Protective effects of fermented Rosa roxburghii Tratt juice against ethanol­induced hepatocyte injury by regulating the NRF2­AMPK signaling pathway in AML­12 cells.

Alcohol­related liver disease (ALD) is a major health concern worldwide. In recent years, there has been growing interest in natural products and functional foods for preventing and treating ALD due to their potential antioxidant and hepatoprotective properties. Rosa roxburghii Tratt, known for its rich content of bioactive compounds, has demonstrated promising health benefits, including anti­inflammatory and antioxidant effects. Fermentation has been utilized as a strategy to enhance the bioavailability and efficacy of natural products. In the present study, using a mixture of Rosa roxburghii Tratt juice, lotus leaf extract and grape seed proanthocyanidins fermented by Lactobacillus plantarum HH­LP56, a novel fermented Rosa roxburghii Tratt (FRRT) juice was discovered that can prevent and regulate ethanol­induced liver cell damage. Following fermentation, the pH was significantly decreased, and the content of VC and superoxide dismutase (SOD) were significantly increased, along with a noticeable enhancement in hydroxyl and 2,2­diphenyl­1­picrylhydrazyl free radical scavenging abilities. Alpha Mouse liver 12 cells were exposed to ethanol for 24 h to establish an in vitro liver cell injury model. The present study evaluated the effects of FRRT on cell damage, lipid accumulation and oxidative stress markers. The results revealed that FRRT pretreatment (cells were pre­treated with 2.5 and 5 mg/ml FRRT for 2 h) significantly reduced lipid accumulation and oxidative stress in liver cells. Mechanistically, FRRT regulated lipid metabolism by influencing key genes and proteins, such as AMP­activated protein kinase, sterol regulatory element binding transcription factor 1 and Stearyl­CoA desaturase­1. Furthermore, FRRT enhanced antioxidant activity by increasing SOD activity, glutathione and catalase levels, while reducing reactive oxygen species and malondialdehyde levels. It also reversed the expression changes of ethanol­induced oxidative stress­related genes and proteins. In conclusion, a novel functional food ingredient may have been discovered with extensive potential applications. These findings indicated that FRRT has antioxidant properties and potential therapeutic benefits in addressing ethanol­induced liver cell damage through its effects on liver lipid metabolism and oxidative stress.

Effects and mechanisms of sciadonic acid on colonic transit function through regulating 5-HT4/cAMP/PKA/AQP4 signaling pathway in STC model mice.

Torreya grandis (T. grandis) oil has been reported to alleviate symptoms of slow transit constipation (STC). However, the impact of sciadonic acid (SA), a distinctive fatty acid found in T. grandis oil, on the pathological progression of STC remains unclear. This study aimed to evaluate the effect of SA on STC and uncover the underlying mechanisms. The STC model was established by feeding Balb/c mice with loperamide. After 2 weeks of intervention, SA significantly improved weight loss and intestinal motility decline induced by STC, along with enhancing plasma indices and reducing colon pathological damage. SA effectively reversed the STC-induced decrease in the 5-HT4/cAMP/PKA/AQP4 signaling pathway genes and expression. Furthermore, 16S rRNA analysis demonstrated that SA mitigated the imbalance of the intestinal microbiota induced by STC, by reducing the ratio of Firmicutes to Bacteroidetes (F/B) and increasing the abundance of beneficial bacteria such as Akkermansia. In conclusion, SA intervention alleviated colonic dysfunction in STC mice. The activation of the SA-mediated 5-HT4/cAMP/PKA/AQP4 signaling pathway may serve as a potential target for STC treatment. These findings suggest that SA holds promise as a treatment option for STC and could potentially be extended to other related gut diseases for further investigation.

Co-occurrence of Erdheim-Chester disease and clonally evolving acute myeloid leukemia with FLT3-ITD and PTPN11 mutations.

Erdheim-Chester disease (ECD) is a rare histiocytosis that tends to co-exist with other myeloid malignancies. Here, we use genetic and transcriptomic sequencing to delineate a case of co-occurring BRAFV600E-mutated ECD and acute myeloid leukemia (AML), followed by AML remission and relapse. The AML relapse involved the extinction of clones with KMT2A-AFDN and FLT3-ITD, and the predominance of PTPN11-mutated subclones with distinct transcriptomic features. This case report has highlighted the screening for other myeloid malignancies at the diagnosis of ECD and the clinical significance of PTPN11-mutated AML subclones that require meticulous monitoring.

Triglyceride levels and risk of cardiovascular disease and all-cause mortality in Chinese adults younger than 40 years old: a prospective cohort study.

Background: Data on the associations of triglyceride (TG) levels with cardiovascular disease (CVD) and all-cause mortality mainly focused on the middle-aged or elderly population, with limited information available for younger adults. This study aimed to identify such associations among Chinese young adults. Methods: This study included Chinese adults younger than 40 years free of CVD, cancer, and lipid-lowering agents at baseline in the Kailuan study who were enrolled during 2006 through 2016. All participants were biennially followed up till December 2020. The enzymatic colorimetric method was used to measure baseline fasting TG. Participants were categorized into four groups by quartiles of TG, with the lowest quartile (Q1) as the reference group. The primary outcomes were CVD [composite of myocardial infarction (MI) and ischemic stroke] and all-cause mortality. CVD and mortality risks were estimated with Cox regression models. Results: A total of 43,882 participants were included. Their mean age was 30.6±5.56 years, and 80.2% were males. During a median follow-up of 11.2 years, 298 CVD events and 345 deaths occurred. The incidences of CVD and all-cause mortality were 0.67 and 0.76 per 1,000 person-years, respectively. Compared with individuals in the lowest quartile (Q1), participants in the highest quartile (Q4) showed a 126% higher risk of developing CVD [adjusted hazard ratio (HR) 2.26; 95% confidence interval (CI): 1.56 to 3.29; P=0.001] and a 61% higher risk of all-cause mortality (adjusted HR 1.61; 95% CI: 1.14 to 2.28; P=0.007). In addition, analyses of CVD subtypes showed that adjusted HRs (Q4 vs. Q1) were 3.25 (95% CI: 1.33 to 7.97; P=0.01) for MI, and 1.88 (95% CI: 1.16 to 3.04; P=0.01) for ischemic stroke. Conclusions: Among Chinese young adults, elevated fasting TG levels were associated with increased CVD and all-cause mortality risks.

Xie Zhuo Tiao Zhi formula ameliorates chronic alcohol-induced liver injury in mice.

This study aimed to evaluate the protective role and potential mechanisms of Xie Zhuo Tiao Zhi decoction (XZTZ) on alcohol-associated liver disease (ALD). XZTZ significantly alleviated alcohol-induced liver dysfunction, based on histological examinations and biochemical parameters after 4-week administration. Mechanically, alcohol-stimulated hepatic oxidative stress was ameliorated by XZTZ, accompanied by the improvement of Nrf2/Keap1 expression and alcohol-activated phosphorylation of pro-inflammatory transcription factors, including JNK, P38, P65, and IκBα, were rescued by XZTZ. In conclusion, XZTZ demonstrates potential in alleviating alcohol-induced liver injury, oxidative stress, and inflammation possibly through modulation of Nrf2/Keap1 and MAPKs/NF-κB signaling pathways, suggesting its potential as a therapeutic option for patients with alcoholic liver disease.

18 F-Florbetapir PET/CT and 68 Ga-FAPI PET/CT in a Case of Light Chain Amyloidosis With Predominant Multiple Tumor-Like Deposits.

ABSTRACT: A 66-year-old man presented with multiple masses in different regions, including the left groin, back subcutaneous area, and lungs. Pathological examination confirmed localized amyloid deposits after 3 surgeries. Serum-free λ light chains were elevated. To evaluate systemic involvement, the patient underwent 18 F-Florbetapir PET/CT and 68 Ga-FAPI-04 PET/CT. Both scans showed increased uptake in multiple masses and nodules throughout the body. This report presents a rare case of light chain (AL) amyloidosis, primarily characterized by multiple localized tumor-like deposits with high activity on 18 F-Florbetapir PET/CT and 68 Ga-FAPI-04 PET/CT.

Torreya grandis Kernel Oil Alleviates Loperamide-Induced Slow Transit Constipation via Up-Regulating the Colonic Expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R in BALB/c Mice.

SCOPE: Torreya grandis kernel has traditionally been used to remove intestinal parasites and increases intestinal motility. However, the effect of Torreya grandis kernel oil (TKO) on constipation has not yet been investigated. Therefore, mouse model is used to investigate the effect of TKO on slow transit constipation (STC) and its possible mechanism. METHODS AND RESULTS: The effects of TKO on intestinal motility of STC mice are evaluated by fecal weight, fecal water content, colon length, defecation test, and intestinal propulsion test. The mechanism of TKO alleviating STC is explored by detecting biochemical analysis, histological analysis, western blot, qRT-PCR, immunohistochemistry, and gut microbiota analysis. The results reveal that TKO effectively promotes defecation and intestinal motility, increases the level of endothelin-1, and restores the histopathological morphology of the colon under LOP pretreatment. The expression levels of occludin, claudin-1, and zonula occludens-1 (ZO-1) mRNA and protein are up-regulated in mice receiving TKO treatment. The colonic 5-hydroxytryptamine 3R/4R (5-HT3R/5-HT4R) expressions are also increased by TKO supplementation. Additionally, TKO rescues LOP-caused disorders of the gut microbiota. CONCLUSION: Consumption of TKO is beneficial to STC recovery, and it can alleviate LOP-induced STC by up-regulating the colonic expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R.

Patterns of Circulating Microbiota during the Acute Phase Following ST-Segment Elevation Myocardial Infarction Predict Long-Term Cardiovascular Events.

Limited information exists regarding whether circulating microbiota could predict long-term clinical outcomes following ST-segment elevation myocardial infarction (STEMI). A total of 244 consecutive patients with STEMI were followed for 2.8 years, and 64 first major adverse cardiovascular events (MACEs) were recorded. Both microbiota abundance [Corynebacterium tuberculostearicum (HR, 1.28; 95% CI, 1.03-1.58) and Staphylococcus aureus (S. aureus) (HR, 1.16; 95% CI, 1.02-1.33) ] and microbiota clusters (Cluster 2 versus Cluster 1: HR, 1.84; 95% CI, 1.04-3.27) could independently predict MACE. Furthermore, a model based on established independent predictors alone was significantly improved by the addition of different microbiota patterns. In addition, CD14++CD16+ monocytes (Mon2) had a significant mediation effect on the microbiota patterns → MACE association. The present study demonstrated that the abundance and clusters of circulating microbiota are associated with future adverse cardiovascular events independent of traditional risk factors, which were partially mediated by an increase in Mon2.

Comparison of Baseline 68Ga-FAPI and 18F-FDG PET/CT for Prediction of Response and Clinical Outcome in Patients with Unresectable Hepatocellular Carcinoma Treated with PD-1 Inhibitor and Lenvatinib.

Fibroblast activation protein contributes to immunosuppression and resistance to immunotherapies. This study aimed to compare baseline 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT and 18F-FDG PET/CT in response and survival prediction in unresectable hepatocellular carcinoma (uHCC) patients treated with the combination of programmed cell death 1 (PD-1) inhibitor and lenvatinib. Methods: In this prospective cohort study, 22 patients with uHCC who underwent baseline 18F-FDG and 68Ga-FAPI PET/CT and soon began taking a combination of PD-1 inhibitor and lenvatinib were recruited. Semiquantitative indices of baseline PET/CT were measured as 18F-FDG SUVmax, metabolic tumor volume, total lesion glycolysis, 68Ga-FAPI SUVmax, 68Ga-FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF). The primary endpoint was durable or nondurable clinical benefit after treatment, and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: The overall response rate of the combination therapy was 41% (9/22). Fifty percent of patients had durable clinical benefit. Median PFS and OS were 4.8 and 14.4 mo, respectively. Patients with nondurable clinical benefit showed a significantly higher FTV and TLF than those with durable clinical benefit, whereas 18F-FDG parameters overlapped. A higher 68Ga-FAPI-avid tumor burden (FTV > 230.46 cm3 or TLF > 961.74 SUVbody weight⋅cm3) predicted both shorter PFS (4.0 vs. 13.5 mo, P = 0.016) and shorter OS (7.8 mo vs. not reached, P = 0.030). Patients with a higher metabolic tumor burden (metabolic tumor volume > 206.80 cm3 or total lesion glycolysis > 693.53 SUVbody weight⋅cm3) showed a shorter OS although the difference did not reach statistical significance (P = 0.085). In multivariate analysis, a higher 68Ga-FAPI-avid tumor burden (hazard ratio [HR], 3.88 [95% CI, 1.26-12.01]; P = 0.020) and macrovascular invasion (HR, 4.00 [95% CI, 1.06-15.14]; P = 0.039) independently predicted a shorter PFS, whereas a higher 68Ga-FAPI-avid tumor burden (HR, 5.92 [95% CI, 1.19-29.42]; P = 0.035) and bone metastases (HR, 5.88 [95% CI, 1.33-25.93]; P = 0.022) independently predicted a shorter OS. Conclusion: Volumetric indices on baseline 68Ga-FAPI PET/CT were potentially independent prognostic factors to predict durable clinical benefit, PFS, and OS in uHCC patients treated with a combination of PD-1 and lenvatinib. Baseline 68Ga-FAPI PET/CT may facilitate uHCC patient selection before combination therapy.

Assessment of knowledge, attitude, and practice of sexual health among students in a Chinese medical college: a cross-sectional study.

Background: Sexual health is an essential part of overall well-being, and medical students' sexual education, level of sexual knowledge, and attitudes toward sexual health will affect their sexual behavior. Aim: To explore the correlation among medical decision tendency, sex education level, and sexual health KAP (knowledge, attitudes, and practices). Methods: We conducted a cross-sectional survey in March 2019. Data were collected via online surveys with a self-developed questionnaire covering sexual KAP and sexual education. We used Spearman correlation to assess the effect of sexual education on KAP after scoring the related questions. Outcomes: Outcomes included descriptive analysis and correlation of medical and nursing students' KAP and education regarding sexual health. Results: Medical and nursing students hold a high level of sexual knowledge (74.8%) and a positive attitude toward premarital sex (87.5%) and homosexuality (94.5%). By conducting the correlation analysis, we observed that medical and nursing students' tendency to support friends' homosexuality was positively correlated with the view that medical intervention for transgender or gay/lesbian people is unnecessary (P < .01). A positive correlation was also found between medical and nursing students who want more diverse sexual education and who would tend to provide patients with more humanistic care regarding their sexual needs (P < .01). Clinical Translation: Medical and nursing students who want more diverse sexual education and who had higher scores in the sexual knowledge test tend to provide their patients with more humanistic care regarding sexual needs. Strengths and Limitations: The research shows the current situation of medical and nursing students' sexual education experience and preference and sexual knowledge, attitudes, and behavior. Heat maps were used to more intuitively describe the correlation between medical students' characteristics and their sexual knowledge, attitudes, and behaviors and sex education. The results may not be generalizable across China, as the participants were from 1 medical school. Conclusion: It is essential to provide sexual education for medical and nursing students to ensure a more humanistic approach to patient care regarding sexual needs; therefore, we recommend that medical schools invest in sexual education for medical and nursing students throughout their education.

Metabolic Tumor Volume Measured by 18F-FDG PET/CT is Associated with the Survival of Unresectable Hepatocellular Carcinoma Treated with PD-1/PD-L1 Inhibitors Plus Molecular Targeted Agents.

Purpose: The combination of PD-1/PD-L1 inhibitors and molecular targeted agents showed promising efficacy for unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the prognostic value of metabolic parameters from 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in patients with uHCC underwent the combined therapies. Patients and Methods: Patients with uHCC treated with a combination of immunotherapy and targeted therapy who underwent baseline 18F-FDG PET/CT between July 2018 and December 2021 were recruited retrospectively. The metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake values (SUVmax), and clinical and biological parameters were recorded. A multivariate prediction model was developed for overall survival (OS) using these parameters together with clinical prognostic factors. Results: Seventy-seven patients were finally included. The median OS was 16.8 months. We found that a high MTV (≥39.65 cm3 as the median value) was significantly associated with OS (P<0.05). In multivariate analyses for OS, a high MTV, high Eastern Cooperative Oncology Group performance status (ECOG-PS, ≥1), Child-Pugh (B-C) grade, and the presence of bone metastasis were significantly associated with poor OS (HR 1.371, HR 3.73, HR 15.384, and HR 2.994, all P<0.05, respectively). A multivariate prognostic model including MTV and prognostic factors, such as ECOG-PS, Child-Pugh grade, and bone metastasis, further improved the identification of different OS subgroups. Conclusion: High MTV is an adverse prognostic factor in patients with uHCC treated with a combination of immunotherapy and molecular targeted agents. Integrating PET/CT parameters with clinical prognostic factors could help to personalize immunotherapy.

Single-cell transcriptome analysis reveals stem cell-like subsets in the progression of Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia (WM) is an uncommon lymphoproliferative disorder, and the precise cellular landscape and the mechanisms of progression from IgM monoclonal gammopathy of undetermined significance (MGUS) to WM remain unclear. We performed single-cell RNA sequencing of CD19 + and CD19-CD38 + cells from healthy donors, IgM MGUS and WM patients. We found that samples from IgM MGUS and WM patients were composed of fewer early B-cell subsets and more T cells and NK cells than those from healthy controls. Compared with those of IgM MGUS patients, mature B cells of WM patients showed upregulation of HES1, GADD45B, NEAT1, DUSP22, RGS1, RGS16, and PIM1. We also identified a subpopulation of CD3 + CD19 + cells in IgM MGUS and WM patients, and trajectory analysis suggested that this subpopulation might be a stem cell-like subset. Further targeted gene sequencing of CD3 + CD19 + and CD3-CD19 + cells proved that MYD88 might be the early events in tumorigenesis according to variant allele fraction analysis. Additional subclonal hits such as CXCR4 and MAP2K1 mutations could be acquired during tumor progression. CXCL signaling, CCL signaling, IL2 signaling and TGFß signaling pathways were involved in communication between CD3 + CD19 + cells and other immune cells. Our findings reveal the composition of CD38 + immune microenvironment together with B cells and plasma cells in IgM MGUS and WM patients, and provide comprehensive insights into mechanisms of progression from IgM MGUS to WM. The rare CD3 + CD19 + cells might be cells with "stemness" feature.

Exosomal circ-PTPN22 and circ-ADAMTS6 mark T cell exhaustion and neutrophil extracellular traps in Asian intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a liver tumor featured by challenges of non-invasive early diagnosis and a higher prevalence rate in Asian countries. These characteristics necessitate the development of liquid biopsy and immunotherapy methods to improve the prognosis of patients with ICC. Herein, we conducted a pilot study on the transcriptome of tumor tissues, adjacent normal tissues, and plasma exosomes of Asian patients with ICC from northern and southern China. We identified a subgroup of immunogenic Asian ICC, which is different from Caucasian ICC and is characterized by T cell exhaustion and neutrophil extracellular traps. The levels of circ-PTPN22 (hsa_circ_0110529) and circ-ADAMTS6 (hsa_circ_0072688), potential circRNA biomarkers, were elevated in the ICC tumor tissues and plasma exosomes of this subgroup than in the other subgroups and normal controls. These circRNAs were derived from post-transcriptional backsplicing of PTPN22 and ADAMTS6 that were expressed in T cells and endothelial cells, respectively, in the ICC microenvironment. Our results revealed a subgroup of Asian ICC characterized by T cell exhaustion and neutrophil extracellular traps and marked by elevated levels of circ-PTPN22 and circ-ADAMTS6 in tumor tissues and plasma exosomes. This subgroup is potentially detectable by plasma exosomal circRNAs and treatable with immune checkpoint blockade.

Donor-Derived Infection's Prevention and Control in Kidney Transplantation.

BACKGROUND: The study aimed to summarize the experience of donor selection and recipient therapy in the face of potential donor-derived infections and improve the quality of donor organ utilization, which would help reduce the risk of infection after recipient operation and decrease the risk of loss or even death of recipient kidney transplantation. METHODS: In this study, 132 kidneys from 70 donors and their recipients who underwent surgery between July 2017 and January 2021 were studied to perform a retrospective analysis of their etiologic examination results and treatment process. RESULTS: In the 70 donors, only 25 had negative etiologic examination results, accounting for 35.71%. Among the 132 recipients, 31.82% had positive culture results, 3 (2.27%) experienced donor-derived infections, and one died. CONCLUSIONS: Although infection in the donor before the donation is quite common, the incidence of donor-derived infections is relatively low. The targeted and preventive application of adequate sensitive antibiotics in the whole course of therapy was the cornerstone for treating recipients at potential risk of potential donor-derived infection. The changes in infection indicators in the recipient should be closely monitored, which would guide medication adjustments timely. These measures could, to a great degree, ensure the prognosis of the recipient, in turn reducing the adverse events caused by donor-derived infections.

Feasibility of 68Ga-Labeled Fibroblast Activation Protein Inhibitor PET/CT in Light-Chain Cardiac Amyloidosis.

BACKGROUND: Systemic amyloid light chain (AL) amyloidosis is the most common type of amyloidosis, leading to cardiomyocyte necrosis and interstitial fibrosis. Gallium-68-labeled fibroblast activation protein inhibitor 04 (68Ga-FAPI-04) has recently been introduced for imaging fibroblast activation in cardiac diseases. To date, cardiac fibroblast and cardiac amyloidosis (CA) phenotype activities have not been mapped. OBJECTIVES: The aim of this study was to evaluate the feasibility of 68Ga-FAPI-04 positron emission tomography (PET)/computed tomography (CT) in assessing AL CA. METHODS: Thirty consecutive patients (mean age: 59.1 ± 7.7 years; 20 men, 10 women) with biopsy-proven AL amyloidosis were enrolled prospectively (including 27 with AL CA and 3 without AL CA). All patients underwent 68Ga-FAPI-04 PET/CT (107.4 ± 26.5 MBq). Global standardized uptake values and left ventricular (LV) molecular volume were calculated in correlation to echocardiography (n = 30), cardiac magnetic resonance (n = 18), and clinical biomarkers. Subsequently, the patients were categorized as having patchy (PET-patchy), extensive (PET-extensive), and negative (PET-negative) patterns. RESULTS: Of all patients, 80% (24 of 30) showed increased LV uptake (PET-patchy [n = 4] vs PET-extensive [n = 20]), whereas 6 patients did not show visible myocardial uptake. Standardized uptake value ratio and LV molecular volume were significantly higher in the PET-extensive than the PET-patchy group (2.79 mL ± 1.22 mL vs 1.53 mL ± 0.66 mL [P = 0.045] and 198.3 mL ± 59.97 mL vs 127.8 mL ± 25.82 [P = 0.005], respectively). Additionally, 68Ga-FAPI-04 uptake was significantly correlated with clinical biomarkers (Mayo stage and N-terminal pro-brain natriuretic peptide), interventricular septal thickness, left ventricular ejection fraction (LVEF), LV end-systolic volume, extracellular volume, and LV global strain (P < 0.05). CONCLUSIONS: 68Ga-FAPI-04 PET/CT is feasible in detecting myocardial fibroblast activation in patients with AL CA in correlation with myocardial remodeling. It might provide complementary information on cardiac molecular characterization and staging of disease.

Cognitive psychology-based artificial intelligence review.

Most of the current development of artificial intelligence is based on brain cognition, however, this replication of biology cannot simulate the subjective emotional and mental state changes of human beings. Due to the imperfections of existing artificial intelligence, this manuscript summarizes and clarifies that artificial intelligence system combined with cognitive psychology is the research direction of artificial intelligence. It aims to promote the development of artificial intelligence and give computers human advanced cognitive abilities, so that computers can recognize emotions, understand human feelings, and eventually achieve dialog and empathy with humans and other artificial intelligence. This paper emphasizes the development potential and importance of artificial intelligence to understand, possess and discriminate human mental states, and argues its application value with three typical application examples of human-computer interaction: face attraction, affective computing, and music emotion, which is conducive to the further and higher level of artificial intelligence research.

Machine Learning-Based Comparative Analysis of Pan-Cancer and Pan-Normal Tissues Identifies Pan-Cancer Tissue-Enriched circRNAs Related to Cancer Mutations as Potential Exosomal Biomarkers.

A growing body of evidence has shown that circular RNA (circRNA) is a promising exosomal cancer biomarker candidate. However, global circRNA alterations in cancer and the underlying mechanism, essential for identification of ideal circRNA cancer biomarkers, remain under investigation. We comparatively analyzed the circRNA landscape in pan-cancer and pan-normal tissues. Using co-expression and LASSO regularization analyses, as well as a support vector machine, we analyzed 265 pan-cancer and 319 pan-normal tissues in order to identify the circRNAs with the highest ability to distinguish between pan-cancer and pan-normal tissues. We further studied their expression in plasma exosomes from patients with cancer and their relation with cancer mutations and tumor microenvironment landscape. We discovered that circRNA expression was globally reduced in pan-cancer tissues and plasma exosomes from cancer patients than in pan-normal tissues and plasma exosomes from healthy controls. We identified dynein axonemal heavy chain 14 (DNAH14), the top back-spliced gene exclusive to pan-cancer tissues, as the host gene of three pan-cancer tissue-enriched circRNAs. Among these three circRNAs, chr1_224952669_224968874_+ was significantly elevated in plasma exosomes from hepatocellular carcinoma and colorectal cancer patients. It was also related to the cancer mutation chr1:224952669: G>A, a splice acceptor variant, and was increasingly transcription-driven in cancer tissues. Moreover, pan-cancer tissue-enriched and pan-normal tissue-enriched circRNAs were associated with distinct tumor microenvironment patterns. Our machine learning-based analysis provides insights into the aberrant landscape and biogenesis of circRNAs in cancer and highlights cancer mutation-related and DNAH14-derived circRNA, chr1_224952669_224968874_+, as a potential cancer biomarker.

Multiomics metabolic and epigenetics regulatory network in cancer: A systems biology perspective.

Genetic, epigenetic, and metabolic alterations are all hallmarks of cancer. However, the epigenome and metabolome are both highly complex and dynamic biological networks in vivo. The interplay between the epigenome and metabolome contributes to a biological system that is responsive to the tumor microenvironment and possesses a wealth of unknown biomarkers and targets of cancer therapy. From this perspective, we first review the state of high-throughput biological data acquisition (i.e. multiomics data) and analysis (i.e. computational tools) and then propose a conceptual in silico metabolic and epigenetic regulatory network (MER-Net) that is based on these current high-throughput methods. The conceptual MER-Net is aimed at linking metabolomic and epigenomic networks through observation of biological processes, omics data acquisition, analysis of network information, and integration with validated database knowledge. Thus, MER-Net could be used to reveal new potential biomarkers and therapeutic targets using deep learning models to integrate and analyze large multiomics networks. We propose that MER-Net can serve as a tool to guide integrated metabolomics and epigenomics research or can be modified to answer other complex biological and clinical questions using multiomics data.