Targeted-lung delivery of bardoxolone methyl using PECAM-1 antibody-conjugated nanostructure lipid carriers for the treatment of lung inflammation.

The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.

Diffusion-weighted imaging in evaluating the efficacy of concurrent chemoradiotherapy in the treatment of non-small cell lung cancer.

OBJECTIVE: To explore the predictive value of diffusion-weighted imaging (DWI) in evaluating the short-term efficacy of concurrent chemoradiotherapy (CCRT) in the treatment of patients with non-small cell lung cancer (NSCLC). METHODS: A total of 192 patients with NSCLC were selected and treated with CCRT. Dynamic contrast-enhanced magnetic resonance imaging combined with DWI was performed on all patients before and after CCRT treatment. Correspondingly, apparent diffusion coefficient (ADC) values were recorded before treatment (ADCpre), during treatment (ADCmid), and after treatment (ADCpost). Tumor response was evaluated as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic power of quantitative DWI parameters in predicting the short-term efficacy of CCRT for patients with NSCLC. RESULTS: There were 21 patients with CR, 82 with PR, 77 with SD, and 12 with PD. The ADCpre was negatively correlated with tumor regression rate, whereas ADCmid, ADCpost, and their respective change rates ∆ADCmid and ∆ADCpost were positively related to tumor regression rate. The ROC curve analysis suggested ADCpre = 1.38 × 10-3 mm2/s, ∆ADCmid = 14.14%, and ∆ADCpost = 20.39% as thresholds to predict the short-term efficacy of CCRT, with corresponding areas under the curve of 0.637, 0.743, and 0.752, respectively. CONCLUSIONS: These findings indicate that DWI provides promising predictive value in evaluating the short-term efficacy of CCRT in the treatment of patients with NSCLC.

Single-port thoracoscopic sympathicotomy using a double-lumen electrocautery tube and cautery hook for primary palmar hyperhidrosis: a randomized controlled trial.

OBJECTIVE: The objective of this study is to assess the use of a novel, double-lumen electrocautery tube (DLET) device for ablating the sympathetic nerve chain in patients with primary palmar hyperhidrosis (PPH). METHODS: Forty-six patients with severe PPH were recruited into the study between November 2010 and February 2012. All patients underwent single port, bilateral video-assisted thoracoscopic sympathicotomy. Twenty-four patients were randomized to receive sympathicotomy using a conventional 5-mm electrocautery hook (hook group) and 22 patients were randomized to the DLET group. RESULTS: The mean postoperative follow-up period was 8.1 months (range: 1 to 15 months). After surgery the hands of all patients became dry and warm. Mean incision size was 10.6 ± 1.0 in the hook group and 6.5 ± 0.5 mm in the DLET group (p = 0.001). The mean pain score was 1.4 ± 0.6 with hook surgery and 0.9 ± 0.6 with the DLET device (p = 0.016). The mean operative time was longer in the hook group (36.8 ± 3.4 min) than in the DLET group (30.5 ± 3.9 min; p = 0.001). There were no significant differences between the two procedures in terms of hospital stay and compensatory sweating, or patient satisfaction. Pneumothorax occurred in two (8.3%) patients in the hook group and in one (4.5%) patient in the DLET group. None of the patients required chest drainage and none developed Horner syndrome. CONCLUSIONS: Single-port video-assisted thoracoscopic sympathicotomy using hook or DLET procedures is effective, safe, and minimally invasive method for palmar hyperhidrosis. The DLET device allows a shorter operation time, smaller incision, better cosmetic results, less pain, and better clarity of video, making it suitable for single-port thoracoscopic sympathicotomy.

Association between NQO1 Pro187Ser polymorphism and esophageal cancer: a meta-analysis.

NAD(P)H: quinone oxidoreductase 1 (NQO1) is an important enzyme which can catalyze the two-electron reduction of quinoid compounds into hydroquinones. NQO1 Pro187Ser polymorphism can change the enzymatic activity of NQO1, and it has been proposed to be associated with risk of esophageal cancer. We performed a meta-analysis to examine the association between NQO1 Pro187Ser polymorphism and esophageal cancer. Odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the association. Twelve case-control studies with 1,725 cases with esophageal cancer and 2,341 controls were finally included in the meta-analysis. Overall, there was an obvious association between NQO1 Pro187Ser polymorphism and esophageal cancer (allele model: OR = 1.24, 95% CI 1.06-1.46, P OR = 0.009; homozygote model: OR = 1.59, 1195% CI 1.10-2.30, P OR = 0.013; dominant model: OR = 1.31, 95% CI 1.05-1.64, P OR = 0.018). In the subgroup analysis by ethnicity, there was an obvious association between NQO1 Pro187Ser polymorphism and esophageal cancer in Asians but not in Caucasians. Therefore, the meta-analysis suggests that NQO1 Pro187Ser polymorphism is associated with esophageal cancer risk.

The tumor suppressor LKB1 antagonizes WNT signaling pathway through modulating GSK3ß activity in cell growth of esophageal carcinoma.

The tumor suppressor LKB1 gene encodes a serine-threonine kinase that regulates cell proliferation and polarity. Inactivation of LKB1 by mutations in LKB1 or loss of its expression is highly correlated with lung, ovarian, and pancreatic cancers, and WNT/ß-catenin pathway is also known to be involved in many human malignancies. However, the relationship between LKB1 and WNT signaling pathway in esophageal carcinoma remains unknown. The expression of LKB1 in 62 cases of esophageal cancer patients was determined by quantitative real-time PCR. It was found that LKB1 mRNA level was significantly lower than the adjacent normal epithelium and that the LKB1 downregulation was correlating with TNM stages. Moreover, the expression of WNT target genes such as Cyclin D1, C-MYC, MMP2, and FZD2 was significantly upregulated in esophageal cancer tissues. LKB1 overexpression in TE10 cells inhibited TOPFlash luciferase reporter activity and WNT target gene expression even in the presence of WNT3A. Conversely, LKB1 knockdown enhanced WNT signaling activity in esophageal cancer cells. It was also found that LKB1 antagonized WNT signaling pathway through interaction with GSK3ß to downregulate ß-catenin expression level. Functional investigation revealed that LKB1 suppressed the promotion effects of WNT3A on the cell growth of TE10 cells. The LKB1 functions in regulating cell growth and WNT target genes expression were impaired by GSK3ß inhibition, suggesting that LKB1 antagonized WNT-induced cell proliferation through enhancement of GSK3ß activity. Together, the interaction between LKB1 and GSK3ß upregulates GSK3ß activity to suppress WNT-induced cell proliferation in esophageal carcinoma cells. Loss of LKB1 expression may result in the deregulation of WNT/ß-catenin pathway to promote malignant progression of esophageal cancer.