Visualizing the multi-level assembly structures of conjugated molecular systems with chain-length dependent behavior.

It remains challenging to understand the structural evolution of conjugated polymers from single chains to solvated aggregates and film microstructures, although it underpins the performance of optoelectrical devices fabricated via the mainstream solution processing method. With several ensemble visual measurements, here we unravel the morphological evolution process of a model system of isoindigo-based conjugated molecules, including the hidden molecular assembly pathways, the mesoscale network formation, and their unorthodox chain dependence. Short chains show rigid chain conformations forming discrete aggregates in solution, which further grow to form a highly ordered film that exhibits poor electrical performance. In contrast, long chains exhibit flexible chain conformations, creating interlinked aggregates networks in solution, which are directly imprinted into films, forming interconnective solid-state microstructure with excellent electrical performance. Visualizing multi-level assembly structures of conjugated molecules provides a deep understanding of the inheritance of assemblies from solution to solid-state, accelerating the optimization of device fabrication.

Accuracy and efficiency of an artificial intelligence-based pulmonary broncho-vascular three-dimensional reconstruction system supporting thoracic surgery: retrospective and prospective validation study.

BACKGROUND: Anthropomorphic phantoms are used in surgical planning and intervention. Ideal accuracy and high efficiency are prerequisites for its clinical application. We aimed to develop a fully automated artificial intelligence-based three-dimensional (3D) reconstruction system (AI system) to assist thoracic surgery and to determine its accuracy, efficiency, and safety for clinical use. METHODS: This AI system was developed based on a 3D convolutional neural network (CNN) and optimized by gradient descent after training with 500 cases, achieving a Dice coefficient of 89.2%. Accuracy was verified by comparing virtual structures predicted by the AI system with anatomical structures of patients in retrospective (n = 113) and prospective cohorts (n = 139) who underwent lobectomy or segmentectomy at the Peking University Cancer Hospital. Operation time and blood loss were compared between the retrospective cohort (without AI assistance) and prospective cohort (with AI assistance) for safety evaluation. The time consumption for reconstruction and the quality score were compared between the AI system and manual reconstruction software (Mimics®) for efficiency validation. This study was registered at https://www.chictr.org.cn as ChiCTR2100050985. FINDINGS: The AI system reconstructed 13,608 pulmonary segmental branches from retrospective and prospective cohorts, and 1573 branches of interest corresponding to phantoms were detectable during the operation for verification, achieving 100% and 97% accuracy for segmental bronchi, 97.2% and 99.1% for segmental arteries, and 93.2% and 98.8% for segmental veins, respectively. With the assistance of the AI system, the operation time was shortened by 24.5 min for lobectomy (p < 0.001) and 20 min for segmentectomy (p = 0.007). Compared to Mimics®, the AI system reduced the model reconstruction time by 14.2 min (p < 0.001), and it also outperformed Mimics® in model quality scores (p < 0.001). INTERPRETATION: The AI system can accurately predict thoracic anatomical structures with higher efficiency than manual reconstruction software. Constant optimization and larger population validation are required. FUNDING: This study was funded by the Beijing Natural Science Foundation (No. L222020) and other sources.

circ_0000567/miR-421/TMEM100 Axis Promotes the Migration and Invasion of Lung Adenocarcinoma and Is Associated with Prognosis.

Purpose: Due to the high metastatic ability and poor prognosis of lung adenocarcinoma (LUAD), we identified novel non-coding RNAs, which constitute approximately 60% of human transcripts, as prognostic biomarkers and potential therapeutic targets for LUAD. Methods: In this study, we downloaded and analyzed microRNA (miRNA) datasets from The Cancer Genome Atlas (TCGA) to identify dysregulated miRNAs correlating with the overall survival (OS) of LUAD patients. miR-421, circ_0000567, and TMEM100 expression levels were examined by quantitative real-time polymerase chain reaction (qRT-PCR) in NSCLC tissues from 73 patients and adjacent normal tissues. Cell migration and invasion were assayed using wound healing and transwell assays. miR-421 target predictions were conducted using starBase, CircInteractome, circBank, TargetScan, miRanda, MirDB, miRpath, and Gene Expression Omnibus (GEO) databases. The circular structure and stability of circ_0000567 were verified by RNase R digestion and qRT-PCR using oligo(dT) and random primers. A luciferase reporter assay was used to evaluate the relationship between miR-421, circ_0000567, and TMEM100. Results: The miRNA panel associated with OS in patients with LUAD was screened according to the hazard ratio (HR) of miRNAs from high to low. Based on the correlation between these miRNAs and OS, as well as miRNA expression levels, miR-421 was selected for further outcome analysis. High miR-421 expression was an independent risk factor for shorter OS in 73 patients collected from our department. Bioinformatic analyses, luciferase reporter assays, and functional assays showed that circ_0000567 could act as a sponge for miR-421 and prevent it from directly targeting the 3'-untranslated region of TMEM100 mRNA and further degrading it in LUAD. miR-421 expression was significantly upregulated, while circ_0000567 and TMEM100 were downregulated in tumor tissues of LUAD, compared to their counterparts in normal tissues. Gain- and loss-of-function assays showed that miR-421 promoted LUAD cell migration and invasion. Overexpression of circ_0000567 inhibited migration and invasion, whereas co-transfection of circ_0000567 and miR-421 mimics partly counteracted this effect. TMEM100 was upregulated by enhanced circ_0000567 in LUAD cells, and the expression of TMEM100 was inversely proportional to miR-421, whereas it was directly proportional to circ_0000567 in 73 LUAD specimens, which confirmed the competitive endogenous RNA (ceRNA) network. Conclusion: Our findings suggest that miR-421 promotes the migration and invasion of lung adenocarcinoma via circ_0000567/miR-421/TMEM100 signaling and could be a prognostic biomarker for LUAD.

The anti-tumor effects of the combination of microwave hyperthermia and lobaplatin against breast cancer cells in vitro and in vivo.

BACKGROUND: Breast cancer is the main lethal disease among females. The combination of lobaplatin and microwave hyperthermia plays a crucial role in several kinds of cancer in the clinic, but its possible mechanism in breast cancer has remained indistinct. METHODS: Mouse models were used to detect breast cancer progression. Cell growth was explored with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphonyl)-2H-tetrazolium) and colony formation assays. Cell migration and invasion were investigated with a transwell assay. Cell apoptosis was probed with flow cytometry. The expression of apoptosis-associated proteins was examined with Western blots. RESULT: Combination treatment decreased breast cancer cell viability, colony formation, cell invasion and metastasis. In addition, the treatment-induced breast cancer cell apoptosis and autophagy, activated the c-Jun N-terminal kinase (JNK) signaling pathway, suppressed the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, and down-regulated IAP and Bcl-2 family protein expression. CONCLUSION: These results indicate that lobaplatin is an effective breast cancer anti-tumor agent. Microwave hyperthermia was a useful adjunctive treatment. Combination treatment was more efficient than any single therapy. The possible mechanism for this effect was mainly associated with activation of the JNK signaling pathway, inactivation of the AKT/mTOR signaling pathway and down-regulation of the Bcl-2 and IAP families.

Genetically Modified T Cells for Esophageal Cancer Therapy: A Promising Clinical Application.

Esophageal cancer is an exceedingly aggressive and malignant cancer that imposes a substantial burden on patients and their families. It is usually treated with surgery, chemotherapy, radiotherapy, and molecular-targeted therapy. Immunotherapy is a novel treatment modality for esophageal cancer wherein genetically engineered adoptive cell therapy is utilized, which modifies immune cells to attack cancer cells. Using chimeric antigen receptor (CAR) or T cell receptor (TCR) modified T cells yielded demonstrably encouraging efficacy in patients. CAR-T cell therapy has shown robust clinical results for malignant hematological diseases, particularly in B cell-derived malignancies. Natural killer (NK) cells could serve as another reliable and safe CAR engineering platform, and CAR-NK cell therapy could be a more generalized approach for cancer immunotherapy because NK cells are histocompatibility-independent. TCR-T cells can detect a broad range of targeted antigens within subcellular compartments and hold great potential for use in cancer therapy. Numerous studies have been conducted to evaluate the efficacy and feasibility of CAR and TCR based adoptive cell therapies (ACT). A comprehensive understanding of genetically-modified T cell technologies can facilitate the clinical translation of these adoptive cell-based immunotherapies. Here, we systematically review the state-of-the-art knowledge on genetically-modified T-cell therapy and provide a summary of preclinical and clinical trials of CAR and TCR-transgenic ACT.

Chimeric Antigen Receptor T-Cell Therapy in Lung Cancer: Potential and Challenges.

Chimeric antigen receptor T (CAR-T) cell therapy has exhibited a substantial clinical response in hematological malignancies, including B-cell leukemia, lymphoma, and multiple myeloma. Therefore, the feasibility of using CAR-T cells to treat solid tumors is actively evaluated. Currently, multiple basic research projects and clinical trials are being conducted to treat lung cancer with CAR-T cell therapy. Although numerous advances in CAR-T cell therapy have been made in hematological tumors, the technology still entails considerable challenges in treating lung cancer, such as on-target, of-tumor toxicity, paucity of tumor-specific antigen targets, T cell exhaustion in the tumor microenvironment, and low infiltration level of immune cells into solid tumor niches, which are even more complicated than their application in hematological tumors. Thus, progress in the scientific understanding of tumor immunology and improvements in the manufacture of cell products are advancing the clinical translation of these important cellular immunotherapies. This review focused on the latest research progress of CAR-T cell therapy in lung cancer treatment and for the first time, demonstrated the underlying challenges and future engineering strategies for the clinical application of CAR-T cell therapy against lung cancer.

Overexpression of Family with Sequence Similarity 83, Member A (FAM83A) Predicts Poor Clinical Outcomes in Lung Adenocarcinoma.

BACKGROUND The aim of this study was to explore the expression levels of family with sequence similarity 83, member A (FAM83A) in lung adenocarcinoma (LUAD) and investigate its clinical prognostic value. MATERIAL AND METHODS Bioinformatics mining methods were used to predict the differential expression levels of FAM83A mRNA in LUAD and normal lung tissues based on the TCGA and Oncomine databases. Immunohistochemical staining was performed to demonstrate the FAM83A protein expression levels in 83 cases of LUAD combined with paired normal lung tissues. The correlation between clinicopathologic factors and FAM83A differential expression levels in LUAD was explored by the chi-square test. Kaplan-Meier univariate and Cox multivariate survival analyses were performed to investigate the clinical prognostic value of FAM83A expression in LUAD patients. RESULTS Results from TCGA and Oncomine databases revealed that FAM83A mRNA expression level was significantly higher in LUAD than that in normal lung tissues (both P<0.05). Immunohistochemical findings demonstrated that the high positive rate of FAM83A in LUAD was 73.49% (61/83), while that of matched normal lung tissues was only 22.89% (19/83). Moreover, LUAD patients with FAM83A mRNA or high protein levels had dramatically lower OS times than those with FAM83A mRNA or low protein levels (All P<0.05). Lastly, Cox multivariate survival analysis showed that FAM83A differential expression level (low vs. high) was the only independent factor predicting the prognosis of LUAD patients (P=0.001). CONCLUSIONS FAM83A was overexpressed in LUAD, and FAM83A overexpression could be used as an independent factor of poor prognosis in LUAD patients.

The Prognostic Value of Expression of the Long Noncoding RNA (lncRNA) Small Nucleolar RNA Host Gene 1 (SNHG1) in Patients with Solid Malignant Tumors: A Systematic Review and Meta-Analysis.

BACKGROUND The long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) is expressed in solid malignant tumors. The aim of this systematic review and meta-analysis was to determine whether expression of the lncRNA SNHG1 was associated with prognosis in patients with malignancy. MATERIAL AND METHODS A literature review from Jan 1970 to July 2018 identified publications in the English language. Databases searched included: PubMed, OVID, Web of Science, the Cochrane Database, Embase, EBSCO, Google Scholar. Systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Newcastle-Ottawa Scale (NOS) assessment tool for risk of bias was used. RESULTS Eight publications (570 patients) and eight solid tumors were identified, including osteosarcoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, esophageal cancer, ovarian cancer, glioma, and gastric cancer. Meta-analysis showed that expression of the lncRNA SNHG1 was significantly correlated with reduced overall survival (OS) (HR=1.917; 95% CI, 1.58-2.31) (P<0.001). Subgroup analysis showed that lncRNA SNHG1 expression was significantly correlated with TNM stage (OR=3.99; 95% CI, 2.48-6.43) and lymph node metastasis (OR=3.12; 95% CI, 1.95-4.98). There were no significant correlations between lncRNA SNHG1 expression and patient gender, tumor subtype, or tumor size. CONCLUSIONS Systematic literature review and meta-analysis identified eight publications that included 570 patients with eight types of solid malignant tumor, and showed that the expression of the lncRNA SNHG1 was significantly associated with worse clinical outcome.

Comparative Efficacy and Safety of Therapies in IgA Nephropathy: A Network Meta-analysis of Randomized Controlled Trials.

The present study aims to compare the relative efficacy and safety of different interventions for IgA nephropathy (IgAN) with proteinuria more than 1 g/d by using network meta-analysis. We searched PubMed, Embase, and the Cochrane Library for studies compared the rate of clinical remission and/or end-stage renal disease (ESRD) and/or serious adverse events in IgAN patients with proteinuria (>1 g/d). The surface under the cumulative ranking area (SUCRA) was calculated to rank the interventions. A total of 21 randomized controlled trials with 1822 participants were included for the comparisons of 7 interventions. The rank of the most effective treatments to induce clinical remission was renin-angiotensin system inhibitors (RASi) plus urokinase, steroid plus tonsillectomy, and RASi plus steroid with a SUCRA of 0.912, 0.710, and 0.583, respectively. As for the prevention of ESRD or doubling of serum creatinine, RASi plus steroid (SUCRA 0.012) was the most effective, followed by RASi (SUCRA 0.282) and steroid (SUCRA 0.494), leaving mycophenolate mofetil as the least effective (SUCRA 0.644). There was no statistical difference among all interventions in the occurrence of serious adverse events. The current network meta-analysis demonstrated for the first time that RASi plus steroid is probably the best therapeutic choice, not only for reducing proteinuria but also for maintaining long-term renal protection.

The decade of exosomal long RNA species: an emerging cancer antagonist.

Exosomes have emerged as a novel approach for the treatment and diagnosis of cancer after RNA content was discovered in exosomes in 2007. As important meditators of intercellular communication, exosomes have become a strong focus of investigation for researchers in the past decade, as witnessed through the exponential increase of research on exosomes. The capability of exosomes to transfer functionally active cargo highlights their importance as promising biomarkers and diagnostic molecules, as well as prospective drug delivery systems. The accessibility of exosomes in nearly all biofluids additionally alludes to its unprecedented ability in various types of cancers due to its extensive impact on tumor formation and progression. This review analyzes the role of exosomal long RNA species, which is comprised of mRNA, lncRNA, and circRNA, in tumor formation and progression, with an emphasis on their potential as future diagnostic biomarkers and treatment vectors in cancer biology. Their alignment with the development of exosomal databases is further examined in this review, in view of the accumulation of studies published on exosomes in the past decade.

NRP1 promotes cell migration and invasion and serves as a therapeutic target in nasopharyngeal carcinoma.

Neuropilin 1 (NRP1) promotes tumor growth, angiogenesis, tumor migration, and invasion. Its higher expression is closely related to the metastasis and poor outcome of many cancers. We have reported that NRP1 was expressed at higher levels in highly metastatic cells in comparison to minimally metastatic cells in nasopharyngeal carcinoma (NPC). However, the role of NRP1 in NPC cell migration and invasion is still unclear, and whether it could serve as a potential therapeutic target for patients with NPC still needs further investigation. In this study, our results demonstrated that ectopic expression of NRP1 in S26 and 6-10B cells promoted cell migration and invasion via wound healing and transwell assays. In contrast, knockdown of NRP1 in HONE1, CNE1 and S18 cells through Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) technology suppressed cell migration and invasion. Moreover, we found that EG00229, a small molecule inhibitor of NRP1, significantly suppressed NRP1-mediated promotion of NPC cells migration and invasion. Mechanistically, we demonstrated that NRP1 promoted migration and invasion by decreasing E-cadherin levels and increasing N-cadherin levels. Collectively, our results showed that NRP1 promotes cell migration and invasion and could function as a promising target for the future treatment of patients with NPC.

Recombinant Adenovirus-p53 Gene Therapy for Advanced Unresectable Soft-Tissue Sarcomas.

Patients with unresectable advanced soft-tissue sarcomas (STS) receiving radiotherapy or/and chemotherapy still have a poor prognosis. This study aimed to evaluate retrospectively the efficacy and safety of recombinant adenovirus-p53 (rAd-p53) gene therapy combined with radiotherapy and hyperthermia for advanced STS. A total of 71 patients with advanced unresectable STS treated at the authors' center from April 2007 to November 2014 were included. Of these 71 patients, 36 cases received rAd-p53 therapy combined with radiotherapy and hyperthermia (p53 group), while 35 cases received radiotherapy and hyperthermia alone (control group). Short-term therapeutic efficacies, long-term survival outcomes, and adverse events were evaluated and compared between groups. Compared to the control group, the p53 group had a significantly higher disease control rate (83.33% vs. 54.29%; p = 0.008) and a lower progressive disease rate (16.67% vs. 45.71%; p = 0.018). In addition, rAd-p53 treatment significantly improved the progression-free survival and overall survival of STS patients. Cox regression indicated that rAd-p53 treatment significantly reduced the risks for disease progression or death event for STS patients. Furthermore, there was no significant difference in all adverse events, except for transient fever, which occurred in 89% of patients with rAd-p53 therapy. rAd-p53 combined with radiotherapy and hyperthermia can effectively improve the therapeutic efficacy and survival outcomes in patients with advanced unresectable STS, providing a new therapeutic strategy.