Real-world Effectiveness and Tolerability of Interferon-free Direct-acting Antiviral for 15,849 Patients with Chronic Hepatitis C: A Multinational Cohort Study.

Background and Aims: As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6. Methods: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021. Results: The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12. Conclusions: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).

Preoperative prediction of central lymph node metastasis in follicular variant of papillary thyroid carcinoma using clinical and ultrasound features.

Background: The most common metastatic site of follicular variant of papillary thyroid carcinoma (FVPTC) is the central lymph nodes, which may be associated with the prognosis and survival of patients. In the present study, we establish a combined model based on preoperative clinical and ultrasound (US) features of FVPTC to predict the risk of central lymph node metastasis (CLNM). Methods: From January 2013 to December 2022, 315 patients with FVPTC were enrolled and randomly divided into the training and validation cohorts in a ratio of 7:3. The independent risk factors for CLNM in FVPTC were analysed using univariate and multivariate logistic regression analyses. Then, three different models were established based on clinical and US data. Subsequently, a nomogram was constructed to predict CLNM. Its predictive effect was evaluated via receiver operating characteristic and calibration curve analyses. Results: Backward multivariate regression analysis revealed that age (P=0.001), thyroid peroxidase antibody (TPOAb) (P=0.11), diameter (P=0.047), irregular/lobulated margin (P=0.15), extrathyroidal extension (P=0.001), nodules with macrocalcifications (P=0.009), nodules with microcalcification (P=0.003) and Thyroid Imaging Reporting and Data System (ACR-TI-RADS) category 5 (P=0.33) were independent risk factors for CLNM in FVPTC. The areas under the curve of the matching nomogram in the training (N=221) and validation cohorts (N=94) were 0.841 [95% confidence interval (CI): 0.788-0.895] and 0.735 (95% CI: 0.621-0.872), respectively. Conclusions: Preoperative thyroid US provides useful features for prediction of CLNM. The nomogram constructed based on combining US and clinical features can better predict the risk of CLNM and may facilitate decision-making in clinical settings.

Metal-organic frameworks-based moisture responsive essential oil hydrogel beads for fresh-cut pineapple preservation.

The preservation of fresh-cut fruits and vegetables has attracted attention to the shelf-life reduction caused by high humidity. Herein, alginate/copper ions cross-linking, in-situ growth and self-assembly techniques of metal-organic frameworks (MOFs) were utilized to prepare a moisture responsive hydrogel bead (HKUST-1@ALG). As the multistage porous structure formation, tea tree essential oil (TTO) load capacity in hydrogel bead (TTO-HKUST-1@ALG) was increased from 6.1% to 21.6%. TTO-HKUST-1@ALG had excellent moisture response performance, and the release rates of TTO increased from 33.89% to 70.98% with moisture increasing from 45% to 95%. Besides, TTO-HKUST-1@ALG exhibited excellent antimicrobial, antioxidant capacity, and biocompatibility. During storage, TTO-HKUST-1@ALG effectively improved the cell membrane integrity by maintaining the balance of reactive oxygen species metabolism. The degradation of cell wall structure and tissue softening were delayed by inhibiting the cell wall-degrading enzymes activity. Briefly, TTO-HKUST-1@ALG improved the storage quality and extended shelf-life of fresh-cut pineapple, which was a promising preservative.

The biotic effects of lignite on humic acid components conversion during chicken manure composting.

Targeted regulation of composting to convert organic matter into humic acid (HA) holds significant importance in compost quality. Owing to its low carbon content, chicken manure compost often requires carbon supplements to promote the humification progress. The addition of lignite can increase HA content through biotic pathways, however, its structure was not explored. The Parallel factor analysis revealed that lignite can significantly increase the complexity of highly humified components. The lignite addition improved phenol oxidase activity, particularly laccase, during the thermophilic and cooling phases. The abundance and transformation functions of core bacteria also indicated that lignite addition can influence the activity of microbial transformation of HA components. The structural equation model further confirmed that lignite addition had a direct and indirect impact on enhancing the complexity of HA components through core bacteria and phenol oxidase. Therefore, lignite addition can improve HA structure complexity during composting through biotic pathways.

Molecular Insights into the Specific Targeting of c-MYC G-Quadruplex by Thiazole Peptides.

Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.

Inhibition of cinnamic acid and its derivatives on polyphenol oxidase: Effect of inhibitor carboxyl group and system pH.

Phenolic acids are promising inhibitors of polyphenol oxidase (PPO), but the effects of carboxyl group and pH on their inhibition effects are still unclear. In this study, methyl cinnamate, cinnamic acid and 4-carboxycinnamic acid were investigated by their inhibitory effects with pH varied from 6.8 to 5.0. Results showed that 4-carboxycinnamic acid had the strongest inhibitory effect on PPO, followed by cinnamic acid and methyl cinnamate. Acidic pH enhanced the inhibitory effects of cinnamic acid and its derivatives on PPO, and the enhancement degree, IC50 and Ki declining degree were followed as 4-carboxycinnamic acid > cinnamic acid > methyl cinnamate. Methyl cinnamate exhibited competitive inhibition on PPO, while cinnamic acid and 4-carboxycinnamic acid exhibited mixed-type inhibition. Inhibitors induced slight changes in the secondary and tertiary structures of PPO, which were enhanced by acidic pH. Molecular docking results showed that 4-carboxycinnamic acid exhibited the strongest binding ability, and the main interaction forces were around carboxyl groups, and acidic pH enhanced the binding effect through more interactions and lower binding energy. This study could provide new insights into industrial application of cinnamic acid and its derivatives for the control of enzymatic browning of fruits and vegetables.

Analysis of Factors Associated with Constipation in the Population with Obesity: Evidence from the National Health and Nutrition Examination Survey.

INTRODUCTION: Obesity and constipation are both global problems, but the factors associated with constipation in individuals with obesity are currently understudied. The aim of our study was to explore the factors associated with constipation in people with obesity. METHODS: From three cycles of the National Health and Nutrition Examination Survey (NHANES) 2005-2010, data from 14,048 persons aged ≥20 years were collected. Variables included demographics, lifestyle, comorbidities, and dietary data. Multiple logistic regression analysis was used to calculate adjusted prevalence odds ratio (OR) and assess the relationship between different variables and constipation in population with obesity. RESULTS: Using stool consistency definition, multivariate analysis revealed that education ≥12th grade (OR: 0.456; 95% CI: 0.300, 0.694; p = 0.00024), hypertension (OR: 0.505; 95% CI: 0.334, 0.763; p = 0.00119), polypharmacy (OR: 1.669; 95% CI: 1.104, 2.521; p = 0.01507), high cholesterol (OR: 0.400; 95% CI: 0.213, 0.750; p = 0.00430), and high dietary fiber (OR: 0.454; 95% CI: 0.245, 0.841; p = 0.01206) were substantially linked with constipation in the population with obesity. For constipation defined using stool frequency, multivariate regression analysis show constipation in people with obesity had a significant association with the female sex (OR: 2.684; 95% CI: 1.379, 5.223; p = 0.00366 multivariate), Mexican American (OR: 0.142; 95% CI, 0.033, 0.616; p = 0.00914 multivariate), hypertension (OR: 0.569; 95% CI: 0.324, 0.998; p = 0.04916), depression (OR: 2.280; 95% CI: 1.240, 4.195; p = 0.00803), occasional/often milk consumption (OR: 0.473; 95% CI: 0.286, 0.782; p = 0.00356), medium energy (OR: 0.318; 95% CI: 0.118, 0.856; p = 0.02338), polypharmacy (OR: 1.939; 95% CI: 1.115, 3.373; p = 0.01907), and medium moisture (OR: 0.534; 95% CI: 0.285, 0.999; p = 0.04959). In nonobese people, constipation was significantly associated with the female sex and high moisture but not with hypertension and polypharmacy. CONCLUSION: This study suggests that the population with obesity has many factors that affect constipation such as hypertension, polypharmacy, cholesterol, dietary fiber, depression, and so on, of which hypertension and polypharmacy were significant associated with constipation, regardless of definitions of constipation. Notably, hypertension might be associated with a reduced risk of constipation in people with obesity.

JAG1 enhances angiogenesis in triple-negative breast cancer through promoting the secretion of exosomal lncRNA MALAT1.

Despite significant improvements in five-year survival rates due to early diagnosis and combination therapy, triple-negative breast cancer (TNBC) treatment remains a major challenge. Finding new and effective targets for diagnosis and drug therapy is urgent for TNBC patients. Jagged-1 (JAG1), one of the canonical ligands of the Notch signaling pathway, is involved in vascular budding and is a poor prognostic factor of TNBC. In this study, combined with quantitative real-time PCR, database analysis, animal experiments, and other means, JAG1 was confirmed to be related to the poor prognosis of TNBC patients. JAG1 was highly expressed in MDA-MB-231 Bone (231B) cells, with stronger invasion and metastasis ability than MDA-MB-231 (231) cells. Treatment of human vascular endothelial cells (HUVEC) with TNBC conditioned medium showed that TNBC JAG1 promoted the angiogenesis of HUVEC. Next, we detected the exosomes extracted from TNBC conditioned medium and found that JAG1 promoted the exosome secretion from 231 cells via ALIX-RAB11A/RAB35. In addition, we also found that the exosomes from JAG1 overexpressed TNBC cells contained more long non-coding RNA (lncRNA) MALAT1, and MALAT1 promoted angiogenesis of HUVEC by targeting miR-140-5p. Finally, the angiogenesis-promoting effect of JAG1 in TNBC was further investigated by matrix gel assay. In conclusion, we reveal that JAG1 has a pro-invasion effect on TNBC and is involved in microenvironment angiogenesis by promoting exosome secretion and the MALAT1-miR-140-5p-JAG1/VEGFA pathway.

PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.

Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated that, upon starvation, autolysosomes recruit Pi4KIIα (Phosphatidylinositol 4-kinase II α) to generate phosphatidylinositol-4-phosphate (PtdIns4P) on their surface and establish endoplasmic reticulum (ER)-autolysosome contacts through PtdIns4P binding proteins Osbp (Oxysterol binding protein) and cert (ceramide transfer protein). We found that the Sac1 (Sac1 phosphatase), Osbp, and cert proteins are required for the reduction of PtdIns4P on autolysosomes. Loss of any of these proteins leads to defective macroautophagy/autophagy and neurodegeneration. Osbp, cert, and Sac1 are required for ER-Golgi contacts in fed cells. Our data establishes a new mode of organelle contact formation - the ER-Golgi contact machinery can be reused by ER-autolysosome contacts by re-locating PtdIns4P from the Golgi apparatus to autolysosomes when faced with starvation.Abbreviations: Atg1: Autophagy-related 1; Atg8: Autophagy-related 8; Atg9: Autophagy-related 9; Atg12: Autophagy-related 12; cert: ceramide transfer protein; Cp1/CathL: cysteine proteinase-1; CTL: control; ER: endoplasmic reticulum; ERMCS: ER-mitochondria contact site; fwd: four wheel drive; GM130: Golgi matrix protein 130 kD; Osbp: Oxysterol binding protein; PG: phagophore; PtdIns4K: phosphatidylinositol 4-kinase; Pi4KIIα: Phosphatidylinositol 4-kinase II α; Pi4KIIIα: Phosphatidylinositol 4-kinase III α; PtdIns4P: phosphatidylinositol-4-phosphate; PR: photoreceptor cell; RT: room temperature; Sac1: Sac1 phosphatase; Stv: starvation; Syx17: Syntaxin 17; TEM: transmission electron microscopy; VAP: VAMP-associated protein.

Synthesis-accessibility-oriented design of c-Jun N-terminal kinase 1 inhibitor.

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with poor prognosis and limited treatment options. The c-Jun N-Terminal Kinase 1 (JNK1), a key component of the MAPK pathway, has been implicated in the pathogenesis of IPF and represents a potential therapeutic target. However, the development of JNK1 inhibitors has been slowed, partly due to synthetic complexity in medicinal chemistry modification. Here, we report a synthesis-accessibility-oriented strategy for designing JNK1 inhibitors based on computational prediction of synthetic feasibility and fragment-based molecule generation. This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC50 = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC50 = 24.4 nM). The anti-fibrotic effect of C6 was further confirmed in animal model of pulmonary fibrosis. Moreover, compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001. Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery.

Effect of sustained-release tea tree essential oil solid preservative on fresh-cut pineapple storage quality in modified atmospheres packaging.

The quality and safety of fresh-cut pineapple deteriorate during handling and storage due to physicochemical and microbial changes, so its preservation has attracted extensive attention. This study prepared sustained-release tea tree essential oil (TTO) solid preservative (SP) with an encapsulation efficiency of 71.45% and applied it on fresh-cut pineapple in modified atmospheres packaging (MAP). Results showed that TTO adsorbed on nano silicon dioxide (SiO2) was embedded in the starch-carboxymethyl cellulose network structure by extrusion. The hydrogen bond and hydrophobic interaction resulted in compact structure and good sustained-release performance of SP. The SP improved sensory quality and reduced nutrient loss and microbial spoilage of fresh-cut pineapple, which extended its shelf-life to four days. In addition, antioxidant capacity was enhanced with increasing antioxidant enzyme activity, antioxidant content, and 2,2-diphenyl-1-picrylhydrazine scavenging capacity and decreasing MDA accumulation. Therefore, sustained-release TTO solid preservative has potential for the preservation of fresh-cut pineapple.

The landscape of aging.

Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

Occurrence and modeling of disinfection byproducts in distributed water of a megacity in China: Implications for human health.

Disinfection byproducts (DBPs) are initially formed in the process of chlorination in the drinking water treatment plants (DWTPs), then further formed in the distribution system due to the presence of residual chlorine and reactive organic matters. However, in China, DBPs are monitored in the effluent from the DWTPs, but less is known about concentrations of DBPs in tap water since they are usually monitored once per half a year. The smart water service system is establishing real-time monitoring of water indices, although DBPs are an urgent need, they are difficult to monitor in real-time due to their diversity and complicated detection methods. If the correlation between DBP concentration and routinely real-time monitored water quality parameters (e.g., pH value, residual chlorine, ammonia) can be evaluated, the concentration of DBPs can be predicted, which will strengthen the control of tap water safety. This article comprehensively assessed the physicochemical parameters and the occurrence of DBP formation in the tap water with an 18-month investigation in Z city (China). DBP formation in tap water of different seasons and different water sources were compared. Based on the relationship between DBPs and physicochemical parameters, linear prediction and nonlinear prediction models of trihalomethanes (THMs), haloacetonitriles (HANs) and haloacetic acids (HAAs) were established, and the accuracy of these models was verified by measured data. Finally, the toxicity and carcinogenic and non-carcinogenic health risk assessment of DBPs in tap water were analyzed.

Polyphenol oxidase inhibited by 4-hydroxycinnamic acid and naringenin: Multi-spectroscopic analyses and molecular docking simulation at different pH.

It is still unclear how pH affects the inhibitory effects of phenolic acids and flavonoids on polyphenol oxidase (PPO). In this study, 4-hydroxycinnamic acid and naringenin were selected to investigate their interactions with PPO from pH 6.8 to 5.0. Results showed that acidic pH could enhance the inhibitory effect of inhibitors and a greater enhancement effect was observed in 4-hydroxycinnamic acid. Fluorescence emission spectra indicated that 4-hydroxycinnamic acid and naringenin interacted with PPO and quenched its intrinsic fluorescence, which was also enhanced by acidic pH. Circular dichroism suggested that 4-hydroxycinnamic acid and naringenin could reversibly bind to PPO molecules and transform α-helix into ß-sheet. Molecular docking results revealed that 4-hydroxycinnamic acid and naringenin interacted with PPO through hydrogen bond and hydrophobic interaction, and more interactions were observed near the carboxyl group. These results indicated that acidic pH could significantly enhance the inhibitory effect of phenolic acid on PPO.

Encapsulation of bitter peptides in water-in-oil high internal phase emulsions reduces their bitterness and improves gastrointestinal stability.

Many peptides exhibit beneficial physiological functions, but their application in foods is limited because of their undesirable taste and their tendency to degrade when exposed to gastrointestinal conditions. In this study, water-in-oil high internal phase emulsions (W/O HIPEs) were used to encapsulate bitter peptides. A combination of confocal fluorescence and electron microscopy was used to confirm the formation of W/O HIPEs. The presence of high concentrations of bitter peptides increased the apparent shear viscosity, shear modulus and sedimentation stability. They also improved the oxidative stability of the HIPEs. Electronic-tongue and sensory analysis showed that encapsulated peptides within the HIPEs substantially reduced their bitterness. Moreover, a simulated gastrointestinal study showed that W/O HIPEs protected peptides from being released in the stomach. Our results show that W/O HIPEs can be used to mask the bitterness and improve the gastrointestinal stability of peptides, which may increase their utilization as bioactive ingredients in foods.

Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis.

Pulmonary senescence is accelerated by unresolved DNA damage response, underpinning susceptibility to pulmonary fibrosis. Recently it was reported that the SARS-Cov-2 viral infection induces acute pulmonary epithelial senescence followed by fibrosis, although the mechanism remains unclear. Here, we examine roles of alveolar epithelial stem cell senescence and senescence-associated differentiation disorders in pulmonary fibrosis, exploring the mechanisms mediating and preventing pulmonary fibrogenic crisis. Notably, the TGF-ß signalling pathway mediates alveolar epithelial stem cell senescence by mechanisms involving suppression of the telomerase reverse transcriptase gene in pulmonary fibrosis. Alternatively, telomere uncapping caused by stress-induced telomeric shelterin protein TPP1 degradation mediates DNA damage response, pulmonary senescence and fibrosis. However, targeted intervention of cellular senescence disrupts pulmonary remodelling and fibrosis by clearing senescent cells using senolytics or preventing senescence using telomere dysfunction inhibitor (TELODIN). Studies indicate that the development of senescence-associated differentiation disorders is reprogrammable and reversible by inhibiting stem cell replicative senescence in pulmonary fibrosis, providing a framework for targeted intervention of the molecular mechanisms of alveolar stem cell senescence and pulmonary fibrosis. Abbreviations: DPS, developmental programmed senescence; IPF, idiopathic pulmonary fibrosis; OIS, oncogene-induced replicative senescence; SADD, senescence-associated differentiation disorder; SALI, senescence-associated low-grade inflammation; SIPS, stress-induced premature senescence; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci; TIS, therapy-induced senescence; VIS, virus-induced senescence.

Mesenchymal stem cell-originated exosomal circDIDO1 suppresses hepatic stellate cell activation by miR-141-3p/PTEN/AKT pathway in human liver fibrosis.

Liver fibrosis is a common pathologic stage of the development of liver failure. It has showed that exosomes loaded with therapeutic circRNAs can be manufactured in bulk by exosome secreted cells in vitro, thus enabling personalized treatment. This study aimed to investigate the role of exosome-based delivery of circDIDO1 in liver fibrosis. Levels of genes and proteins were examined by qRT-PCR and Western blot. Cell proliferation, apoptosis, and cell cycle were analyzed by using cell counting kit-8 (CCK-8) assay, EdU assay, and flow cytometry, respectively. The binding between circDIDO1 and miR-141-3p was confirmed by dual-luciferase reporter, RNA pull-down and RIP assays. Exosomes were isolated by ultracentrifugation, and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. CircDIDO1 overexpression or miR-141-3p inhibition suppressed the proliferation, reduced pro-fibrotic markers, and induced apoptosis as well as cell cycle arrest in hepatic stellate cells (HSCs) by blocking PTEN/AKT pathway. Mechanistically, circDIDO1 acted as an endogenous sponge for miR-141-3p, further rescue experiments showed that circDIDO1 suppressed HSC activation by targeting miR-141-3p. Extracellular circDIDO1 could be incorporated into exosomes isolated from mesenchymal stem cells (MSCs), and transmitted to HSCs to restrain HSC activation. Clinically, low levels of serum circDIDO1 in exosome were correlated with liver failure, and serum exosomal circDIDO1 had a well diagnostic value for liver fibrosis in liver failure patients. Transfer of circDIDO1 mediated by MSC-isolated exosomes suppressed HSC activation through the miR-141-3p/PTEN/AKT pathway, gaining a new insight into the prevention of liver fibrosis in liver failure patients.

Lipid profiling in malignant mesothelioma reveals promising signatures for diagnosis and prognosis: A plasma-based LC-MS lipidomics study.

BACKGROUND AND AIM: Malignant mesothelioma (MM), being a rare and aggressive carcinoma, can barely be cured. Incidence of this cancer will keep climbing up in the next few decades since its major carcinogen, asbestos, is still in use in many countries. Unfortunately, prognosis of MM is unsatisfactory principally due to poor early diagnosis as a result of its long latency period and ambiguous symptoms. Lipids are known to contribute to cellular structure, signaling, and energy storage, and are widely reported to be related with tumorigenesis. Therefore, we aim to discover novel lipid biomarkers by plasma-based lipidomics that may improve MM diagnosis. METHODS: Plasma samples from 25 MM patients and 32 healthy controls (HCs) were collected and analysed using a high-throughput liquid chromatography-mass spectrometry (LC-MS). Univariate and multivariate analyses were subsequently performed to visualize the separation trend between two groups and to screen for differential feature ions. Ions were annotated using LipidSearch 4.2 and their enriched pathways were detected on LIPEA. Receiver operating characteristic (ROC) curves were used for analysing each annotated lipid's diagnostic value. Survival analyses were performed to investigate each lipid's prognostic value. RESULTS: In supervised partial least squares discriminant analysis (PLS-DA), clear separation between MM and HC groups was observed. A total of 34 differential lipids were annotated, among which 5 upregulated and 29 downregulated. Levels of plasma triacylglycerols (TGs) were higher in smoking versus non-smoking patients, and lower in female versus male patients. The top six lipids possessing highest diagnostic value included two phosphatidylethanolamines (PEs), two phosphatidylcholines (PCs) and two ceramides. Moreover, elevated circulating TG levels were associated with poorer survival, whereas increased monohexosylceramide (Hex1Cer) might be beneficial. CONCLUSIONS: Our study revealed differentially expressed lipid patterns in MM compared to HC. PC, PE, and ceramides showed outstanding diagnostic performance, while TG and Hex1Cer exhibited significant prognostic values. Nevertheless, more studies should verify these trends as well as further investigating on underlying mechanisms.