Magnolol promotes the autophagy of esophageal carcinoma cells by upregulating HACE1 gene expression.

Esophagus cancer (EC) is one of the most aggressive malignant digestive system tumors and has a high clinical incidence worldwide. Magnolol, a natural compound, has anticancer effects on many cancers, including esophageal carcinoma, but the underlying mechanism has not been fully elucidated. Here, we first find that magnolol inhibits the proliferation of esophageal carcinoma cells and enhances their autophagy activity in a dose- and time-dependent manner. This study demonstrates that magnolol increases the protein levels of LC3 II, accompanied by increased HACE1 protein levels in both esophageal carcinoma cells and xenograft tumors. HACE1-knockout (KO) cell lines are generated, and the ablation of HACE1 eliminates the anti-proliferative and autophagy-inducing effects of magnolol on esophageal carcinoma cells. Additionally, our results show that magnolol primarily promotes HACE1 expression at the transcriptional level. Therefore, this study shows that magnolol primarily exerts its antitumor effect by activating HACE1-OPTN axis-mediated autophagy. It can be considered a promising therapeutic drug for esophageal carcinoma.

Polaron Formation in Conducting Polymers: A Novel Approach to Designing Materials with a Larger NLO Response.

Substantial efforts have been made to design and investigate new approaches for high-performance nonlinear optical (NLO) materials. Herein, we report polaron formation in conducting polymers as a new approach to designing materials with a large NLO response. A comparative study of polypyrrole and polypyrrole-based polaron (nPy+ where n = 1, 3, 5, 7, and 9) is carried out for optoelectronic and NLO properties. The studied polarons (PPy+) show excellent electronic properties and have reduced ionization potential (IP) as compared to neutral PPy, and a monotonic decrease is observed with increased chain lengths (1Py to 9Py). Interesting trends of global reactivity descriptors can be seen; the softness (S) increases with an increase in the chain length of PPy, while the hardness (η) decreases in the same fashion. The EH-L gaps for the PPy+ polaronic state are significantly lower than their corresponding neutral PPy. In the polaronic model (PPy+), radicals decisively reduce the crucial excitation energy, reminiscent of excess electrons (alkali metals). The performed TDOS spectral analysis further justifies the better conductive and electronic properties of polarons (PPy+) with increased chain lengths (conjugation). The static hyperpolarizability response (ßo) is recorded up to 1.3 × 102 au for 9Py, while for polaron 9Py+, it has increased up to 3.2 × 104 au. The static hyperpolarizability of the 9Py+ polaronic state is 246 times higher than that of the corresponding neutral analogue, 9Py. It is observed that the values of ßo obtained at the CAM-B3LYP/6-311+G(d,p) level of theory are comparable to those obtained at the LC-BLYP and ωB97XD functionals. The ßvec values show a strong correlation with the total hyperpolarizability (ßo). Furthermore, the calculated second harmonic generation (SHG) values are up to 4.0 × 106 au at 532 nm, whereas electro-optic Pockel's effect (EOPE) is much more pronounced at the smaller dispersion frequency (1064 nm). The TD-DFT study reveal the red-shifted absorption maxima (λmax) with an increased length of PPy+. A significant reduction in excitation energy (ΔE) is observed with increased length of PPy and PPy+, which also favors the improved NLO response. Hence, the studied thermally conducting polypyrrole-based polarons (PPy+) are new entries into NLO materials with better electrical and optical features.

Identification and validation of prognostic and immunotherapeutic responses in esophageal squamous carcinoma based on hypoxia phenotype-related genes.

The study aimed to investigate the clinical significance of the interaction between hypoxia and the immune system in esophageal squamous cell carcinoma (ESCC) microenvironment. A comprehensive evaluation of 13 hypoxia phenotype-related genes (HPRs) was conducted using data from TCGA-ESCC and two GEO cohorts. Three distinct HPRclusters were identified, and the HPRscore was established as an independent prognostic factor (p = 0.001), with higher scores indicating poorer prognosis. The HPRscore was validated in various immunotherapy cohorts, demonstrating its efficacy in evaluating immunotherapy and chemotherapy outcomes. Additionally, phenome-wide association study (PheWAS) analysis showed that PKP1 had no significant correlation with other traits at the gene level. PKP1 was identified as a potential prognostic marker for ESCC, with upregulated expression observed in ESCC patients. In vitro experiments showed that the knockdown of PKP1 inhibited ESCC cell proliferation and migration. These findings suggest that the novel HPRscore and PKP1 may serve as prognostic tools and therapeutic targets for ESCC patients.

[Analysis of the efficacy of high tibial osteotomy combined with medial meniscus centralization in knee osteoarthritis].

OBJECTIVE: To explore the efficacy of high tibial osteotomy （HTO） combined with medial meniscus centralization in knee osteoarthritis. METHODS: A total of 26 patients who underwent surgery from October 2018 to October 2020 were reviewed. Among them, 14 patients underwent high tibial osteotomy combined with arthroscopic meniscus centralization surgery were centralized group, including 8 males and 6 females, with an average age of （50.2±1.4） years old and follow-up time of （16.8±4.0） months. Twelve patients with high tibial osteotomy were in the control group, including 6 males and 6 females, with an average age of （50.9±1.8） years and follow-up time of （19.0±4.8） months. Operation time, the knee Lysholm score, knee 2000 IKDC score, MRI, femoral tibial angle（FTA）, hip knee ankle angle （HKA）, and intraoperative and postoperative complications were recorded. RESULTS: All the incisions healed without any complication. The operation time in the centralized group was longer than that in the control group[（65.0±2.1）min vs（52.0±2.1）min, P<0.05]. The medial meniscus extrusion reduction value in the centralized group was significantly reduced compared with the control group[（2.8±1.4） mm vs （1.1±2.2） mm, P<0.05]. The FTA, HKA, knee Lyshlom score, and 2000 IKDC score between two groups were no significantly （P>0.05）. Postoperative knee Lyshlom score and knee 2000 IKDC score improved in both groups（P<0.05）. CONCLUSION: HTO combined with centralization of medial meniscus can improve the reduction of medial meniscus and improve knee function. The medium and long-term curative effect still needs long-term follow-up of more cases.

A novel disulfidptosis-related prognostic gene signature and experimental validation identify ACTN4 as a novel therapeutic target in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent form of malignancy globally. Disulfidptosis is novel programmed cell death pathway based on disulfide proteins, may have a positive impact on the development of LUAD treatment strategies. OBJECTIVE: To investigate the impact of disulfidptosis-related genes (DRGs) on the prognosis of LUAD, developed a risk model to facilitate the diagnosis and prognostication of patients. We also explored ACTN4 (DRGs) as a new therapeutic biomarker for LUAD. METHODS: We investigated the expression patterns of DRGs in both LUAD and noncancerous tissues. To assess the prognostic value of the DRGs, we developed risk models through univariate Cox analysis and lasso regression. The expression and function of ACTN4 was evaluated by qRT-PCR, immunohistochemistry and in vitro experiments. The TIMER examined the association between ACTN4 expression and immune infiltration in LUAD. RESULTS: Ten differentially expressed DRGs were identified. And ACTN4 was identified as potential risk factors through univariate Cox regression analysis (P< 0.05). ACTN4 expression and riskscore were used to construct a risk model to predict overall survival in LUAD, and high-risk demonstrated a significantly higher mortality rate compared to the low-risk cohort. qRT-PCR and immunohistochemistry assays indicated ACTN4 was upregulated in LUAD, and the upregulation was associated with clinicopathologic features. In vitro experiments showed the knockdown of ACTN4 expression inhibited the proliferation in LUAD cells. The TIMER analysis demonstrated a correlation between the expression of ACTN4 and the infiltration of diverse immune cells. Elevated ACTN4 expression was associated with a reduction in memory B cell count. Additionally, the ACTN4 expression was associated with m6A modification genes. CONCLUSIONS: Our study introduced a prognostic model based on DRGs, which could forecast the prognosis of patients with LUAD. The biomarker ACTN4 exhibits promise for the diagnosis and management of LUAD, given its correlation with tumor immune infiltration and m6A modification.

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

Multi-omics analyses reveal spatial heterogeneity in primary and metastatic oesophageal squamous cell carcinoma.

BACKGROUND: Biopsies obtained from primary oesophageal squamous cell carcinoma (ESCC) guide diagnosis and treatment. However, spatial intra-tumoral heterogeneity (ITH) influences biopsy-derived information and patient responsiveness to therapy. Here, we aimed to elucidate the spatial ITH of ESCC and matched lymph node metastasis (LNmet ). METHODS: Primary tumour superficial (PTsup ), deep (PTdeep ) and LNmet subregions of patients with locally advanced resectable ESCC were evaluated using whole-exome sequencing (WES), whole-transcriptome sequencing and spatially resolved digital spatial profiling (DSP). To validate the findings, immunohistochemistry was conducted and a single-cell transcriptomic dataset was analysed. RESULTS: WES revealed 15.72%, 5.02% and 32.00% unique mutations in PTsup , PTdeep and LNmet , respectively. Copy number alterations and phylogenetic trees showed spatial ITH among subregions both within and among patients. Driver mutations had a mixed intra-tumoral clonal status among subregions. Transcriptome data showed distinct differentially expressed genes among subregions. LNmet exhibited elevated expression of immunomodulatory genes and enriched immune cells, particularly when compared with PTsup (all P < .05). DSP revealed orthogonal support of bulk transcriptome results, with differences in protein and immune cell abundance between subregions in a spatial context. The integrative analysis of multi-omics data revealed complex heterogeneity in mRNA/protein levels and immune cell abundance within each subregion. CONCLUSIONS: This study comprehensively characterised spatial ITH in ESCC, and the findings highlight the clinical significance of unbiased molecular classification based on multi-omics data and their potential to improve the understanding and management of ESCC. The current practices for tissue sampling are insufficient for guiding precision medicine for ESCC, and routine profiling of PTdeep and/or LNmet should be systematically performed to obtain a more comprehensive understanding of ESCC and better inform treatment decisions.

Immune-related gene prognostic index (IRGPI) for lung adenocarcinoma predicts patient prognosis and immunotherapy response.

OBJECTIVE: We searched for a predictive biomarker that also predicts whether patients would benefit from immune checkpoint blockade (ICB) treatment from a few angles, because existing biomarkers no longer wholly replicate the interconnections of distinctive elements in the tumor microenvironment (TME). METHODS: We identified 55 pivotal IRGs by performing a WGCNA and univariate Cox regression analysis on a lung adenocarcinoma dataset from the TCGA database. The IRGPI model was then constructed using multivariate Cox regression analysis, which identified 16 genes and verified the use of the GSE68465 database. The AUC of the IRGPI was compared to those of the current biomarkers to determine its predictive potential. Then we examined the molecular and immunological properties of ICB and assessed its effectiveness using CTLA4 expression and TIDE. RESULTS: Patients with a high IRGPI had a later clinical stage, more severe symptoms, and a worse prognosis. Patients with a low IRGPI had a higher immune escape potential and were less responsive to immunotherapy. CONCLUSION: The IRGPI may be a biomarker for determining the prognosis of patients and whether they respond favorably to ICB therapy.

A novel Fas ligand plays an important role in cell apoptosis of Crassostrea hongkongensis: molecular cloning, expression profiles and functional identification of ChFasL.

Background: Apoptosis regulates normal development, homeostasis, immune tolerance and response to environmental stress by eliminating unwanted or diseased cells, and plays a key role in non-specific immunity of invertebrates. The exogenous pathway mediated by death receptors and death ligands is a very important pathway for cell apoptosis. Death ligands are mainly members of the tumour necrosis factor (TNF) family, of which FasL is an important member. The deep involvement of FasL in vertebrates cell apoptosis and immunity has been reported many times, but there is limited research on the FasL gene in shellfish, and its functional importance in oyster cell apoptosis and immunity remains unclear. Methods: The full length of ChFasL was identified and cloned based on the genome of Crassostrea hongkongensis. Quantitative PCR was used to detect the relative expression of ChFasL in different developmental stages and tissues, as well as the changes of relative expression in hemocytes after bacterial infection. The expression position of ChFasL in HEK293T cells was also located by subcellular localization, and the effect of increased recombinant protein content on the activity of reporter genes p53 and p21 was studied by dual-fluorescence reporter gene. Finally, the changes of apoptosis rate in hemocytes after ChFasL silencing was identified by RNA interference technology. Results: We identified a novel FasL gene from C. hongkongensis and named it ChFasL. We found that ChFasL has potential N-linked glycosylation site, a transmembrane domain and a TNF region, which was a typical characteristics of TNF family. ChFasL was expressed in all developmental stages of larvae and in all tissues of oysters. After stimulation by V. alginolyticus or S. haemolyticus, its relative expression in hemocytes increased significantly, suggesting that ChFasL was deeply engaged in the immune response process of C. hongkongensis to external microbial stimulation. The results of subcellular localization showed that ChFasL was mainly distributed in the cytoplasm of HEK293T cells. With the overexpression of the recombinant protein pcDNA3 1- ChFasL, the activity of p53 and p21 significantly increased, showing a positive regulatory effect. Moreover, after dsRNA successfully reduced the relative expression of ChFasL, the apoptosis rate of hemocytes was significantly lower than that the dsGFP group. Conclusion: These results comprehensively confirmed the important role of ChFasL in the apoptosis process of C. hongkongensis, which provided the basis and premise for the in-depth understanding of the immune function of apoptosis in molluscs, and also contributed to the research on the pathogenic death mechanism and disease resistance breeding of marine bivalves.

Silencing of long non-coding RNA SDCBP2-AS1/microRNA-656-3p/CRIM1 axis promotes ferroptosis of lung cancer cells.

Long non-coding RNAs (lncRNAs) play central roles in lung cancer progression by acting as competing endogenous RNAs (ceRNAs). This study aimed to explore the roles of lncRNA SDCBP2-AS1 in lung cancer and the molecular mechanism. The expression of SDCBP2-AS1, microRNA (miR)-656-3p, and cysteine-rich transmembrane BMP regulator 1 (CRIM1) was measured using quantitative real-time polymerase chain reaction. Ferroptosis was evaluated by analyzing cell death, ferrous content, reactive oxygen species (ROS) level, and protein levels of ferroptosis markers. The binding relationship was assessed using a dual-luciferase reporter assay. We observed that SDCBP2-AS1 was highly expressed in lung cancer cells. Knockdown of SDCBP2-AS1 promoted ferroptosis of lung cancer cells. SDCBP2-AS1 is a sponge of miR-656-3p, which directly targets CRIM1. Rescue experiments confirmed that SDCBP2-AS1 regulates ferroptosis by miR-656-3p, and overexpression of CRIM1 abrogated the effects of miR-656-3p on ferroptosis. In conclusion, depletion of SDCBP2-AS1 promoted lung cancer cell ferroptosis via the miR-656-3p/CRIM1 axis.

Dissecting the effect of ileal faecal diversion on the intestine using single-cell sequencing.

BACKGROUND: Although ileal faecal diversion is commonly used in clinical settings, complications accompany it. Elucidating the intestinal changes caused by ileal faecal diversion will help resolve postoperative complications and elucidate the pathogenic mechanisms of associated intestinal disorders, such as Crohn's disease (CD). Therefore, our study aimed to provide new insights into the effects of ileal faecal diversion on the intestine and the potential mechanisms. METHODS: Single-cell RNA sequencing was performed on proximal functional and paired distal defunctioned intestinal mucosae from three patients with ileal faecal diversion. We also performed in vitro cellular and animal experiments, tissue staining and analysed public datasets to validate our findings. RESULTS: We found that the epithelium in the defunctioned intestine tended to be immature, with defective mechanical and mucous barriers. However, the innate immune barrier in the defunctioned intestine was enhanced. Focusing on the changes in goblet cells, we demonstrated that mechanical stimulation promotes the differentiation and maturation of goblet cells through the TRPA1-ERK pathway, indicating that the absence of mechanical stimulation may be the main cause of defects in the goblet cells of the defunctioned intestine. Furthermore, we found obvious fibrosis with a pro-fibrotic microenvironment in the defunctioned intestine and identified that monocytes may be important targets for faecal diversion to alleviate CD. CONCLUSIONS: This study revealed the different transcription landscapes of various cell subsets and the potential underlying mechanisms within the defunctioned intestine, when compared to the functional intestine, based on the background of ileal faecal diversion. These findings provide novel insights for understanding the physiological and pathological roles of the faecal stream in the intestine.

LncRNA HOXD-AS2 regulates miR-3681-5p/DCP1A axis to promote the progression of non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC) is the most common malignancy in lung cancer, with a low survival rate and unfavorable prognosis. Dysregulated long non-coding RNAs (lncRNAs) play vital functions in tumor progression. This study intended to probe the expression pattern and function of HOXD-AS2 in NSCLC. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to analyze the expression of HOXD-AS2, miR-3681-5p, CCR1, mRNA-decapping enzyme 1A (DCP1A), and PPP3R1. Cell viability, migration, and invasion were separately examined via 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) and transwell experiments. Luciferase reporter assay was conducted to evaluate the binding of miR-3681-5p with HOXD-AS2 or DCP1A. Protein expression of DCP1A was assessed via Western blot. NSCLC animal models were constructed through injection of H1975 cells transfected with lentivirus (LV)-sh-HOXD-AS2 into nude mice, followed by hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) analysis. Results: In this study, HOXD-AS2 was upregulated in NSCLC tissues and cells, and high HOXD-AS2 predicted short overall survival (OS). Downregulation of HOXD-AS2 could impair the proliferation, migration, and invasion abilities of H1975 and A549 cells. MiR-3681-5p was shown to bind with HOXD-AS2 and be lowly expressed in NSCLC. Suppression of miR-3681-5p could abolish the inhibitory effect of HOXD-AS2 silencing on proliferation, migration, and invasion. DCP1A was screened as the target of miR-3681-5p and its overexpression could rescue miR-3681-5p upregulation-repressed proliferation, migration, and invasion activities. Moreover, animal experiments affirmed that HOXD-AS2 promoted tumor growth in vivo. Conclusions: HOXD-AS2 modulates the miR-3681-5p/DCP1A axis to boost the progression of NSCLC, which founds the basis of HOXD-AS2 as a new diagnostic biomarker and molecular target for NSCLC therapy.

Shenlingcao oral liquid for patients with non-small cell lung cancer receiving adjuvant chemotherapy after radical resection: A multicenter randomized controlled trial.

BACKGROUND: Low quality of life (QoL) in patients with non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy after radical resection is a major global health issue. High-quality evidence for the effectiveness of Shenlingcao oral liquid (SOL) as a complementary treatment in this patients is lacking at present. PURPOSE: To determine whether complementary SOL treatment in NSCLC patients receiving adjuvant chemotherapy would yield greater improvements in QoL than chemotherapy alone. STUDY DESIGN: We conducted a multicenter, randomized controlled trial of stages IIA-IIIA NSCLC patients undergoing adjuvant chemotherapy in seven hospitals. METHODS: Using stratified blocks, participants were randomized in a 1:1 ratio to receive SOL combined with conventional chemotherapy or conventional chemotherapy alone. The primary outcome was the change in global QoL from baseline to the fourth chemotherapy cycle, and intention-to-treat analysis was applied with a mixed-effect model. Secondary outcomes were functional QoL, symptoms, and performance status scores at the 6-month follow-up. Missing data were handled with multiple imputation and a pattern-mixture model. RESULTS: Among 516 randomized patients, 446 (86.43%) completed the study. After the fourth chemotherapy cycle, in comparison with the control group, patients receiving SOL showed a lower reduction in mean global QoL (-2.76 vs. -14.11; mean difference [MD], 11.34; 95% confidence interval [CI], 8.28 to 14.41), greater improvement in physical function (MD, 11.61; 95% CI, 8.57 to 14.65), role function (MD, 10.15; 95% CI, 5.75 to 14.54), and emotional function (MD, 4.71; 95% CI, 1.85 to 7.57), and greater improvements in lung cancer-related symptoms (e.g., fatigue, nausea/vomiting, and appetite loss) and performance status during the 6-month follow-up period (treatment main effect, p < 0.05). CONCLUSION: SOL treatment for NSCLC patients receiving adjuvant chemotherapy can significantly improve QoL and performance status within 6 months after radical resection. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03712969.

Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial.

OBJECTIVES: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been approved for EGFR-mutant non-small-cell lung cancer (NSCLC). We aimed to evaluate the efficacy and safety of neoadjuvant osimertinib in patients with EGFR-mutant resectable locally advanced NSCLC. MATERIALS AND METHODS: This single-arm, phase 2b trial (ChiCTR1800016948) was conducted at six centers in mainland China. Patients with a measurable stage IIA-IIIB (T3-4 N2) lung adenocarcinoma and EGFR exon 19 and/or 21 mutations were enrolled. The patients were treated with osimertinib 80 mg orally once per day for six weeks, followed by surgical resection. The primary endpoint was the objective response rate (ORR) assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. RESULTS: Between October 17, 2018, and June 08, 2021, 88 patients were screened for eligibility. Forty patients were enrolled and treated with neoadjuvant osimertinib therapy. The ORR was 71.1 % (27/38) (95 % confidence interval: 55.2-83.0) in 38 patients who completed the 6-week osimertinib treatment. Thirty-two patients underwent surgery, and 30 (93.8 %) underwent successful R0 resection. Thirty (75.0 %) of 40 patients had treatment-related adverse events during neoadjuvant treatment, and three (7.5 %) had treatment-related adverse events of grade 3. The most common treatment-related adverse events were rash (n = 20 [50 %]), diarrhea (n = 12 [30 %]), and oral ulceration (n = 12 [30 %]). CONCLUSIONS: The third-generation EGFR TKI osimertinib, with satisfying efficacy and acceptable safety profile, could be a promising neoadjuvant therapy in patients with resectable EGFR-mutant NSCLC.

Construction and validation of a prognostic model based on ten signature cell cycle-related genes for early-stage lung squamous cell carcinoma.

BACKGROUND: We performed a bioinformatics analysis to screen for cell cycle-related differentially expressed genes (DEGs) and constructed a model for the prognostic prediction of patients with early-stage lung squamous cell carcinoma (LSCC). METHODS: From a gene expression omnibus (GEO) database, the GSE157011 dataset was randomly divided into an internal training group and an internal testing group at a 1:1 ratio, and the GSE30219, GSE37745, GSE42127, and GSE73403 datasets were merged as the external validation group. We performed single-sample gene set enrichment analysis (ssGSEA), univariate Cox analysis, and difference analysis, and identified 372 cell cycle-related genes. Additionally, we combined LASSO/Cox regression analysis to construct a prognostic model. Then, patients were divided into high-risk and low-risk groups according to risk scores. The internal testing group, discovery set, and external verification set were used to assess model reliability. We used a nomogram to predict patient prognoses based on clinical features and risk values. Clinical relevance analysis and the Human Protein Atlas (HPA) database were used to verify signature gene expression. RESULTS: Ten cell cycle-related DEGs (EIF2B1, FSD1L, FSTL3, ORC3, HMMR, SETD6, PRELP, PIGW, HSD17B6, and GNG7) were identified and a model based on the internal training group constructed. From this, patients in the low-risk group had a higher survival rate when compared with the high-risk group. Time-dependent receiver operating characteristic (tROC) and Cox regression analyses showed the model was efficient and accurate. Clinical relevance analysis and the HPA database showed that DEGs were significantly dysregulated in LSCC tissue. CONCLUSION: Our model predicted the prognosis of early-stage LSCC patients and demonstrated potential applications for clinical decision-making and individualized therapy.

Significance of CD80 as a Prognostic and Immunotherapeutic Biomarker in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the primary cause of death among pulmonary cancer patients. Upregulation of CD80 may interact with cytotoxic T lymphocyte antigen 4 (CTLA4) to promote tumor progression and provide a potential target for biological antitumor therapy. However, the role of CD80 in LUAD is still unclear. To investigate the function of CD80 in LUAD, we collected transcriptomic data from 594 lung samples from The Cancer Genome Atlas of America (TCGA) database, along with the corresponding clinical information. We systematically explored the role of CD80 in LUAD using bioinformatics methods, including GO enrichment analysis, KEGG pathway analysis, Gene Set Enrichment Analysis (GSEA), co-expression analysis, and the CIBERSORT algorithm. Finally, we investigated the differences between the two subgroups of CD80 expression in terms of some drug sensitivity, using the pRRophetic package to screen small molecular drugs for therapeutic use. A predictive model based on CD80 for LUAD patients was successfully constructed. In addition, we discovered that the CD80-based prediction model was an independent prognostic factor. Co-expression analysis revealed 10 CD80-related genes, including oncogenes and immune-related genes. Functional analysis showed that the differentially expressed genes in patients with high CD80 expression were mainly located in immune-related signaling pathways. CD80 expression was also associated with immune cell infiltration and immune checkpoints. Highly expressing patients were more sensitive to several drugs, such as rapamycin, paclitaxel, crizotinib, and bortezomib. Finally, we found evidence that 15 different small molecular drugs may benefit the treatment of LUAD patients. This study found that elevated CD80 pairs could improve the prognosis of LUAD patients. CD80 is likely to be a potential as a prognostic and therapeutic target. The future use of small molecular drugs in combination with immune checkpoint blockade to enhance antitumor therapy and improve prognosis for LUAD patients is promising.

Effect and mechanism of simultaneous cadmium-tetracycline removal by a self-assembled microbial-photocatalytic coupling system.

Electrochemical bacteria Shewanella oneidensis MR-4 (MR-4) was used to biologically generate cadmium sulfide (bio-CdS) nanocrystals and construct a self-assembled intimately coupled photocatalysis-biodegradation system (SA-ICPB) to remove cadmium (Cd) and tetracycline hydrochloride (TCH) from wastewater. The characterization using EDS, TEM, XRD, XPS, and UV-vis confirmed the successful CdS bio-synthesis and its visible-light response capacity (520 nm). 98.4% of Cd2+ (2 mM) was removed during bio-CdS generation within 30 min. The electrochemical analysis confirmed the photoelectric response capability of the bio-CdS as well as its photocatalytic efficiency. Under visible light, SA-ICPB entirely eliminated TCH (30 mg/L). In 2 h, 87.2% and 43.0% of TCH were removed separately with and without oxygen. 55.7% more chemical oxygen demand (COD) was removed with oxygen participation, indicating the degradation intermediates elimination by SA-ICPB required oxygen participation. Biodegradation dominated the process under aerobic circumstances. Electron paramagnetic resonance analysis indicated that h+ and ·O2- played a decisive role in photocatalytic degradation. Mass spectrometry analysis proved that TCH was dehydrated, dealkylated, and ring-opened before mineralizing. In conclusion, MR-4 can spontaneously generate SA-ICPB and rapidly-deeply eliminate antibiotics by coupling photocatalytic and microbial degradation. Such an approach was efficient for the deep degradation of persistent organic pollutants with antimicrobial properties.

Exosomal circ-ADRM1 promotes lung adenocarcinoma progression and induces macrophage M2 polarization through regulating MMP14 mRNA and protein.

OBJECTIVE: Lung adenocarcinoma (LUAD) is one of the frequent subtypes of lung cancer, featuring high rates of incidence and mortality. Matrix metalloproteinase 14 (MMP14) is known as a regulator in multiple cancers, whereas its upstream molecular mechanism remains to be investigated. This study aims to reveal the upstream molecular mechanism of MMP14 in LUSC progression. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were conducted to examine the levels of MMP14 mRNA and protein in LUAD cells, respectively. Cell counting kit-8 (CCK-8), transwell assay and wound healing assay were implemented to unveil LUAD cell proliferation, migration and invasion after indicated transfections. Flow cytometry analysis was applied to evaluate macrophage polarization. Mechanism experiments such as western blot, co-immunoprecipitation (Co-IP), RNA pulldown assay, luciferase reporter assay and RNA-binding protein immunoprecipitation (RIP) assay were used to explore relevant molecular mechanisms. RESULTS: MMP14 facilitated LUAD cell proliferation, invasion and migration. MMP14 is the target gene of miR-1287-5p. Circ-ADRM1 upregulates MMP14 expression through sponging miR-1287-5p. Circ-ADRM1 recruits USP12 to impede the ubiquitination of MMP14 protein, thereby enhancing the stability of MMP14 protein. LUAD-derived exosomes induced macrophage M2 polarization by delivering circ-ADRM1. CONCLUSIONS: Circ-ADRM1 promotes LUAD cell proliferation, invasion and migration through upregulating MMP14. Additionally, circ-ADRM1 induces macrophage M2 polarization in an exosome-dependent manner.

Staplers versus energy devices for the intersegmental plane separation in thoracoscopic segmentectomy: a comparative study.

BACKGROUND: In segmentectomy, in addition to the anatomy of the segmental hilum, the identification and separation of the intersegmental plane is also an important step of the operation. Because of its simplicity and high efficiency, most thoracic surgeons choose the staplers. But the energy devices also have its unique advantages in the separation of the intersegmental plane. This study compared the clinical efficacy of staplers and energy devices in the separation of the intersegmental planes during the uniport thoracoscopic segmentectomy through the clinical data. METHODS: Clinical data of 89 patients undergoing uniport VATS lung segmentectomy from January 2019 to October 2020 at the First Affiliated Hospital of Soochow University were analyzed retrospectively. According to the different treatment methods of intersegmental plane, the patients were divided into two groups, 55 in the stapler group and 34 in the energy device group. The clinical data of the two groups were compared and analyzed statistically. And the univariate and multivariate logistic regression were also used to explore the influencing factors of postoperative complications. RESULTS: Lung segmentectomy was successfully operated in both groups. There were statistically significant differences in operative duration, number of staplers used, surgical expenses and postoperative complications (P < 0.05). In terms of general data, including tumor location, operative hemorrhage, drainage volume on the first postoperative day, total postoperative drainage volume, postoperative chest tube retention duration, postoperative hospital stay, postoperative blood routine indexes, and postoperative pulmonary function indexes after 3 months, no significant differences were observed (P > 0.05). Smoking history (OR 5.08, 95% CI 1.05-24.56, P = 0.043) and intersegmental plane treatment (OR 3.18, 95% CI 1.11-9.14, P = 0.031) were risk factors for postoperative complications. Patients of the energy device group had a higher incidence of postoperative complications. CONCLUSIONS: In uniport thoracoscopic segmentectomy, the use of energy devices to treat the intersegmental plane will result in longer operative duration and higher postoperative complication rate, but it does not affect postoperative recovery and can help reduce surgical expenses. Both methods are safe and reliable. Clinically, the two methods can be reasonably selected according to the specific situation.

Integrated single-cell and transcriptome sequencing analyses determines a chromatin regulator-based signature for evaluating prognosis in lung adenocarcinoma.

Background: Accumulating evidence has highlighted the significance of chromatin regulator (CR) in pathogenesis and progression of cancer. However, the prognostic role of CRs in LUAD remains obscure. We aim to detect the prognostic value of CRs in LUAD and create favorable signature for assessing prognosis and clinical value of LUAD patients. Methods: The mRNA sequencing data and clinical information were obtained from TCGA and GEO databases. Gene consensus clustering analysis was utilized to determine the molecular subtype of LUAD. Cox regression methods were employed to set up the CRs-based signature (CRBS) for evaluating survival rate in LUAD. Biological function and signaling pathways were identified by KEGG and GSEA analyses. In addition, we calculated the infiltration level of immunocyte by CIBERSORT algorithm. The expressions of model hub genes were detected in LUAD cell lines by real-time polymerase chain reaction (PCR). Results: KEGG analysis suggested the CRs were mainly involved in histone modification, nuclear division and DNA modification. Consensus clustering analysis identified a novel CRs-associated subtype which divided the combined LUAD cohort into two clusters (C1 = 217 and C2 = 296). We noticed that a remarkable discrepancy in survival rate among two clusters. Then, a total of 120 differentially expressed CRs were enrolled into stepwise Cox analyses. Four hub CRs (CBX7, HMGA2, NPAS2 and PRC1) were selected to create a risk signature which could accurately forecast patient outcomes and differentiate patient risk. GSEA unearthed that mTORC1 pathway, PI3K/Akt/mTOR and p53 pathway were greatly enriched in CRBS-high cohort. Moreover, the infiltration percentages of macrophage M0, macrophage M2, resting NK cells, memory B cells, dendritic cells and mast cells were statistically significantly different in the two groups. PCR assay confirmed the differential expression of four model biomarkers. Conclusions: Altogether, our project developed a robust risk signature based on CRs and offered novel insights into individualized treatment for LUAD cases.