Hollow CoFe Nanozymes Integrated with Oncolytic Peptides Designed via Machine-Learning for Tumor Therapy.

Developing novel substances to synergize with nanozymes is a challenging yet indispensable task to enable the nanozyme-based therapeutics to tackle individual variations in tumor physicochemical properties. The advancement of machine learning (ML) has provided a useful tool to enhance the accuracy and efficiency in developing synergistic substances. In this study, ML models to mine low-cytotoxicity oncolytic peptides are applied. The filtering Pipeline is constructed using a traversal design and the Autogluon framework. Through the Pipeline, 37 novel peptides with high oncolytic activity against cancer cells and low cytotoxicity to normal cells are identified from a library of 25,740 sequences. Combining dataset testing with cytotoxicity experiments, an 80% accuracy rate is achieved, verifying the reliability of ML predictions. Peptide C2 is proven to possess membranolytic functions specifically for tumor cells as targeted by Pipeline. Then Peptide C2 with CoFe hollow hydroxide nanozyme (H-CF) to form the peptide/H-CF composite is integrated. The new composite exhibited acid-triggered membranolytic function and potent peroxidase-like (POD-like) activity, which induce ferroptosis to tumor cells and inhibits tumor growth. The study suggests that this novel ML-assisted design approach can offer an accurate and efficient paradigm for developing both oncolytic peptides and synergistic peptides for catalytic materials.

Transcatheter arterial chemoembolisation combined with lenvatinib plus camrelizumab as conversion therapy for unresectable hepatocellular carcinoma: a single-arm, multicentre, prospective study.

Background: The synergistic effect of locoregional therapy in combination with systemic therapy as a conversion therapy for unresectable hepatocellular carcinoma (uHCC) is unclear. The purpose of this study was to evaluate the efficacy and safety of transcatheter arterial chemoembolisation (TACE) combined with lenvatinib and camrelizumab (TACE + LEN + CAM) as conversion therapy for uHCC. Methods: This single-arm, multicentre, prospective study was conducted at nine hospitals in China. Patients (aged 18-75 years) diagnosed with uHCC, an Eastern Cooperative Oncology Group performance score (ECOG-PS) of 0-1 and Child-Pugh class A received camrelizumab (200 mg, every 3 weeks) and lenvatinib (bodyweight ≥60 kg: 12 mg/day; <60 kg: 8 mg/day) after TACE treatment. Surgery was performed after tumour was assessed as meeting the criteria for resection. Patients who did not meet the criteria for surgery continued to receive triple therapy until disease progression or intolerable toxicity. Primary endpoints were objective response rate (ORR) according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) and safety. Secondary endpoints included the surgical conversion rate, radical (R0) resection rate, and disease control rate (DCR). This study was registered with Chinese Clinical Trial Registry (ChiCTR2100050410). Findings: Between Oct 25, 2021, and July 20, 2022, 55 patients were enrolled. As of the data cutoff on June 1, 2023, the median follow-up was 13.3 months (IQR 10.6-15.9 months). The best tumour response to triple therapy was complete response (CR) in 9 (16.4%) patients, partial response (PR) in 33 (60.0%) patients, stable disease (SD) in 5 (9.1%) patients, or progressive disease (PD) in 7 (12.7%) patients. The ORR was 76.4% (42/55, 95% CI, 65.2-87.6%), and the DCR was 85.5% (47/55, 95% CI, 76.2-94.8%) per mRECIST. Twenty-four (43.6%) of the 55 patients suffered from grade 3-4 treatment-related adverse events (TRAEs). No grade 5 TRAEs occurred. A total of 30 (30/55, 54.5%) patients were converted to resectable HCC and 29 (29/55, 52.7%) patients underwent resection. The R0 resection rate was 96.6% (28/29). The major pathologic response (MPR) and pathologic complete response (pCR) rates in the surgery population were 65.5% (19/29) and 20.7% (6/29), respectively. Only one patient developed a Clavien-Dindo IIIa complication (abdominal infection). No Clavien-Dindo IIIb-V complications occurred. The median OS and median PFS were not reached. Interpretation: The triple therapy (TACE + LEN + CAM) is promising active for uHCC with a manageable safety. Moreover, triple therapy has good conversion efficiency and the surgery after conversion therapy is feasible and safe. To elucidate whether patients with uHCC accepting surgical treatment after the triple therapy can achieve better survival benefits than those who receive triple therapy only, well-designed randomised controlled trials are needed. Funding: This study was funded by the Natural Science Foundation of Fujian Province, China (2022J01691) and the Youth Foundation of Fujian Province Health Science and Technology Project, China (2022QNA035).

Comprehensively prognostic and immunological analysis of VRK Serine/Threonine Kinase 1 in pan-cancer and identification in hepatocellular carcinoma.

BACKGROUND: VRK1 is a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases, which is related to the occurrence and development of malignant tumors. The expression pattern, predictive value, and biological function of VRK1 in various cancers remain largely elusive and warrant further investigation. METHODS: Public databases, such as TCGA, GTEx, and UCEC, were utilized to comprehensively analyze the expression of VRK1 across multiple cancer types. Prognostic significance was assessed through Univariate Cox regression and Kaplan-Meier analyses. Additionally, Spearman's correlation analysis was employed to explore the potential associations between VRK1 expression and various factors, including tumor microenvironment scores, immune cell infiltration, and immune-related genes. Moreover, to validate the findings, differential expression of VRK1 in HCC tissues and cell lines was further confirmed using qPCR, Western blot, and immunohistochemistry techniques. RESULTS: The upregulation of VRK1 was observed in most cancer types, and was associated with worse prognosis in ACC, KICH, KIRP, LGG, LIHC, LUAD, MESO, and PCPG. In various cancers, VRK1 expression exhibited positive correlations with immune infiltrating cells, immune checkpoint-related genes, TMB, and MSI. Furthermore, the promoter methylation status of VRK1 varied across different tumor types, and this variation was associated with patient prognosis in certain cancers. In our experimental analyses, we observed significantly elevated expression of VRK1 in both HCC tissues and HCC cells. Functionally, we found that the downregulation of VRK1 had a profound impact on HCC cells, leading to a significant decrease in their proliferation, migration, and invasion capabilities. CONCLUSION: The expression of VRK1 exerts a notable influence on the prognosis of several tumors and exhibits a strong correlation with tumor immune infiltration. Moreover, in the context of HCC, VRK1 may act as an oncogene, actively promoting tumor progression.

Integration of CoAl-Layered Double Hydroxides on Commensal Bacteria to Enable Targeted Tumor Inhibition and Immunotherapy.

Combining targeted therapy and immunotherapy brings hope for a complete cancer cure. Due to their selective colonization and immune activation capacity, some bacteria have the potential to realize targeted immunotherapy. Herein, a biohybrid system was designed and synthesized by cladding NO3--intercalated cobalt aluminum layered double hydroxides (LDH) on anaerobic Propionibacterium acnes (PA) (PA@LDH). In this system, the covering of LDH reduces the pathogenicity of PA to normal tissues and alters its surface charge for prolonged in vivo circulation. Once the tumor site is reached, the acid-responsive degradation of LDH enables PA exposure. PA can colonize and convert nitrate ions to nitric oxide (NO) through denitrification. Then, NO reacts with intracellular O2·- to produce toxic reactive nitrogen species ONOO- and induce tumor cell apoptosis. In addition, cobalt ions released from LDH can inhibit the activity of superoxide dismutase (SOD), thus increasing the level of O2·- and further enhancing the antitumor effect. Moreover, PA exposure activates M2-to-M1 macrophage polarization and a range of immune responses, thereby achieving a sustained antitumor activity. In vitro and in vivo results reveal that the biohybrid system eliminates solid tumors and inhibits tumor metastasis effectively. Overall, the biohybrid strategy provides a new avenue for realizing simultaneous immunotherapy and targeted therapy.

Comprehensive prognostic and immunological analysis of Ubiquitin Specific Peptidase 28 in pan-cancers and identification of its role in hepatocellular carcinoma cell lines.

BACKGROUND: Ubiquitin Specific Peptidase 28 (USP28), as a member of the DUBs family, has been reported to regulate the occurrence and development of some tumors, but its oncogenic role in tumor immunity is still unknown. METHODS: The comprehensive view of USP28 expression in tumor and normal samples was obtained from public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE). We analyzed the genomic alterations of USP28 in various cancers using the cBioPortal dataset. Besides, gene set enrichment analysis was used to analyze the associated cancer hallmarks with USP28 expression, and TIMER2.0 was taken to investigate the immune cell infiltrations related to the USP28 level. RESULTS: USP28 is highly expressed in most tumors and has prognostic value across various cancer types. Moreover, a significant correlation exists between USP28 and immune regulators, clinical staging, checkpoint inhibitor response, MSI, TMB, CNV, MMR defects, and DNA methylation. Additionally, USP28 expression is strongly associated with the infiltration levels of neutrophils and NK cells in most tumor types. One of the most significant findings of our study was that USP28 could serve as a significant predictor of anti-CTLA4 therapy response in melanoma patients. Additionally, our molecular biology experiments validated that the knockdown of USP28 substantially reduced the proliferative and invasive abilities of the HCC cell lines. CONCLUSIONS: Our study suggests that USP28 could potentially serve as a biomarker for cancer immunologic infiltration and poor prognosis, with potential applications in developing novel cancer treatment strategies.

A bifunctional bortezomib-loaded porous nano-hydroxyapatite/alginate scaffold for simultaneous tumor inhibition and bone regeneration.

Treatments of osteolytic lesions due to malignant metastasis remain one of the major clinical challenges. The residual tumor cells after surgical resections and an acidic tumor microenvironment are unfavorable for osteogenic induction. Bortezomib (BTZ), a proteasome inhibitor used in chemotherapy, also has an osteogenic potential in concentration- and Ca2+-dependent manners. In this study, controlled delivery of BTZ in a novel bifunctional scaffold based on nano-hydroxyapatite (nHA) and sodium alginate (SA) nanocomposite, namely BTZ/nHA@SA, has been explored. By smartly adjusting microenvironments, a sustainable release of Ca2+ from nHA could be achieved, which was not only able to cross-link SA but also to regulate the switch between the dual functions of tumor inhibition and bone regeneration of BTZ to promote the osteogenic pathway. The freeze-dried BTZ/nHA@SA scaffold has excellent interconnectivity, is capable to promote the attachment and proliferation of mouse embryonic osteoblast precursor cells, as well as effectively induces breast cancer cell death in vitro. Furthermore, in vivo, studies using a mouse tumor model and a rabbit femoral defect model showed that the BTZ/nHA@SA scaffold could promote tumor ablation, and also enhance bone repair. Therefore, the BTZ/nHA@SA scaffold has unique dual functions of inhibiting tumor recurrence and promoting bone tissue regeneration simultaneously. This smart bi-functional scaffold offers a promising novel approach for oncological treatments by synchronously orchestrating tumor inhibition and tissue regeneration for the repair of neoplastic bone defects.

What Matters in Radiological Image Segmentation? Effect of Segmentation Errors on the Diagnostic Related Features.

Segmentation is a crucial step in extracting the medical image features for clinical diagnosis. Though multiple metrics have been proposed to evaluate the segmentation performance, there is no clear study on how or to what extent the segmentation errors will affect the diagnostic related features used in clinical practice. Therefore, we proposed a segmentation robustness plot (SRP) to build the link between segmentation errors and clinical acceptance, where relative area under the curve (R-AUC) was designed to help clinicians to identify the robust diagnostic related image features. In experiments, we first selected representative radiological series from time series (cardiac first-pass perfusion) and spatial series (T2 weighted images on brain tumors) of magnetic resonance images, respectively. Then, dice similarity coefficient (DSC) and Hausdorff distance (HD), as the widely used evaluation metrics, were used to systematically control the degree of the segmentation errors. Finally, the differences between diagnostic related image features extracted from the ground truth and the derived segmentation were analyzed, using the statistical method large sample size T-test to calculate the corresponding p values. The results are denoted in the SRP, where the x-axis indicates the segmentation performance using the aforementioned evaluation metric, and the y-axis shows the severity of the corresponding feature changes, which are expressed in either the p values for a single case or the proportion of patients without significant change. The experimental results in SRP show that when DSC is above 0.95 and HD is below 3 mm, the segmentation errors will not change the features significantly in most cases. However, when segmentation gets worse, additional metrics are required for further analysis. In this way, the proposed SRP indicates the impact of the segmentation errors on the severity of the corresponding feature changes. By using SRP, one could easily define the acceptable segmentation errors in a challenge. Additionally, the R-AUC calculated from SRP provides an objective reference to help the selection of reliable features in image analysis.

An implantable composite scaffold for amplified chemodynamic therapy and tissue regeneration.

Tissue regeneration and tumor cell killing after surgical resection are the two keys to achieving effective tumor therapy. In this study, an implantable system with combined functions of tumor therapy and tissue repair was constructed. Tannic acid (TA)/Fe3+ nanoparticles with Fenton catalytic activity were loaded with GSH inhibitor BSO drug (BTF), and acted as the therapeutic factor to realize amplified chemodynamic tumor treatment. Bioactive glass (BG) fibers loaded with vascular endothelial growth factor (VEGF) were used as the drug carrier matrix with tissue repair function (BGV). Then the BGV@BTF composite fibers were obtained by anchoring BTF nanoparticles on the surface of BGV fibers. Under tumorous acidic conditions, BTF nanoparticles can be released from the composite fibers, and taken up by tumor cells. Facilitated by BSO with the GSH suppression effect and TA with Fe3+ reducing properties, BTF nanoparticles can realize high oxidative stress in tumor cells and subsequent cell death. In addition, BG fibers and VEGF can both promote tissue regeneration and accelerate postoperative wound healing. The simultaneous suppression of tumor growth and promotion of tissue repair in this work is inspiring in the field of postoperative tumor treatment and recovery.

Three-dimensionally printed navigational template: a promising guiding approach for lung biopsy.

Background: Percutaneous transthoracic lung biopsy is customarily conducted under computed tomography (CT) guidance, which primarily depends on the conductors' experience and inevitably contributes to long procedural duration and radiation exposure. Novel technique facilitating lung biopsy is currently demanded. Methods: Based on the reconstructed anatomical information of CT scans, a three-dimensionally printed navigational template was customized to guide fine-needle aspiration (FNA). The needle insertion site and angle could be indicated by the template after proper placement according to the reference landmarks. From June 2020 to August 2020, patients with peripheral indeterminate lung lesions ≥30 mm in diameter were enrolled in a pilot trial. Cases were considered successful when the virtual line indicated by the template in the first CT scan was pointing at the target, and the rate of success was recorded. The insertion deviation, procedural duration, radiation exposure, biopsy-related complications, and diagnostic yield were documented as well. Results: A total of 20 patients consented to participate, and 2 withdrew. The remaining 18 participants consisting of 11 men and 7 women with a median age of 63 [inter-quartile range (IQR), 50-68] years and a median body mass index (BMI) of 23.5 (IQR, 20.8-25.8) kg/m2 received template-guided FNA. The median nodule size of the patients was 41.2 (IQR, 36.2-51.9) mm and 17 lesions were successfully targeted (success rate, 94.4%). One lesion was not reached through the designed trajectory due to an unpredictable alteration of the lesion's location resulting from pleural effusion. The median deviation between the actual position of the needle tip and the designed route was 9.4 (IQR, 6.8-11.7) mm. The median procedural duration was 10.7 (IQR, 9.7-11.8) min, and the median radiation exposure was 220.9 (IQR, 198.6-249.5) mGy×cm. No major biopsy-related complication was encountered. Definitive diagnosis of malignancy was reached in 13 of the 17 (76.5%) participants. Conclusions: The feasibility and safety of navigational template-guided FNA were preliminarily validated in lung biopsy cohort. Nonetheless, patients with pleural effusion were not recommended to undergo FNA guided by such technique. Trial Registration: This study was registered with ClinicalTrials.gov (identifier: NCT03325907).

Relationship between inpatient satisfaction and the quality of surgery.

BACKGROUND: This study sought to investigate the correlation between inpatient satisfaction and surgical quality evaluation indicators, and explore the factors affecting inpatient satisfaction. METHODS: A total of 5,000 inpatients who underwent surgery at 10 tertiary. A hospital in Chongqing were randomly selected and asked to complete an inpatient satisfaction questionnaire developed by our team in a previous study. A logistic regression was undertaken to analyze the factors affecting inpatient satisfaction, and the relationship between inpatient satisfaction and evaluation indicators of surgical quality. RESULTS: The overall satisfaction level of inpatients undergoing surgery was high. Specifically, the satisfaction level was 88.7%, and the dissatisfaction level was 11.3%. A univariate analysis showed that age, marital status, education level, monthly family income, the source of medical costs, the average length of the hospital stay, first hospitalization or not, doctor-patient communication, the quality of surgery, service attitude, 30-day postoperative mortality, major and minor complications, the rescue failure rate, readmission, and the incision infection rate affected the patient satisfaction, and the difference between satisfied and dissatisfied patients in each group was statistically significant (all P=0.000). The results of the logistic regression analysis showed that the factors related to the satisfaction of surgical quality indicators were postoperative 30-day mortality, major and minor complications, the rescue failure rate, the incision infection rate, and the average length of the hospital stay (all P<0.05), and the factors related to a decrease in inpatient satisfaction were increased postoperative 30-day mortality, a high incidence of major and minor complications, a high rescue failure rate, and a high incision infection rate. CONCLUSIONS: There was a significant correlation between inpatient satisfaction and surgical quality evaluation indicators (i.e., 30-day mortality, major and minor complications, the rescue failure rate, the incision infection rate, and the average length of the hospital stay).

Hippo Pathway Core Genes Based Prognostic Signature and Immune Infiltration Patterns in Lung Squamous Cell Carcinoma.

BACKGROUND: We investigated the prognostic effects and their patterns of immune infiltration of hippo pathway core genes in lung squamous cell carcinoma, in order to find some clues for underlying mechanisms of LUSC tumorigenesis and help developing new therapeutic methods. METHODS: The mutational data, transcriptome data and corresponding clinical medical information of LUSC patients were extracted from The Cancer Genome Atlas (TCGA) database. Differential expression genes (DEGs) and Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were explored. Survival analysis for the hippo core genes and the prognostic model were performed. Immune infiltration was estimated by CIBERSORT algorithm and some immune checkpoints-related genes were further investigated. RESULTS: Overall, 551 LUSC samples were included in our study, consisting of 502 LUSC tumor samples and 49 adjacent normal samples, respectively. There were 1910 up-regulated DEGs and 2253 down-regulated DEGs were finally identified. The top five mutational hippo pathway core genes were LATS1 (4%), WWC1 (2%), TAOK1 (2%), TAOK3 (2%), and TAOK2 (2%), respectively. the mutation of LATS2 was highly associated with co-mutational NF2 (P <0.05) and TAOK1 (P <0.05). In survival analyses, we found only WWC1 (log-rank p = 0.046, HR = 1.32, 95% CI = 1-1.73) and LATS2 (log-rank p = 0.013, HR = 1.41, 95%CI = 1.08-1.86) had significant prognostic roles. After getting the three subgroups according to the subtyping results, we demonstrated that T cell gamma delta (p = 5.78e-6), B cell memory (p = 4.61e-4) and T cell CD4+ memory resting (p = 2.65e-5) had significant differences among the three groups. SIGLEC15 (P <0.01) and CD274 (P <0.05) also had statistical differences among the three subgroups. CONCLUSIONS: Our study verified the prognostic roles of WWC1 and LATS2 in LUSC patients. Immune checkpoints-related genes SIGLEC15 and CD274 had statistical differences among the three subgroups, which may provide new perceptions on the molecular mechanisms in LUSC and maybe helpful for precisely selecting specific LUSC patients with potential immunotherapy benefits.

Clinicopathological and prognostic analyses of 86 resected pulmonary lymphoepithelioma-like carcinomas.

BACKGROUND: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of primary lung cancer. The present study aims at investigating clinicopathological features and prognostic characteristics of the resected pulmonary LELC. METHODS: Patients with resected pulmonary LELC were identified in our hospital from December 2008 to December 2018. Data of these patients were retrospectively reviewed, clinicopathological features and prognostic characteristics were analyzed subsequently. RESULTS: In total, 86 patients were enrolled in the study, including 39 (45.3%) males and 47 (54.7%) females. Most of the serum tumor markers were normal. Immunohistochemical staining result showed frequent differentiation traits of epithelial tissue such. Positive PD-L1 (15 of 19, 78.9%) and PD-1 (13 of 17, 76.5%) were also common, but cancer-related genetic mutation was scarce (1 of 47, 2.1%). Survival analyses demonstrated that the N stage (p = .011) and extent of resection (p = .023) were identified as independent predictive factors for overall survival. CONCLUSIONS: Pulmonary LELC is a distinctive subtype of lung cancer with several exclusive traits, such as the trend to happen among nonsmoking young people, epithelial origin of tumor differentiation, frequent expression of the immune checkpoint, and scarce presence of driver mutation. In addition, pulmonary LELC was apt to get a favorable outcome, especially in cases diagnosed and treated in the early stage.

TEAD4 promotes tumor development in patients with lung adenocarcinoma via ERK signaling pathway.

OBJECTIVE: Whether TEAD4 itself plays a vital role in the tumorigenesis and development of lung adenocarcinoma remains unclear. In our study, we aim to investigate the expression pattern and biological functions of TEAD4 and further investigate the potential mechanisms. METHODS: Clinical tumor and paired normal samples were collected for preparing tissue microarray. Western blot and immunohistochemical (IHC) staining of TEAD4 expression in these tissues were conducted to explore the expression pattern. Moreover, A549 cell line was select for investigating the function of TEAD4 for lung adenocarcinoma in vitro and in vivo. RNA sequencing was finally performed to further detect the potential downstream genes. RESULTS: The elevated TEAD4 expression level was observed in tumor tissues and the patients with higher TEAD4 expression tended to have worse overall survival. The knockdown of TEAD4 inhibits A549 cells proliferation ability and migration ability. A total of 431 differentially expressed genes (DEGs), including 239 down-regulated genes and 191 up-regulated genes, were finally identified and some of DEGs were validated. Moreover, knockdown of TEAD4 led to the down-regulation of pERK, which maybe the potential TEAD4-targeted signaling pathway to play the pro-tumorigenic function. CONCLUSIONS: The expression level of TEAD4 is high in lung adenocarcinoma tumor tissues and positively associated with worse prognosis. Up-regulation of TEAD4 may lead to excessive transcription and phosphorylation of ERK proteins and therefore accelerates the process of tumor development. Our results demonstrate that overexpression of TEAD4 is a new mechanism of dysregulation of Hippo pathway.

Multifunctional Supramolecular Hydrogel for Prevention of Epidural Adhesion after Laminectomy.

Postoperative epidural adhesion remains a clinically challenging problem in spine surgery. Currently there are no effective and safe antifibrotic and antiadhesion biomaterials that have been specifically developed for this complication in clinical practice. Herein we designed and engineered an advanced antiadhesion hydrogel with multiple functionalities, including temperature-responsive gelation, self-healing, tissue adhesiveness, antioxidation, anti-inflammation, and antifibrosis. This multifunctional supramolecular hydrogel can be facilely constructed by integrating three functional modules, i.e., a thermosensitive triblock copolymer, poloxamer 407 (PX); a reactive oxygen species-eliminating and anti-inflammatory nanoparticle (TPCD NP); and an adhesion-enhancing compound, tannic acid (TA). The optimal formulation (PXNT) was hierarchically screened based on in vitro properties and in vivo activities. Therapeutically, local treatment with PXNT hydrogel effectively prevented epidural fibrosis and adhesion after laminectomy in both rats and rabbits. Of note, PXNT hydrogel showed more beneficial efficacy than different control thermosensitive hydrogels and a commercially available barrier product, Interceed. Mechanistically, PXNT hydrogel significantly attenuated local oxidative stress, inhibited inflammatory responses, and reduced fibrotic tissue formation. Moreover, treatment with PXNT hydrogel did not cause systemic adverse effects and neurological symptoms. Consequently, PXNT hydrogel is a highly promising biomaterial for preventing postlaminectomy epidural adhesion and adhesions after other surgeries.

A comprehensive study of construction and analysis of competitive endogenous RNA networks in lung adenocarcinoma.

BACKGROUND: Long noncoding RNAs (lncRNAs) have gain increasing attention in lung adenocarcinoma. In this study, we aimed at constructing and analyzing the lncRNAs and the related proteins based competitive endogenous RNA (ceRNA) network. METHODS: RNA expression data of lung adenocarcinoma were extracted from the TCGA database. Differentially expressed (DE) lncRNAs, messenger RNAs (mRNAs) and microRNAs (miRNAs) were identified and then a DElncRNA-DEmiRNA-DEmRNA ceRNA network was constructed for lung adenocarcinoma. We also analyzed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of the DEgenes. Kaplan-Meier survival curves were also been further utilized for exploring the prognostic factors. RESULTS: After compared and calculated lncRNA, mRNA and miRNA expression profiles between lung adenocarcinoma and normal samples, 1709 differential expressed lncRNAs, 2554 differential expressed mRNAs and 116 differential expressed miRNAs were finally identified. Afterwards, a lncRNA mediated ceRNA network was constructed, according to the interactions among 544 pairs of DElncRNA-DEmiRNA relationships and 47 pairs of DEmiRNA-DEmRNA relationships. As for the survival analyses, we found 10 DElncRNAs, 25 DEmRNAs and 7 miRNAs have statistically prognostic significance for overall survival, respectively. CONCLUSIONS: This study provides meaningful information for deeper understanding the underlying molecular mechanism of lung adenocarcinoma and for evaluating prognosis, which could monitor recurrence, guide clinical treatment drugs and subsequent related researches.

High mobility group AT-hook 2 and c-MYC as potential prognostic factors in pancreatic ductal adenocarcinoma.

The present study investigated if c-MYC and high mobility group AT-hook 2 (HMGA2) expression was associated with prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). A total of 102 patients undergoing surgery for PDAC were retrospectively reviewed. Immunohistochemistry was used to detect c-MYC and HMGA2 protein expression in PDAC and peritumoral tissue samples. Expression of c-MYC and HMGA2 was associated with clinicopathological characteristics and prognoses of patients with PDAC using multivariate analysis. HMGA2 and c-MYC protein expression was significantly higher in PDAC tissues compared with peritumoral tissue (P<0.001). HMGA2 and c-MYC expression was also significantly higher in patients with PDAC who had lymph node metastasis, invasion of regional tissues and tumor node metastasis (TNM) stage III or IV disease compared with those who had no lymph node metastasis, no invasion of regional tissues and TNM stage I or II disease (P<0.001). Multivariate logistic regression analysis was used to identify TNM stage (P=0.007) and invasion (P=0.003) as significant independent predictors of c-MYC expression (model AUC=0.8201), and lymph node metastasis (P=0.002) and invasion (P=0.003) as significant independent predictors of HMGA2 expression (model AUC=0.7638). Cox multivariate analysis showed that expression of c-MYC (P=0.019) and HMGA2 (P<0.001), TNM stage (P=0.014) and lymph node metastasis (P=0.032) were associated with reduced overall survival time. HMGA2 and c-MYC may be important biological markers and potential therapeutic targets involved in the tumorigenesis, metastasis, invasion and prognosis of PDAC.

RNA m6A Modification in Cancers: Molecular Mechanisms and Potential Clinical Applications.

N6-Methyladenosine (m6A) RNA modification brings a new dawn for RNA modification researches in recent years. This posttranscriptional RNA modification is dynamic and reversible, and is regulated by methylases ("writers"), demethylases ("erasers"), and proteins that preferentially recognize m6A modifications ("readers"). The change of RNA m6A modification regulates RNA metabolism in eucaryon, including translation, splicing, exporting, decay, and processing. Thereby the dysregulation of m6A may lead to tumorigenesis and progression. Given the tumorigenic role of abnormal m6A expression, m6A regulators may function as potential clinical therapeutic targets for cancers. In this review, we emphasize on the underlying mechanisms of m6A modifications in tumorigenesis and further introduce the potential m6A regulators-associated therapeutic targets for tumor therapy.

A Meta-Analysis And Systematic Review Of Accuracy Of Endoscopic Ultrasound For N Staging Of Gastric Cancers.

BACKGROUND: Endoscopic ultrasonography (EUS) is widely used as a staging modality for gastric cancer. However, the results of studies on the use of EUS for N staging in gastric cancer vary. This study aimed at studying the overall diagnostic accuracy of EUS for N staging of gastric cancer. METHODS: Published studies were identified through searching the MEDLINE, Web of Science, EMBASE, SpringerLink and ScienceDirect databases. A bivariate random effect model was used to estimate the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). A hierarchical summary receiver operating characteristic curves (HSROC) based on the pooled data was also computed. RESULTS: Fifty studies (5223 patients) were included in this analysis. The pooled sensitivity, specificity, PLR, NLR and DOR of EUS for N staging were 0.82 (95% CI 0.78 to 0.85), 0.68 (0.63 to 0.73), 2.6 (2.2 to 3.0), 0.27 (0.22 to 0.32), and 10 (8 to 12), respectively. The area under the HSROC was 0.83. CONCLUSION: The EUS may provide a clinically useful tool to guide physicians in the N staging of gastric cancer. However, physicians must note that the EUS has a relatively low specificity.

Biocompatible iron(II)-doped carbon dots as T1-weighted magnetic resonance contrast agents and fluorescence imaging probes.

The one-pot synthesis of iron-doped carbon quantum dots (Fe-CQDs) for use as both magnetic resonance (MR) and fluorescent (dual-mode) imaging nanoprobes is described. Comprehensive characterizations of the material confirmed the successful doping of the CQDs with Fe(II) ions. The imaging probe has a longitudinal relaxivity of 3.92 mM-1∙s-1 and a low r2/r1 ratio of 1.27, both of which are critical for T1-weighted contrast agents. The maximum emission of Fe-CQDs locates at 450 nm under 375 nm excitation, which also can be applied to fluorescence imaging. Biotoxicity assessment showed good biocompatibility of the Fe-CQDs. The in-vitro experiments with A549 cells indicated that the Fe-CQDs are viable candidates as dual-mode (MR/fluorescence) imaging nanoprobes. For in-vivo experiments, they exhibit high contrast efficiency, thereby improving the positive contrast in T1-weighted MR images. In-vivo time-dependent MRI of major organs showed that the Fe-CQDs undergo fast glomerular filtration and can evade immuno-absorption due to their ultra-small size and excellent biocompatibility. Graphical abstract Schematic presentation of the synthesis of Fe-CQDs and applications to magnetic resonance and fluorescent dual-mode imaging.