Abstract Background Aberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identify a non-invasive DNA methylation-based screening approach using cell-free DNA (cfDNA) for early detection of hepatocellular carcinoma (HCC). Methods Differentially, DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, liver cirrhosis, and normal tissue samples with high throughput DNA bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated blocks (DMBs). This model was tested in a cohort consisting of 120 HCC, 92 liver cirrhotic, and 290 healthy plasma samples including 65 hepatitis B surface antigen-seropositive (HBsAg+) samples, independently validated in a cohort consisting of 67 HCC, 111 liver cirrhotic, and 242 healthy plasma samples including 56 HBsAg+ samples. Results Based on methylation profiling of tissue samples, 2321 DMBs were identified, which were subsequently used to construct a cfDNA-based HCC screening model, achieved a sensitivity of 86% and specificity of 98% in the training cohort and a sensitivity of 84% and specificity of 96% in the independent validation cohort. This model obtained a sensitivity of 76% in 37 early-stage HCC (Barcelona clinical liver cancer [BCLC] stage 0-A) patients. The screening model can effectively discriminate HCC patients from non-HCC controls, including liver cirrhotic patients, asymptomatic HBsAg+ and healthy individuals, achieving an AUC of 0.957(95% CI 0.939–0.975), whereas serum α-fetoprotein (AFP) only achieved an AUC of 0.803 (95% CI 0.758–0.847). Besides detecting patients with early-stage HCC from non-HCC controls, this model showed high capacity for distinguishing early-stage HCC from a high risk population (AUC=0.934; 95% CI 0.905–0.963), also significantly outperforming AFP. Furthermore, our model also showed superior performance in distinguishing HCC with normal AFP (< 20ng ml −1 ) from high risk population (AUC=0.93; 95% CI 0.892–0.969). Conclusions We have developed a sensitive blood-based non-invasive HCC screening model which can effectively distinguish early-stage HCC patients from high risk population and demonstrated its performance through an independent validation cohort. Trial registration The study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). The study is registered at ClinicalTrials.gov(# NCT04383353 ).
Background: An effective blood-based method for hepatocellular carcinoma (HCC) early detection has not yet been developed. Aberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identified a non-invasive DNA methylation-based diagnostic approach using cell-free DNA for HCC early detection in high risk population.Methods: Differentially methylated DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, cirrhotic and healthy liver tissues using targeted bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated makers using plasma samples from 120 HCC patients, 92 cirrhotic patients and 290 healthy individuals. This model was independently validated in a cohort consisting of 67 HCC patients, 115 cirrhotic patients and 242 healthy individuals. The clinical parameters of misclassified samples were also investigated. Findings: Based on methylation profiling of tissue samples, a total of 2,321 DNA methylation markers were derived, which were subsequently used to construct a cfDNA-based HCC screening model, achieving a sensitivity of 86% and specificity of 97% in the training cohort and a sensitivity of 82% and specificity of 96% in the independent validation cohort. The HCC screening model can effectively discriminate HCC patients from non-HCC patients, including patients with cirrhosis, HBV infection and healthy individuals, achieving an AUC of 0.956; whereas serum alpha-fetoprotein (AFP) achieved an AUC of 0.803.Interpretation: We have developed and validated an HCC screening model which can effectivelydistinguish early stage HCC patients from cirrhotic patients and symptomatic HBsAg-seropositiveindividuals.Funding: Key Research and Development Program of Hunan Province, Natural ScienceFoundation of Hunan Province, China.Declaration of Interest: None to declare. Ethical Approval: The study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). All collection and usage of human sample and clinical data were in accordance with the principles of the Declaration of Helsinki. Written informed content was obtained from every participant for the use of their tissue or plasma samples.
Long non-coding RNA tissue differentiation-inducing non-protein coding (TINCR) is associated with the carcinogenesis of several cancers. However, little is known about the function and mechanism of TINCR in lung adenocarcinoma (LUAD). Here, we aimed to analyze expression of TINCR and elucidate its mechanistic involvement in the progression of LUAD. The expression of TINCR was investigated according to Gene Expression Profiling Interactive Analysis at first and then detected in 29 LUAD tissues and paired adjacent normal tissues using qRT-PCR. Results indicated that TINCR was evidently downregulated in LUAD. The association between TINCR and clinicopathological parameters was analyzed by Pearson's chi-square test, suggesting TINCR was closely correlated with TNM stage and lymph mode metastasis. Subsequently, the function role of TINCR was examined by gain- and loss-of-function studies in LUAD (A549 and NCI-H292) cells. As analyzed by the scratch wound-healing and transwell assays, results revealed that TINCR suppressed the migration and invasion of A549 and NCI-H292 cells. However, TINCR exerted no effects on the cell proliferation as determined by CCK8 assay. Furthermore, we reported that loss of Sp1 could inhibit TINCR expression. Expressions of miR-107/miR-1286 were detected by qRT-PCR assay in A549 and NCI-H292 cells after TINCR knockdown or overexpression. In addition, the direct binding ability of the predicted miR-107 or miR-1286 binding site on TINCR was validated by luciferase activity assay. Results indicated TINCR could constrain the expression of miR-107/miR-1286, and was a target of them in LUAD cells. Bioinformatics analyses showed that BTRC and RAB14 was the potential target gene of miR-107 and miR-1286, respectively. These data revealed a possible regulatory mechanism in which upregulation of TINCR induced by Sp1 could constrain the migration and invasion through regulating miR-107 or miR-1286 in LUAD cells. Conjointly, our findings provide a valuable insight into the regulatory mechanism of TINCR in LUAD, supportive to its potential of therapeutic target for LUAD patients.
Lung adenocarcinoma is a malignant tumor that is prone to distant metastasis. Common metastatic sites are brain, adrenal gland, liver, bone, and so on. Skin soft tissue metastasis is unusual, and breast metastasis is even rarer. This case is a middle-aged female patient who had experienced multi-line treatments for upper limbs, abdominal skin, and bilateral breast tissue metastases.The patient's multiple metastases were susceptible to radiation therapy.Reviewing the entire treatment process of this patient can find that the rational use of individualized comprehensive treatment methods and appropriate timing of genetic testing are very important for patients with lung adenocarcinoma to prolong their survival time and improve their quality of life.肺腺癌是一种容易出现远处转移的恶性肿瘤，其常见转移部位为脑、肾上腺、肝、骨等。皮肤软组织转移不常见，乳腺转移更为罕见。此病例为中年女性患者，经历多线治疗先后出现上肢、腹壁皮肤、双侧乳腺组织转移，多处转移灶对放射治疗敏感。回顾此患者整个治疗过程可发现合理运用个体化综合治疗手段，在适当时机选择基因检测对于延长肺腺癌患者生存期和提高其生存质量十分重要。.
Messenger RNA (mRNA) vaccine has fueled a great hope for cancer immunotherapy. However, low immunogenicity, caused by inefficient mRNA expression and weak immune stimulation, hampers the efficacy of mRNA vaccines. Here, we present an mRNA compartmentalization–based cancer vaccine, comprising a multimodule DNA nanostructure (MMDNS)–assembled compartment for efficient mRNA translation via in situ localizing mRNA concentration and relevant reaction molecules. The MMDNS is constructed via programmable DNA hybridization chain reaction (HCR)–based strategy, with integrating antigen-coded mRNA, CpG oligodeoxynucleotides (ODNs), acidic-responsive DNA sequence, and dendritic cells targeting aptamer. MMDNS undergoes in situ assembly in acidic lysosomes to form a micro-sized aggregate, inducing an enhanced CpG ODN adjuvant efficacy. Subsequently, the aggregates escape into cytoplasm, providing a moderate compartment which supports the efficient translation of spatially proximal mRNA transcripts via localizing relevant reaction molecules. The mRNA compartmentalization–based vaccine boosts a strong immune response and effectively inhibits tumor growth and metastasis, offering a robust strategy for cancer immunotherapy.
The main purpose of this study was to identify the correlation between the expression of long non-coding RNA (lncRNA) HAGLR in plasma exosomes and the detection rate of circulating tumor cells (CTCs) in patients with non-small cell lung cancer (NSCLC).LncRNA HAGLR expression was detected in plasma exosomes of 40 patients with NSCLC and 8 healthy subjects using qRT-PCR. CTCs were enriched and separated using CTC-BIOPSY® abnormal cell separator. The correlations between lncRNA HAGLR expression in plasma exosomes and CTCs of patients with NSCLC and clinical pathological parameters were also analyzed. Bioinformatics analyses indicated HAGLR was evidently down-regulated in NSCLC tissues when compared to normal controls. The relationship between differential expression of HAGLR with different stages of NSCLC and clinical prognosis were elucidated using corresponding statistical methods.HAGLR was significantly decreased in NSCLC, and there was obvious correlation with overall survival (P<0.05). CTCs were detected in peripheral blood of patients with NSCLC with the positive rate of 70.0%. In lung squamous cell carcinoma (LUSC), compared with the high expression group of HAGLR, the low expression group had a better overall survival (P<0.05). At the same time, the high expression of HAGLR was positively correlated with the high detection rate of CTCs (P<0.05), suggesting that the disease may have a later tumor stage, and poor prognosis.lncRNA HAGLR and CTCs could be used as potential biomarkers for NSCLC metastasis risk prediction.
Background: The main purpose of this study was to identify the correlation between the expression of long non-coding RNA (lncRNA) HAGLR in plasma exosomes and the detection rate of circulating tumor cells (CTCs) in patients with non-small cell lung cancer (NSCLC). Methods: LncRNA HAGLR expression was detected in plasma exosomes of 40 patients with NSCLC and 8 healthy subjects using qRT-PCR. CTCs were enriched and separated using CTC-BIOPSY® abnormal cell separator. The correlations between lncRNA HAGLR expression in plasma exosomes and CTCs of patients with NSCLC and clinical pathological parameters were also analyzed. Bioinformatics analyses indicated HAGLR was evidently down-regulated in NSCLC tissues when compared to normal controls. The relationship between differential expression of HAGLR with different stages of NSCLC and clinical prognosis were elucidated using corresponding statistical methods.
Results: HAGLR was significantly decreased in NSCLC, and there was obvious correlation with overall survival (P Conclusions: lncRNA HAGLR and CTCs could be used as potential biomarkers for NSCLC metastasis risk prediction.
About 70% of patients with radical surgery Cholangiocarcinoma (CCA) have recurrence and metastasis. There are few studies on the relationship between CCA adjuvant chemotherapy (mono or combined therapy), recurrence pattern (local, regional, distant recurrence) and prognosis [(Disease free survival, DFS), (Overall survival, OS)] after radical surgery. This study focuses on the correlation between CCA adjuvant chemotherapy, recurrence pattern and prognosis.The study involved retrospective analysis of data: preoperative hematology, clinical pathology, adjuvant chemotherapy regimens, recurrence pattern, DFS and OS, of 207 patients with CCA. Chi-square test was used to analyze the correlation between related factors and postoperative recurrence. Survival curves were plotted by Kaplan-Meier method, P-values were calculated by Log-rank for univariate analysis, multivariate COX regression method for multivariate analysis.Using chi-square test, there were correlations between high carbohydrate antigen 19-9 level(CA19-9≥35), vascular invasion, single-agent adjuvant chemotherapy and postoperative recurrences (p=0.04, p=0.04, p=0.02), COX multivariate regression analysis showed that adjuvant chemotherapy (single vs. doublet drug regimen) was an independent prognostic factor for DFS (11.0 vs. 24.6 months, HR=2.88, P=0.01), whereas recurrence pattern (local vs. distant; regional vs. distant) was an independent prognostic factor for OS (31.2 months vs. 20.4 months, HR=0.58, p=0.01; 32.0 months vs. 20.4 months, HR=0.51, p=0.01).Adjuvant chemotherapy regimen was an independent prognostic factor of DFS, whereas recurrence patterns were independent prognostic factors for OS. adjuvant chemotherapy with doublet drug regimen was correlated with longer DFS, and different recurrence modes affect OS.
Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial lung disease with a poor prognosis. However, there are currently few drugs available for its treatment. Nintedanib is clinically effective but is associated with gastrointestinal adverse effects and weight loss. Due to drug intolerance, the overall outcomes of nintedanib therapy are substantially compromised in quite a few patients. In the present study, we synthesized nintedanib-loaded biomimetic liposomes (Nin-lipo) to improve the antifibrotic efficacy and drug tolerance of nintedanib. It was observed that nebulized inhalation of small doses of Nin-lipo (2 mg/kg) resulted in greater delivery efficiency and higher drug concentrations in lung tissue than conventional oral doses of nintedanib (60 mg/kg). Furthermore, Nin-lipo significantly inhibited bleomycin (BLM)-induced pulmonary fibrosis and improved lung function in mice. The possible molecular mechanism of anti-fibrosis by Nin-lipo was investigated. Nin-lipo was found to act mechanistically on alveolar macrophages via alveolar surfactant proteins A and D (SP-A/D) by simulating pulmonary surfactants and inhibiting the polarization of M2 macrophages. These effects thereby reduced the secretion of transforming growth factor 1 (TGF-β1) in macrophages. Moreover, Nin-lipo demonstrated significant efficacy against weight loss and liver function abnormalities in a mouse model caused by nintedanib. Therefore, nebulized Nin-lipo could greatly improve the antifibrotic efficacy of nintedanib while maintaining an excellent safety profile. Nin-lipo could potentially be developed as a new therapy for IPF.
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