT3 pathway with ulixertinib for managing brain metastasis from lung cancer.

Targeting the SREBP-1/Hsa-Mir-497/SCAP/FASN Oncometabolic Axis Inhibits the Cancer Stem-like and Chemoresistant Phenotype of Non-Small Cell Lung Carcinoma Cells.

BACKGROUND: Lung cancer remains a leading cause of cancer-related death, with an annual global mortality rate of 18.4%. Despite advances in diagnostic and therapeutic technologies, non-small cell lung carcinoma (NSCLC) continues to be characterized by a poor prognosis. This may be associated with the enrichment of cancer stem cells (CSCs) and the development of chemoresistance-a double-edged challenge that continues to impede the improvement of long-term outcomes. Metabolic reprogramming is a new hallmark of cancer. Sterol regulatory element-binding proteins (SREBPs) play crucial regulatory roles in the synthesis and uptake of cholesterol, fatty acids, and phospholipids. Recent evidence has demonstrated that SREBP-1 is upregulated in several cancer types. However, its role in lung cancer remains unclear. OBJECTIVE: This study investigated the role of SREBP-1 in NSCLC biology, progression, and therapeutic response and explored the therapeutic exploitability of SREBP-1 and SREBP-1-dependent oncometabolic signaling and miRNA epigenetic regulation. METHODS: We analyzed SREBP-1 levels and biological functions in clinical samples and the human NSCLC cell lines H441 and A549 through shRNA-based knock down of SREBP function, cisplatin-resistant clone generation, immunohistochemical staining of clinical samples, and cell viability, sphere-formation, Western blot, and quantitative PCR assays. We conducted in-silico analysis of miRNA expression in NSCLC samples by using the Gene Expression Omnibus (GSE102286) database. RESULTS: We demonstrated that SREBP-1 and SCAP are highly expressed in NSCLC and are positively correlated with the aggressive phenotypes of NSCLC cells. In addition, downregulation of the expression of tumor-suppressing hsa-miR-497-5p, which predictively targets SREBP-1, was observed. We also demonstrated that SREBP-1/SCAP/FASN lipogenic signaling plays a key role in CSCs-like and chemoresistant NSCLC phenotypes, especially because the fatostatin or shRNA targeting of SREBP-1 significantly suppressed the viability, cisplatin resistance, and cancer stemness of NSCLC cells and because treatment induced the expression of hsa-miR-497. CONCLUSION: Targeting the SREBP-1/hsa-miR-497 signaling axis is a potentially effective anticancer therapeutic strategy for NSCLC.

Spectral Entropy Monitoring Accelerates the Emergence from Sevoflurane Anesthesia in Thoracic Surgery: A Randomized Controlled Trial.

The clinical efficacy of spectral entropy monitoring in improving postoperative recovery remains unclear. This trial aimed to investigate the impact of M-Entropy (GE Healthcare, Helsinki, Finland) guidance on emergence from anesthesia and postoperative delirium in thoracic surgery. Adult patients undergoing video-assisted thoracoscopic surgery for lung resection at a medical center were randomly allocated into the M-Entropy guidance group (n = 39) and the control group (n = 37). In the M-Entropy guidance group, sevoflurane anesthesia was titrated to maintain response and state entropy values between 40 and 60 intraoperatively. In the control group, the dosing of sevoflurane was adjusted based on clinical judgment and vital signs. The primary outcome was time to spontaneous eye opening. M-Entropy guidance significantly reduced the time proportion of deep anesthesia (entropy value <40) during surgery, mean difference: −21.5% (95% confidence interval (CI): −32.7 to −10.3) for response entropy and −24.2% (−36.3 to −12.2) for state entropy. M-Entropy guidance significantly shortened time to spontaneous eye opening compared to clinical signs, mean difference: −154 s (95% CI: −259 to −49). In addition, patients of the M-Entropy group had a lower rate of emergence agitation (absolute risk reduction: 0.166, 95% CI: 0.005−0.328) and delirium (0.245, 0.093−0.396) at the postanesthesia care unit. M-Entropy-guided anesthesia hastened awakening and potentially prevented emergence agitation and delirium after thoracic surgery. These results may provide an implication for facilitating postoperative recovery and reducing the complications associated with delayed emergence and delirium.

Recruitment maneuvers in patients undergoing thoracic surgery: a meta-analysis.

OBJECTIVE: Pulmonary atelectasis is a common postoperative complication that may lead to intrapulmonary shunt, refractory hypoxemia, and respiratory distress. Recruitment maneuvers may relieve pulmonary atelectasis in patients undergoing thoracic surgery. This meta-analysis of randomized controlled trials (RCTs) is to evaluate the effectiveness and safety of recruitment maneuvers in patients undergoing thoracic surgery. METHODS: We performed a literature search on the PubMed, Embase, and Cochrane Library databases and the ClinicalTrials.gov registry for trials published before April 2021. We investigated postoperative pulmonary atelectasis incidence, intrapulmonary shunt fraction, static lung compliance, and mean arterial pressure. RESULTS: Six RCTs involving 526 patients were reviewed. Patients receiving a recruitment maneuver exhibited a significant decrease in intrapulmonary shunt fraction [weighted mean difference (WMD) - 0.02, 95% CI - 0.03 to - 0.01], improved static lung compliance (WMD 2.16; 95% CI 1.14-3.18), and PaO2/FIO2 ratio (WMD 31.31; 95% CI 12.11-50.52) without a significant difference in mean arterial pressure (WMD - 0.64; 95% CI - 4.92 to 3.64). The incidence pulmonary atelectasis favored recruitment maneuver group, but was not statistically significant (RR 0.55; 95% CI 0.27-1.12). CONCLUSIONS: Recruitment maneuvers may be a viable treatment for reducing intra-pulmonary shunt and improving static lung compliance and PaO2/FIO2 ratio without the disturbance of hemodynamics in patients undergoing thoracic surgery.

Indwelling pleural catheter versus talc pleurodesis for malignant pleural effusion: a meta-analysis.

Malignant pleural effusion (MPE) results from primary mesothelioma or the spreading of metastatic cancer. Both talc pleurodesis (TP) and indwelling pleural catheter (IPC) improve MPE symptoms. We performed a meta-analysis of randomized controlled trials to compare the efficacy of TP with that of IPC in patients with MPE. PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched for studies published before February 2020. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate a pooled effect size by using random effects models. In total, 4 trials with 500 patients were reviewed. Difference in pleurodesis success rate and change in dyspnea scores at 4 and 6 weeks between MPE patients treated with IPC and those treated with TP for pleurodesis were nonsignificant. The number of hospital inpatient days was significantly lower among patients who were treated with IPC (weight mean difference: 2.19; 95% confidence interval 0.70-3.67) than among those who were treated with TP. No significant difference was shown in adverse event profile between patients treated with IPC and those treated with TP for pleurodesis. In conclusion, both TP and IPC are equally effective in treating patients with MPE. The number of hospitalization days was significantly lower for patients who were treated with IPC, but the magnitude of the difference is of uncertain clinical importance.

Does Surgery Reduce the Risk of Complications Among Patients with Multiple Rib Fractures? A Meta-analysis.

BACKGROUND: Multiple rib fractures are common in trauma patients, who are prone to trauma-associated complications. Surgical or nonsurgical interventions for the aforementioned conditions remain controversial. QUESTIONS/PURPOSES: The purpose of our study was to perform a meta-analysis to evaluate the clinical prognosis of surgical fixation of multiple rib fractures in terms of (1) hospital-related endpoints (including duration of mechanical ventilation, ICU length of stay [LOS] and hospital LOS), (2) complications, (3) pulmonary function, and (4) pain scores. METHODS: We screened PubMed, Embase, and Cochrane databases for randomized and prospective studies published before January 2018. Individual effect sizes were standardized; the pooled effect size was calculated using a random-effects model. Primary outcomes were duration of mechanical ventilation, intensive care unit length of stay (ICU LOS), and hospital LOS. Moreover, complications, pulmonary function, and pain were assessed. RESULTS: The surgical group had a reduced duration of mechanical ventilation (weighted mean difference [WMD], -4.95 days; 95% confidence interval [CI], -7.97 to -1.94; p = 0.001), ICU LOS (WMD, -4.81 days; 95% CI, -6.22 to -3.39; p < 0.001), and hospital LOS (WMD, -8.26 days; 95% CI, -11.73 to -4.79; p < 0.001) compared with the nonsurgical group. Complications likewise were less common in the surgical group, including pneumonia (odds ratio [OR], 0.41; 95% CI, 0.27-0.64; p < 0.001), mortality (OR, 0.24; 95% CI, 0.07-0.87; p = 0.030), chest wall deformity (OR, 0.02; 95% CI. 0.00-0.12; p < 0.001), dyspnea (OR, 0.23; 95% CI, 0.09-0.54; p < 0.001), chest wall tightness (OR, 0.11; 95% CI, 0.05-0.22; p < 0.001) and incidence of tracheostomy (OR, 0.34; 95% CI, 0.20-0.57; p < 0.001). There were no differences between the surgical and nonsurgical groups in terms of pulmonary function, such as forced vital capacity (WMD, 6.81%; 95% CI: -8.86 to 22.48; p = 0.390) and pain scores (WMD, -11.41; 95% CI: -42.09 to 19.26; p = 0.470). CONCLUSIONS: This meta-analysis lends stronger support to surgical fixation, rather than conservative treatment, for multiple rib fractures. Nevertheless, additional trials should be conducted to investigate surgical indications, timing, and followup for quality of life. LEVEL OF EVIDENCE: Level I, therapeutic study.

Regulation of metastatic ability and drug resistance in pulmonary adenocarcinoma by matrix rigidity via activating c-Met and EGFR.

Lung fibrosis is a poor prognostic factor for pulmonary adenocarcinoma, and the effect of a rigid microenvironment on cancer behavior is unclear. We cultured A549 cells on matrices of 0.2, 2, and 25 kPa to mimic the rigidities of normal lung parenchyma, progressive fibrotic change, and lung fibrosis, respectively. Lung tissue from patients with pulmonary adenocarcinoma was used to confirm the in vitro findings. Increased matrix rigidity promoted cell proliferation and upregulated the epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-Met), and Snail expression in A549 cells. A549 cells became more resistant to the EGFR inhibitor (Erlotinib) and c-Met inhibitor (PHA-665752) when matrix rigidity increased; however, a high concentration of PHA-665752 reversed the rigidity-induced morphological pleomorphism. In human lung tissue, expression of type I collagen was more consistent with clinical fibrosis than the expression of alpha-smooth muscle antibody was. c-Met- and Snail-expressing tumor cells, rather than EGFR-experssing cells, were localized with lung parenchyma rich in type I collagen. Our findings suggest that c-Met causes the rigidity-induced biophysical reaction in pulmonary adenocarcinoma. Treatment targeting both EGFR and c-Met should be considered for patients with lung fibrosis and who are abundant type I collagen expression in the tumor mass.