Supercoiled DNA percentage: A key in-process control of linear DNA template for mRNA drug substance manufacturing.

The development of messenger RNA (mRNA) vaccines and therapeutics necessitates the production of high-quality in vitro-transcribed mRNA drug substance with specific critical quality attributes (CQAs), which are closely tied to the uniformity of linear DNA template. The supercoiled plasmid DNA is the precursor to the linear DNA template, and the supercoiled DNA percentage is commonly regarded as a key in-process control (IPC) during the manufacturing of linear DNA template. In this study, we investigate the influence of supercoiled DNA percentage on key mRNA CQAs, including purity, capping efficiency, double-stranded RNA (dsRNA), and distribution of poly(A) tail. Our findings reveal a significant impact of supercoiled DNA percentage on mRNA purity and in vitro transcription yield. Notably, we observe that the impact on mRNA purity can be mitigated through oligo-dT chromatography, alleviating the tight range of DNA supercoiled percentage to some extent. Overall, this study provides valuable insights into IPC strategies for DNA template chemistry, manufacturing, and controls (CMC) and process development for mRNA drug substance.

LncRNA NEAT1/miR-211/IL-10 Axis Regulates Inflammation of Peripheral Blood Mononuclear Cells in Acute Myocardial Infarction.

This study aimed to explore the expression of long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) in patients with acute myocardial infarction (AMI) and its inflammatory regulation mechanism through miR-211/interleukin 10 (IL-10) axis.A total of 75 participants were enrolled in this study: 25 healthy people in the control group, 25 patients with stable angina pectoris (SAP) in the SAP group, and 25 patients with AMI in the AMI group. Real-time qPCR was used to detect mRNA expression levels of NEAT1, miR-211, and IL-10. The interaction between miR-211, NEAT1, and IL-10 was confirmed by dual-luciferase reporter assay, and protein expression was detected using western blot.High expression of NEAT1 in peripheral blood mononuclear cells (PBMCs) of patients with AMI was negatively related to serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor-α (TNF-α), IL-6, and IL-1ß and was positively correlated with left ventricular ejection fraction (LVEF). In THP-1 cells, miR-211 was confirmed to target and inhibit IL-10 expression. NEAT1 knockdown and miR-211-mimic markedly decreased IL-10 protein levels, whereas anti-miR-211 markedly increased IL-10 protein levels. Importantly, miR-211 level was negatively related to NEAT1 and IL-10 levels, whereas IL-10 level was positively related to the level of NEAT1 expression in PBMCs of patients with AMI.LncRNA NEAT1 was highly expressed in PBMCs of patients with AMI, and NEAT1 suppressed inflammation via miR-211/IL-10 axis in PBMCs of patients with AMI.

Nasopharyngeal carcinoma with leptomeningeal metastases has been treated with comprehensive treatment for long-term survival: A case report and literature review.

RATIONALE: Nasopharyngeal carcinoma has a high incidence in East and Southeast Asia, often with distant metastasis. However, leptomeningeal metastasis (LM) is extremely rare and usually has a poor prognosis. This paper reports the clinical treatment of a patient with meningeal metastasis of nasopharyngeal carcinoma (NPC) in order to improve the clinician's understanding of the disease. Early diagnosis of the disease can alleviate the pain of patients and prolong their survival time. PATIENT CONCERNS: We report the case of a 55-year-old female with a history of NPC with LM. Brain magnetic resonance imaging showed temporal lobe enhancement, peripheral edema, and enhancement of the adjacent meninges. Cerebrospinal fluid cytology suggests the presence of malignant tumor cells. DIAGNOSES: The patient was diagnosed with LM from NPC. INTERVENTIONS: The patients were regularly given targeted therapy with nimotuzumab, immunotherapy with karyolizumab, and lumbar intrathecal methotrexate chemotherapy and supportive treatment. OUTCOMES: The patient had survived for 3 years since the diagnosis of LM and was in good condition and still under active antitumor treatment. LESSONS: Leptomeningeal metastasis of NPC is a rare disease. Although there is currently no unified treatment plan, the neurological symptoms can still be controlled and the quality of life can be improved through active treatment.

Mediating effect of adiponectin between free fatty acid and tumor necrosis factor-α in patients with diabetes.

BACKGROUND/OBJECTIVES: Increased free fatty acid (FFA) promotes adiponectin secretion in healthy subjects and induces inflammation in diabetes. Given the potential pro-inflammatory role of adiponectin in "adiponectin paradox", we performed this study in patients with type 2 diabetes mellitus (T2DM) to assess the association of FFA with adiponectin and to investigate whether adiponectin mediates FFA-related inflammation. METHODS: This cross-sectional study consisted of adult patients with T2DM. FFA, adiponectin, and tumor necrosis factor-α (TNF-α) were assayed from fasting venous blood after overnight fasting for at least 8 h. Multivariable linear regression analysis and restricted cubic splines (RCS) analysis were performed to identify the association between FFA and adiponectin. Mediation analysis was performed to determine the mediating effect of adiponectin on the association between FFA and TNF-α. RESULTS: This study included 495 participants, with 332 males (67.1%) and a mean age of 47.0 ± 11.2 years. FFA was positively associated with adiponectin (b = 0.126, 95%CI: 0.036-0.215, P = 0.006) and was the main contributor to the increase of adiponectin (standardized b = 0.141). The RCS analysis demonstrated that adiponectin increased with FFA when FFA was less than 0.7 mmol/L but did not further increase thereafter (Poverall < 0.001 and Pnon-linear < 0.001). In addition, adiponectin mediated the association between FFA and TNF-α. The mediating effect was 0.08 (95%CI: 0.03-0.13, P = 0.003) and the mediating effect percentage was 26.8% (95%CI: 4.5-49.2, P = 0.02). CONCLUSIONS: In patients with T2DM, FFA was positively associated with adiponectin when FFA was less than 0.7 mmol/L. Elevated adiponectin mediated FFA-related inflammation. This study may provide insights into the pro-inflammatory effect of adiponectin in T2DM.

Exosomal circ50547 as a potential marker and promotor of gastric cancer progression via miR-217/HNF1B axis.

BACKGROUND: Exosomes, one of small extracellular vesicles, play a vital role in cell to cell communication and contribute to the advancement of tumors through their cargo molecules. Exosomal circRNAs have emerged as significant players in various types of tumors. Thus, this study aimed to investigate how exosomal circRNAs are involved in the diagnosis and progression of gastric cancer (GC). METHODS: Serum exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis and Western blot. CCK-8, colony formation and transwell assays were conducted to study the function of hsa_circ_0050547 (named as circ50547). qRT-PCR was used to quantify the expression of circ50547 in GC tissues and serum exosomes. Fluorescence in situ hybridization was applied to detect the cellular distribution of circ50547. Stemness and drug-resistance were detected by sphere formation, WB, flow cytometry and half-maximal inhibitory concentration analyses. Bioinformatic analyses, luciferase experiments, qRT-PCR and WB were used to investigate molecular mechanisms. RESULTS: We discovered for the first time a new type of GC-derived exosomal circRNA, circ50547. We found that circ50547 is highly expressed in both GC tissues and serum exosomes. Interestingly, we observed that the diagnostic value of exosomal circ50547 is superior to that of serum circ50547. Circ50547 overexpression enhanced the proliferation, migration, invasion, stemness and drug resistance of GC cells, while knockdown of circ50547 showed the opposite effect. Mechanistically, circ50547 acted as a sponge for miR-217 to regulate the expression of HNF1B, which promoted gastric cancer progression. CONCLUSION: Exosomal circ50547 may be a promising marker for the diagnosis and prognosis prediction of GC. These findings suggest that it plays an oncogenic role through miR-217/HNF1B signaling pathway in GC.

Cordyceps militaris Extract and Cordycepin Alleviate Oxidative Stress, Modulate Gut Microbiota and Ameliorate Intestinal Damage in LPS-Induced Piglets.

Cordycepin is considered a major bioactive component in Cordyceps militaris extract. This study was performed to evaluate the ameliorative effect of Cordyceps militaris extract (CME) and cordycepin (CPN) supplementation on intestinal damage in LPS-challenged piglets. The results showed that CPN or CME supplementation significantly increased the villus height (p < 0.01) and villus height/crypt depth ratio (p < 0.05) in the jejunum and ileum of piglets with LPS-induced intestinal inflammation. Meanwhile, CPN or CME supplementation alleviated oxidative stress and inflammatory responses by reducing the levels of MDA (p < 0.05) and pro-inflammatory cytokines in the serum. Additionally, supplementation with CPN or CME modulated the structure of the intestinal microbiota by enriching short-chain fatty acid-producing bacteria, and increased the level of butyrate (p < 0.05). The RNA-seq results demonstrated that CME or CPN altered the complement and coagulation-cascade-related genes (p < 0.05), including upregulating gene KLKB1 while downregulating the genes CFD, F2RL2, CFB, C4BPA, F7, C4BPB, CFH, C3 and PROS1, which regulate the complement activation involved in inflammatory and immune responses. Correlation analysis further demonstrated the potential relation between the gut microbiota and intestinal inflammation, oxidative stress, and butyrate in piglets. In conclusion, CPN or CME supplementation might inhibit LPS-induced inflammation and oxidative stress by modulating the intestinal microbiota and its metabolite butyrate in piglets.

Erratum: Circular RNA Hsa_circRNA_101996 promotes the development of Gastric Cancer via Upregulating Matrix Metalloproteinases-2/Matrix Metalloproteinases-9 through MicroRNA-143/Ten-eleven translocation-2 Pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.62121.].

A dynamic visualization clinical tool constructed and validated based on the SEER database for screening the optimal surgical candidates for bone metastasis in primary kidney cancer.

The implementation of primary tumor resection (PTR) in the treatment of kidney cancer patients (KC) with bone metastases (BM) has been controversial. This study aims to construct the first tool that can accurately predict the likelihood of PTR benefit in KC patients with BM (KCBM) and select the optimal surgical candidates. This study acquired data on all patients diagnosed with KCBM during 2010-2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was utilized to achieve balanced matching of PTR and non-PTR groups to eliminate selection bias and confounding factors. The median overall survival (OS) of the non-PTR group was used as the threshold to categorize the PTR group into PTR-beneficial and PTR-Nonbeneficial subgroups. Kaplan-Meier (K-M) survival analysis was used for comparison of survival differences and median OS between groups. Risk factors associated with PTR-beneficial were identified using univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC), area under the curve (AUC), calibration curves, and decision curve analysis (DCA) were used to validate the predictive performance and clinical utility of the nomogram. Ultimately, 1963 KCBM patients meeting screening criteria were recruited. Of these, 962 patients received PTR and the remaining 1061 patients did not receive PTR. After 1:1 PSM, there were 308 patients in both PTR and non-PTR groups. The K-M survival analysis results showed noteworthy survival disparities between PTR and non-PTR groups, both before and after PSM (p < 0.001). In the logistic regression results of the PTR group, histological type, T/N stage and lung metastasis were shown to be independent risk factors associated with PTR-beneficial. The web-based nomogram allows clinicians to enter risk variables directly and quickly obtain PTR beneficial probabilities. The validation results showed the excellent predictive performance and clinical utility of the nomograms for accurate screening of optimal surgical candidates for KCBM. This study constructed an easy-to-use nomogram based on conventional clinicopathologic variables to accurately select the optimal surgical candidates for KCBM patients.

Assessment and evaluation of online education and virtual simulation technology in dental education: a cross-sectional survey.

BACKGROUND: The global outbreak of coronavirus disease (COVID-19) has led medical universities in China to conduct online teaching. This study aimed to assess the effectiveness of a blended learning approach that combines online teaching and virtual reality technology in dental education and to evaluate the acceptance of the blended learning approach among dental teachers and students. METHODS: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist was followed in this study. A total of 157 students' perspectives on online and virtual reality technology education and 54 teachers' opinions on online teaching were collected via questionnaires. Additionally, 101 students in the 2015-year group received the traditional teaching method (TT group), while 97 students in the 2017-year group received blended learning combining online teaching and virtual reality technology (BL group). The graduation examination results of students in the two groups were compared. RESULTS: The questionnaire results showed that most students were satisfied with the online course and the virtual simulation platform teaching, while teachers held conservative and neutral attitudes toward online teaching. Although the theoretical score of the BL group on the final exam was greater than that of the TT group, there was no significant difference between the two groups (P = 0.805). The skill operation score of the BL group on the final exam was significantly lower than that of the TT group (P = 0.004). The overall score of the BL group was lower than that of the TT group (P = 0.018), but the difference was not statistically significant (P = 0.112). CONCLUSIONS: The blended learning approach combining online teaching and virtual reality technology plays a positive role in students' learning and is useful and effective in dental education.

Radiofrequency ablation using the ThermoCool SmartTouch Catheter guided by ablation index versus antiarrhythmic drugs in atrial fibrillation treatment in China: a cost-consequence analysis.

Aim: To evaluate the costs and consequences of two front-line atrial fibrillation (AF) treatments from Chinese healthcare system perspective: radiofrequency catheter ablation (RFCA) using ThermoCool SmartTouch Catheter guided by Ablation Index (STAI), in comparison to antiarrhythmic drugs (AADs). Patients & methods: We simulated clinical and economic consequences for AF patients initially receiving STAI or AADs using a short-term decision tree model leading to a 10-year long-term Markov model. The model projected both clinical consequences and costs associated with, among others, AF, heart failure (HF), strokes, and deaths due to AF or AF related complications. Data informing the models included combination of a local real-world study and published clinical studies. Results: STAI was advantageous versus AADs on all 4 main clinical outcomes evaluated; AF: 25.83% lower (12.84% vs 38.67%), HF: 2.22% lower (1.33% vs 3.55%), stroke or post stroke: 1.82% lower (10.00% vs 11.82%) and deaths due to AF or AF related complications: 0.64% lower (4.11% vs 4.75%). The average total cost per patient in STAI group was ¥16,682 lower (¥123,124 vs ¥139,806). The one-way sensitivity analysis indicated that the difference in total cost was most sensitive to annual AF recurrence probability in AADs-treated patients. Probabilistic sensitivity analysis indicated a 98.5% probability that RFCA treatment would result in cost savings by the end of the 10th year. Conclusion: Radiofrequency catheter ablation using SmartTouch catheter guided by Ablation Index was superior to AADs as the first-line AF treatment in Chinese setting with better clinical outcomes and at lower costs over a 10-year time horizon.

Circular RNA CDR1as Mediated by Human Antigen R (HuR) Promotes Gastric Cancer Growth via miR-299-3p/TGIF1 Axis.

Background: Gastric cancer (GC) remains a common malignancy worldwide with a limited understanding of the disease mechanisms. A novel circular RNA CDR1as has been recently reported to be a crucial regulator of human cancer. However, its biological role and mechanism in the GC growth are still far from clear. Methods: Small interfering RNAs (siRNAs), lentivirus or plasmid vectors were applied for gene manipulation. The CDR1as effects on the GC growth were evaluated in CCK8 and colony formation assays, a flow cytometry analysis and mouse xenograft tumor models. A bioinformatics analysis combined with RNA immunoprecipitation (RIP), RNA pull-down assays, dual-luciferase reporter gene assays, Western blot, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and functional rescue experiments were used to identify the CDR1as target miRNA, the downstream target gene and its interaction with human antigen R (HuR). Results: The CDR1as overexpression promoted the GC growth in vitro and in vivo and reduced the apoptotic rate of GC cells. Its knockdown inhibited the GC cell proliferation and viability and increased the cell apoptotic rate. Proliferation-related proteins PCNA and Cyclin D1 and apoptosis-related proteins Bax, Bcl-2, Caspase-3 and Caspase-9 were regulated. Mechanically, the cytoplasmic CDR1as acted as a miR-299-3p sponge to relieve its suppressive effects on the GC cell growth. Oncogenic TGIF1 was a miR-299-3p downstream target gene that mediated the promotive effects of CDR1as and regulated the PCNA and Bax levels. HuR interacted with CDR1as via the RRM2 domain and positively regulated the CDR1as level and its oncogenic role as well as downstream target TGIF1. Conclusions: CDR1as promotes the GC growth through the HuR/CDR1as/miR-299-3p/TGIF1 axis and could be used as a new therapeutic target for GC.

Effect of maternal age on foetal chromosomal defects: an investigation based on non-invasive prenatal testing.

BACKGROUND: This study aimed to evaluate the value of non-invasive prenatal testing (NIPT) in the prenatal screening of foetal aneuploidy-associated diseases at different gestational ages. METHODS: Briefly, cell-free foetal DNAs were extracted from plasma first, followed by DNA sequencing and bioinformatics analyses for chromosome aneuploidy (T21, T18, and T13), sex chromosome aneuploidy (SCA), and microdeletion/microduplication. Subsequently, the positive results were subject to karyotype analyses. RESULTS: The pregnant women included in this study were divided into six groups, and the results, such as chromosome diagnoses, and clinical phenotypes, were collected for data analyses. According to the results of the data analysis, the positivity rates of foetal chromosomal abnormalities in pregnant women under 20, 20-24, 25-29, 30-34, 35-39, and >40 years old were 0%, 0.17%, 0.25%, 0.27%, 0.60%, and 1.66%, respectively. The positive predictive value (PPV) in the 20-24 years group was 41.67%, that in the 25-29 years group was 62.5%, that in the 30-34 years group was 66.67%, that in the 35-39 years group was 90.74%, and that in the >40 years group was 90.32%. CONCLUSION: Overall, NIPT detection in elderly pregnant women has excellent clinical application value in reducing the incidence of either birth defects or abortion caused by invasive chromosome examination.

It is critical to diagnose foetal chromosome aneuploidy in time through prenatal screening to prevent birth defects. This study aimed to evaluate the value of non-invasive prenatal testing (NIPT) in prenatal screening of foetal aneuploidy-associated diseases at different gestational ages. A retrospective analysis based on NIPT screening data at a medical laboratory was performed. The results showed that the total positivity rate and total positive predictive value of trisomy 21, trisomy 18, and trisomy 13 in older pregnant women (≥35 years old) were significantly higher than those in younger pregnant women, and there was an increasing trend with increasing maternal ages. This study indicated that NIPT detection in elderly pregnant women has an excellent application value in clinical practice to reduce the incidence of birth defects and abortion caused by invasive chromosome examination.

Cerebrospinal fluid circulating tumour DNA genotyping and survival analysis in lung adenocarcinoma with leptomeningeal metastases.

PURPOSE: The prognosis of patients with leptomeningeal metastasis (LM) remains poor. Circulating tumour DNA (ctDNA) has been proven to be abundantly present in cerebrospinal fluid (CSF); hence, its clinical implication as a biomarker needs to be further verified. METHODS: We conducted a retrospective study of 35 lung adenocarcinoma (LUAD) patients with LM, and matched CSF and plasma samples were collected from all patients. All paired samples underwent next-generation sequencing (NGS) of 139 lung cancer-associated genes. The clinical characteristics and genetic profiling of LM were analysed in association with survival prognosis. RESULTS: LM showed genetic heterogeneity, in which CSF had a higher detection rate of ctDNA (P = 0.003), a higher median mutation count (P < 0.0001), a higher frequency of driver mutations (P < 0.01), and more copy number variation (CNV) alterations (P < 0.001) than plasma. The mutation frequencies of the EGFR, TP53, CDKN2A, MYC and CDKN2B genes were easier to detect in CSF than in LUAD tissue (P < 0.05), possibly reflecting the underlying mechanism of LM metastasis. CSF ctDNA is helpful for analysing the mechanism of EGFR-TKI resistance. In cohort 1, which comprised patients who received 1/2 EGFR-TKIs before the diagnosis of LM, TP53 and CDKN2A were the most common EGFR-independent resistant mutations. In cohort 2, comprising those who progressed after osimertinib and developed LM, 7 patients (43.75%) had EGFR CNV detected in CSF but not plasma. Furthermore, patient characteristics and various genes were included for interactive survival analysis. Patients with EGFR-mutated LUAD (P = 0.042) had a higher median OS, and CSF ctDNA mutation with TERT (P = 0.013) indicated a lower median OS. Last, we reported an LM case in which CSF ctDNA dynamic changes were well correlated with clinical treatment. CONCLUSIONS: CSF ctDNA could provide a more comprehensive genetic landscape of LM, indicating the potential metastasis-related and EGFR-TKI resistance mechanisms of LM patients. In addition, genotyping of CSF combined with clinical outcomes can predict the prognosis of LUAD patients with LM.

Potential causal association between aspirin use and the reduced risk of hayfever or allergic rhinitis: a Mendelian randomization study.

Background: The evidence from observational studies on the association between the use of aspirin and the risk of hayfever or allergic rhinitis is conflicting, with a dearth of high-quality randomized controlled trials. Objective: This study aims to investigate the causal relationship between aspirin use and the risk of hayfever or allergic rhinitis. Methods: We conducted a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We utilized publicly available summary statistics datasets from genome-wide association studies (GWAS) meta-analyses on aspirin use in individuals of European descent (n = 337,159) as the exposure variable, and a GWAS on doctor-diagnosed hayfever or allergic rhinitis in individuals from the UK Biobank (n = 83,529) as the outcome variable. Results: We identified 7 single nucleotide polymorphisms (SNPs) at genome-wide significance from the GWASs associated with aspirin use as instrumental variables (P<5×10-8; linkage disequilibrium r2 <0.1). The IVW method provided evidence supporting a causal association between aspirin use and reduced risk of hayfever or allergic rhinitis (ß = -0.349, SE = 0.1356, P = 0.01008). MR-Egger regression indicated no causal association between aspirin use and hayfever or allergic rhinitis (ß = -0.3742, SE = 0.3809, P = 0.371), but the weighted median approach yielded evidence of a causal association (ß = -0.4155, SE = 0.1657, P = 0.01216). Cochran's Q test and the funnel plot indicated no evidence of heterogeneity and asymmetry, indicating no directional pleiotropy. Conclusion: The findings of the MR analysis support a potential causal relationship between aspirin use and the reduced risk of hayfever or allergic rhinitis.

Construction of novel predictive tools for post-surgical cancer-specific survival probability in patients with primary chondrosarcoma and external validation in Chinese cohorts: a large population-based retrospective study.

BACKGROUND: Surgery is the predominant treatment modality for chondrosarcoma. This study aims to construct a novel clinic predictive tool that accurately predicts the 3-, 5-, and 8-year probability of cancer-specific survival (CSS) for primary chondrosarcoma patients who have undergone surgical treatment. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 982 primary chondrosarcoma patients after surgery, who were randomly divided into two sets: training set (60%) and internal validation set (40%). Cox proportional regression analyses were used to screen post-surgical independent prognostic variables in primary chondrosarcoma patients. These identified variables were used to construct a nomogram to predict the probability of post-surgical CSS of primary chondrosarcoma patients. The k-fold cross-validation method (k = 10), Harrell's concordance index (C-index), receiver operating characteristic curve (ROC) and area under curve (AUC) were used to assess the predictive accuracy of the nomogram. Calibration curve and decision curve analysis (DCA) were used to validate the clinical application of the nomogram. RESULTS: Age, tumor size, disease stage and histological type were finally identified post-surgical independent prognostic variables. Based the above variables, a nomogram was constructed to predict the 3-, 5- and 8-year probability of post-surgical CSS in primary chondrosarcoma patients. The results of the C-index showed excellent predictive performance of the nomogram (training set: 0.837, 95% CI: 0.766-0.908; internal validation set: 0.835, 95% CI: 0.733-0.937; external validation set: 0.869, 95% CI: 0.740-0.998). The AUCs of ROC were all greater than 0.830 which again indicated that the nomogram had excellent predictive performance. The results of calibration curve and DCA indicated that the clinical applicability of this nomogram was outstanding. Finally, the risk classification system and online access version of the nomogram was developed. CONCLUSION: We constructed the first nomogram to accurately predict the 3-, 5- and 8-year probability of post-surgical CSS in primary chondrosarcoma patients. This nomogram would assist surgeons to provide individualized post-surgical survival predictions and clinical strategies for primary chondrosarcoma patients.

Engineered Exosomes for Drug Delivery in Cancer Therapy: A promising approach and application.

A significant amount of research effort is currently focused on investigating the role of exosomes in various cancers. These tiny vesicles, apart from acting as biomarkers, also play a crucial role in tumor formation and development. Several studies have demonstrated that exosomes can be a drug delivery vehicle for cancer therapy. In this paper, we highlight the key advantages of exosomes as a drug delivery candidate, with a particular focus on their low immunogenicity, natural targeting ability and suitable mechanical properties. Furthermore, we propose that the selection of appropriate exosomes and drug loading methods based on therapeutic goals and product heterogeneity is essential for preparing engineered exosomes. We comprehensively analyzed the superiorities of current drug-loading methods to improve the creation of designed exosomes. Moreover, we systematically review the applications of engineered exosomes in various therapies such as immunotherapy, gene therapy, protein therapy, chemotherapy, indicating that engineered exosomes have the potential to be reliable and, safe drug carriers that can address the unmet needs in cancer clinical practice.

The novel dynamic nomogram and risk classification system constructed for predicting post-surgical overall survival and mortality risk in primary chondrosarcoma: a population study based on SEER database.

BACKGROUND: Surgery is the predominant method to improve the prognosis of primary chondrosarcoma patients. We aimed to construct the first reliable nomogram to predict the post-surgical overall survival (OS) of primary chondrosarcoma patients. METHODS: We downloaded all primary chondrosarcoma patients treated with surgery between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database, and randomized them into training set (60%) and validation set (40%). Cox proportional regression analysis was applied to the training set to identify independent prognostic variables, and then constructed a nomogram for predicting 3-, 5-, and 8-year OS. The Harrell's concordance index (C-index), receiver operating characteristic curve (ROC), the area under curve (AUC), calibration curve and decision curve analysis (DCA) was used to assess the predictive efficacy and clinical applicability of the nomogram. The nomogram was also compared with The American Joint Committee on Cancer (AJCC) staging system. RESULTS: A total of 1005 post-surgical primary chondrosarcoma patients were included in this study. We finally identified five independent prognostic variables to construct the nomogram, being age, grade, tumor size, disease stage and histological type. The C-index results showed that the prediction performance of the nomogram was significantly better than the AJCC staging system. In the training set, (C-index: 0.805, 95% CI 0.879-0.730 vs 0.686, 95% CI 0.606-0.766); in the validation set, (C-index: 0.811, 95% CI 0.895-0.727 vs 0.697, 95% CI 0.647-0.799). Additionally, the AUC values generated by the ROC were all greater than 0.8, which also indicated the excellent predictive performance of the nomogram. The calibration curves showed that the predicted survival rate was highly similar to the actual. Time-dependent ROC and DCA showed that the nomogram has better predictive performance and net clinical benefits than the AJCC staging system. Finally, a risk stratification system based on nomogram was constructed. CONCLUSION: We successfully constructed and validated the first nomogram that could reliably predict 3-, 5-, and 8-year post-surgical OS in primary chondrosarcoma patients. Furthermore, the web-based dynamic nomogram could be more conveniently applied to clinic, providing assistance to surgeons and patients.

Web-based nomogram and risk stratification system constructed for predicting the overall survival of older adults with primary kidney cancer after surgical resection.

BACKGROUND: Kidney cancer (KC) is one of the most common malignant tumors in adults which particularly affects the survival of elderly patients. We aimed to construct a nomogram to predict overall survival (OS) in elderly KC patients after surgery. METHODS: Information on all primary KC patients aged more than 65 years and treated with surgery between 2010 and 2015 was downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression analysis was used to identify the independent prognostic factors. Consistency index (C-index), receiver operating characteristic curve (ROC), the area under curve (AUC), and calibration curve were used to assess the accuracy and validity of the nomogram. Comparison of the clinical benefits of nomogram and the TNM staging system is done by decision curve analysis (DCA) and time-dependent ROC. RESULTS: A total of 15,989 elderly KC patients undergoing surgery were included. All patients were randomly divided into training set (N = 11,193, 70%) and validation set (N = 4796, 30%). The nomogram produced C-indexes of 0.771 (95% CI 0.751-0.791) and 0.792 (95% CI 0.763-0.821) in the training and validation sets, respectively, indicating that the nomogram has excellent predictive accuracy. The ROC, AUC, and calibration curves also showed the same excellent results. In addition, DCA and time-dependent ROC showed that the nomogram outperformed the TNM staging system with better net clinical benefits and predictive efficacy. CONCLUSIONS: Independent influencing factors for postoperative OS in elderly KC patients were sex, age, histological type, tumor size, grade, surgery, marriage, radiotherapy, and T-, N-, and M-stage. The web-based nomogram and risk stratification system could assist surgeons and patients in clinical decision-making.

Two novel clinical tools to predict the risk of bone metastasis and overall survival in esophageal cancer patients: a large population-based retrospective cohort study.

BACKGROUND: The aim of this study was to construct two web-based nomograms to predict the probability of bone metastasis (BM) in esophageal cancer (EC) patients and the prognostic of EC patients with BM (ECBM). METHODS: We collected the data of EC and ECBM patients in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2015. Independent risk variables for the development of BM in EC patients were identified using univariate and multivariate logistic regression analyses. Univariate and multivariate Cox regression analyses were used to assess independent prognostic variables in ECBM patients. And then, constructed two nomograms to predict the risk of bone metastases and overall survival (OS) of ECBM patients. Survival differences were studied by Kaplan-Meier (K-M) survival analysis. The predictive efficacy and clinical applicability of these two nomograms were assessed by using receiver operating characteristic (ROC) curve, the area under curve (AUC), calibration curve and decision curve analysis (DCA). RESULTS: We selected a total of 6839 patients with EC, of which 326 (4.77%) had BM at the time of initial diagnosis. The results of K-M survival and Cox regression analysis showed significant effects of BM on the OS in EC patients. Age, N stage, tumor size and brain/liver/lung organ metastasis were identified as BM-related risk variables. Chemotherapy and brain/liver organ metastasis were identified as ECBM-related prognostic variables. The ROC, AUC, calibration curves and DCA of two nomograms all showed excellent predictive efficacy and clinical applicability. CONCLUSIONS: These two nomograms were constructed and validated, which could objectively predict the risk of BM in EC patients and the prognostic in ECBM patients. These tools are expected to make valuable contributions in clinical work, informing surgeons in making decisions about patient care.

Exosomal circRNA: emerging insights into cancer progression and clinical application potential.

Exosomal circRNA serves a novel genetic information molecule, facilitating communication between tumor cells and microenvironmental cells, such as immune cells, fibroblasts, and other components, thereby regulating critical aspects of cancer progression including immune escape, tumor angiogenesis, metabolism, drug resistance, proliferation and metastasis. Interestingly, microenvironment cells have new findings in influencing tumor progression and immune escape mediated by the release of exosomal circRNA. Given the intrinsic stability, abundance, and broad distribution of exosomal circRNAs, they represent excellent diagnostic and prognostic biomarkers for liquid biopsy. Moreover, artificially synthesized circRNAs may open up new possibilities for cancer therapy, potentially bolstered by nanoparticles or plant exosome delivery strategies. In this review, we summarize the functions and underlying mechanisms of tumor cell and non-tumor cell-derived exosomal circRNAs in cancer progression, with a special focus on their roles in tumor immunity and metabolism. Finally, we examine the potential application of exosomal circRNAs as diagnostic biomarkers and therapeutic targets, highlighting their promise for clinical use.