MRTO4 Enhances Glycolysis to Facilitate HCC Progression by Inhibiting ALDOB.

BACKGROUND MRT4 Homolog, Ribosome Maturation Factor (MRTO4) is often upregulated in cancer cells. However, its impact in hepatocellular carcinoma (HCC) is less well understood. Herein, we explored the prognostic and energy metabolism reprogramming role of MRTO4 in HCC. MATERIAL AND METHODS Clinical data were obtained from The Cancer Genome Atlas (TCGA), and the expression of MRTO4 in clinical samples was analyzed. The association between different variables and overall survival (OS) was studied, as well as their potential as independent prognostic factors, using Cox regression analysis. We constructed a nomogram including clinical pathological variables and MRTO4 expression to provide a predictive model for prognosis. Heatmaps, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the relationship between energy metabolism pathways and MRTO4. We used classic molecular biology research methods, including RT-qPCR, Western blotting, CCK8, TUNEL, Clone formation, Transwell assay, ELISA, and immunohistochemistry, to study the role of MRTO4 in promoting the progression of HCC through glycolysis regulation. RESULTS Our study showed that MRTO4 is an independent prognostic risk factor for HCC and that MRTO4 accelerates glycolysis of HCC cells, promotes proliferation and invasion, and suppresses apoptosis of HCC cells. The underlying mechanism involves MRTO4 promoting glycolysis and accelerating HCC by inhibiting ALDOB. CONCLUSIONS Our study revealed a novel mechanism by which MRTO4 promotes glycolysis and accelerates HCC progression, and suggests that inhibiting MRTO4 could be a potential therapeutic strategy for HCC.

Clinical nephrotoxicity induced by cyclosporin A combined with hormone therapy for nephrotic syndrome.

This study aims to explore the nephrotoxicity due to use of combination of cyclosporine A and hormone in the treatment of nephrotic syndrome. From January 2018 to November 2019, 100 patients with primary nephrotic syndrome were divided into experimental and control groups, with 50 patients per group. The experimental group took oral cyclosporine A and prednisone tablets, while the control group received oral cyclosporine A combined with shock therapy. The contents of white blood cells, triglycerides, urine protein and cholesterol in the experimental group were lower than those in the control group, while their albumin content was significantly higher than the control values. Blood concentrations of cyclosporine A were significantly lower in non-nephrotoxic patients than in nephrotoxic patients. The high blood cyclosporine A level in patients (>200ng/mL) may be a factor for inducement of nephrotoxicity. Basal serum creatinine levels in nephrotoxic patients were significantly higher than those in non-nephrotoxic patients. Therefore, high basal creatinine level may be a contributing factor to nephrotoxicity. The combination of cyclosporine A and hormone is effective in the treatment of nephrotic syndrome. Blood cyclosporine A levels greater than 200ng/ml or elevated basal serum creatinine may be the cause of nephrotoxicity.

Exosomal IGFBP2 derived from highly metastatic promotes hepatocellular carcinoma metastasis by inducing epithelial mesenchymal transition.

Liver cancer metastasis is the main cause of death in liver cancer patients. Exosomes, which are small vesicles released by cancer cells, play a crucial role in the metastasis of cancer. The aim of this study was to investigate the effect of exosomes derived from high metastatic potential liver cancer cells acting as cell to cell communication on liver cancer metastasis. Bioinformatics analysis was used to obtain the differential expression of exosomal mRNAs from the plasma of both liver cancer patients and healthy volunteers. Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and protein blot were employed to characterize the exosomes. The molecular mechanisms and were explored by conducting CCK8, Transwell, Tunel, RTqPCR, western blot, and immunofluorescence staining. We examined IGFBP2 special expression in the plasma exosomes of both liver cancer patients and healthy volunteers, and its presence was associated with a poor prognosis in liver cancer patients. Furthermore, we observed that exosomes from highly metastatic liver cancer cells (MHCC97H) contained high levels of IGFBP2 and could enhance the metastatic potential of less aggressive liver cancer cells (Hep3B). Additionally, we discovered that IGFBP2 in MHCC97H-derived exosomes activated ERK signaling pathway, which triggered epithelial-mesenchymal transition (EMT) in Hep3B cells. Our study underscores the significance of exosomal IGFBP2 from highly metastatic liver cancer cells as a driver of metastasis in less invasive liver cancer cells. This suggests that targeting IGFBP2 in exosomes could be a promising strategy for the treatment and prognosis of liver cancer patients.

A Comparative Visual Analytics Framework for Evaluating Evolutionary Processes in Multi-Objective Optimization.

Evolutionary multi-objective optimization (EMO) algorithms have been demonstrated to be effective in solving multi-criteria decision-making problems. In real-world applications, analysts often employ several algorithms concurrently and compare their solution sets to gain insight into the characteristics of different algorithms and explore a broader range of feasible solutions. However, EMO algorithms are typically treated as black boxes, leading to difficulties in performing detailed analysis and comparisons between the internal evolutionary processes. Inspired by the successful application of visual analytics tools in explainable AI, we argue that interactive visualization can significantly enhance the comparative analysis between multiple EMO algorithms. In this paper, we present a visual analytics framework that enables the exploration and comparison of evolutionary processes in EMO algorithms. Guided by a literature review and expert interviews, the proposed framework addresses various analytical tasks and establishes a multi-faceted visualization design to support the comparative analysis of intermediate generations in the evolution as well as solution sets. We demonstrate the effectiveness of our framework through case studies on benchmarking and real-world multi-objective optimization problems to elucidate how analysts can leverage our framework to inspect and compare diverse algorithms.

Poly (lactic acid) electrospun nanofiber membranes: Advanced characterization for biomedical applications with drug loading performance studies.

Traditional dressings have shortcomings such as poor moisture absorption and easy to adhere, making the development of new dressings crucial. In this work, a PLA/PVP crosslinked drug-loaded nanofiber membrane was prepared through electrospinning and ultraviolet crosslinking, with poly (lactic acid) (PLA), polyvinylpyrrolidone (PVP), and salicylic acid (SA) as starting materials. The results demonstrated that the inclusion of PVP notably boosted the viscosity and conductivity of the blend spinning solution. The roughness of the fabricated fiber was elevated, and the diameter of the fibers was more uniform. Additionally, the incorporation of PVP not only enhanced the porosity of the fiber membrane but also effectively decreased its contact angle. Notably, when the PVP content reached 40 %, the contact angle underwent a substantial reduction, decreasing significantly from 125.4° to 82.2°. The SA drug-loaded fiber membrane exhibited a notable bacteriostatic effect against Escherichia coli and Staphylococcus aureus, with its release behavior adhering to Fick's diffusion law. In the cell viability experiment, the cell proliferation rate increased from 94 % to 129 % after 3 days. This shows that the prepared membrane has good antibacterial effect and cell compatibility, which provides a theoretical basis for the construction of a new medical dressing.

Electrospun high hydrophilicity antimicrobial poly (lactic acid)/silk fibroin nanofiber membrane for wound dressings.

Antimicrobial wound dressings can aid wound healing by preventing bacterial infection. This is particularly true of electrospun ones, which have a porous structure and can be easily loaded with antimicrobial drugs. Here, Poly lactic acid (PLA), Silk Fibroin (SF) and antimicrobial agents of Silver nanoparticles (Ag NPs) and Silver oxide (Ag2O) to prepare the PLA/SF composites antimicrobial nanofiber membrane by electrospinning. The PLA with 30 % SF nanofiber membrane show the water vapor permeability (WVP) and the liquid absorption of 36 g·mm/(m2·d·kPa) and 1721 %. With the increasing of SF contents, the degradation rate and surface hydrophilicity of the nanofiber membrane increase significantly. The nanofiber membrane exhibited excellent antimicrobial activity against Pseudomonas aeruginosa (P. aeruginosa) with the inhibition circle reach at 18.2 mm. The resultant nanofiber membrane showed high cytosolic activity, good cytocompatibility and strong antimicrobial ability, which laid a theoretical foundation for the construction of a new PLA/SF composites antimicrobial fiber membrane.

DNA damage response in breast cancer and its significant role in guiding novel precise therapies.

DNA damage response (DDR) deficiency has been one of the emerging targets in treating breast cancer in recent years. On the one hand, DDR coordinates cell cycle and signal transduction, whose dysfunction may lead to cell apoptosis, genomic instability, and tumor development. Conversely, DDR deficiency is an intrinsic feature of tumors that underlies their response to treatments that inflict DNA damage. In this review, we systematically explore various mechanisms of DDR, the rationale and research advances in DDR-targeted drugs in breast cancer, and discuss the challenges in its clinical applications. Notably, poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated favorable efficacy and safety in breast cancer with high homogenous recombination deficiency (HRD) status in a series of clinical trials. Moreover, several studies on novel DDR-related molecules are actively exploring to target tumors that become resistant to PARP inhibition. Before further clinical application of new regimens or drugs, novel and standardized biomarkers are needed to develop for accurately characterizing the benefit population and predicting efficacy. Despite the promising efficacy of DDR-related treatments, challenges of off-target toxicity and drug resistance need to be addressed. Strategies to overcome drug resistance await further exploration on DDR mechanisms, and combined targeted drugs or immunotherapy will hopefully provide more precise or combined strategies and expand potential responsive populations.

Wearables are a viable digital health tool for older Indigenous adults living remotely in Australia (research).

Objective: Health programs for Indigenous people are most effective, acceptable, and sustainable when Indigenous perspectives are prioritized. Codesign builds on Indigenous people's creativity and propensity to experiment with new technologies and ensures research is designed and implemented in a culturally safe and respectful manner. Limited research has focused on older Indigenous people as partners in digital health. No research has focused on the acceptability and feasibility of older Indigenous people using wearables for heart health monitoring. This study provides insights into the acceptability and feasibility for ≥55-year-old Indigenous people living in remote locations to use wearables (watches and patches) to detect atrial fibrillation (AF) and high blood pressure. Methods: This mixed methods study was codesigned and coimplemented with the local Aboriginal Controlled Health Service in a remote area of New South Wales, Australia. It included active involvement and codesign with the participants. The devices used in this study included a Withings Scan watch and a Biobeat patch. Results: Despite challenging conditions (>36°C) and variable internet connectivity, 11 Indigenous older adults participated in a five-day wearables program in a remote location. Participants indicated that using digital health devices was acceptable and feasible for older Indigenous users. They described high levels of comfort, safety and convenience when using wearables (patches and watches) to detect AF. They were active participants in codesigning the program. Conclusion: Older Indigenous Australians are motivated to use wearable health devices. They are keen to participate in codesign innovative health tech programs to ensure new health technologies are acceptable to Indigenous people and feasible for remote locations.

Oxymatrine ameliorates myocardial injury by inhibiting oxidative stress and apoptosis via the Nrf2/HO-1 and JAK/STAT pathways in type 2 diabetic rats.

The necessity of increasing the efficiency of organ preservation has encouraged researchers to explore the mechanisms underlying diabetes-related myocardial injuries. This study intended to evaluate the protective effects of oxymatrine (OMT) in myocardial injury caused by type 2 diabetes mellitus. A model of diabetic rats was established to simulate type 2 diabetes mellitus using an intraperitoneal injection of a single dose of 65 mg/kg streptozotocin with a high-fat and high-cholesterol diet, and diabetic rats were subsequently treated with OMT (60, 120 mg/kg) by gavage for 8 weeks. Thereafter, diabetic rats demonstrated notable decreases in left ventricular systolic pressure (LVSP), ±dp/dtmax, and in the activities of glutathione peroxidase, superoxide dismutase, and catalase. Moreover, we found notable increases in left ventricular end-diastolic pressure, fasting blood glucose, and malondialdehyde, as well as changes in cell apoptosis and decreased expression levels of Nrf2, HO-1, tyrosine protein kinase JAK (JAK), and signal transducer and transcription activator (STAT). Treatment with OMT alleviated all of the measured parameters. Collectively, these findings suggest that activation of the Nrf2/HO-1 and inhibition of the JAK/STAT signaling are involved in mediating the cardioprotective effects of OMT and also highlight the benefits of OMT in ameliorating myocardial injury in diabetic rats.

Single nucleotide polymorphisms associated with female breast cancer susceptibility in Chinese population.

Breast cancer is a complex disease influenced by both external and internal factors, among which genetic factors play a critical role. Single-nucleotide polymorphisms (SNPs) are major contributors to the heritability of breast cancer, and their frequencies vary across ethnic groups. In this study, we aimed to investigate the association between 34 SNPs identified in previous genome-wide association studies (GWAS) and overall breast cancer risk, as well as breast cancer subtypes, in the Chinese female population. To accomplish this, we conducted an extensive association analysis using the high-throughput Sequenom MassARRAY® platform in a case-control study comprising 1848 breast cancer patients and 709 healthy controls. Our analysis, which utilized the SNPassoc package in R based on chi-squared (χ2) test and genetic model analysis, identified significant associations between breast cancer risk and SNP rs12493607 (TGFBR2, risk allele C, OR = 1.28 [1.11-1.47], P = 0.0005), as well as a less conservatively significant association with rs4784227 (CASC16, risk allele T, OR = 1.24 [1.08-1.42], P = 0.0017) and rs2046210 (ESR1, risk allele A, OR = 1.50 [1.16-1.95], P = 0.0016). Furthermore, our stratified analyses revealed that rs12493607 was significantly associated with invasive carcinoma, estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, HER2-negative, and young (aged younger than 45) breast cancer. SNP rs4784227 and rs3803662 (CASC16) were associated with invasive carcinoma and ER-positive breast cancer, while rs2046210 was linked to ductal carcinoma in situ, ER-negative, PR-negative, HER2-positive, and elder (aged more than 45) breast cancers. SNPs rs10484919 (ESR1) and rs1038304 (CCDC170) showed links to HER2-positive breast cancer, and rs616488 (PEX14) with premenopausal breast cancer. In summary, our study shed light on the relationship between SNPs and breast cancer susceptibility within a vast Chinese cohort, supporting the development of polygenetic risk scores for the Chinese population. These findings provide valuable insights into the genetic basis of breast cancer and have important implications for risk prediction, early detection, and personalized treatment of this disease.

Biomarkers and experimental models for cancer immunology investigation.

The rapid advancement of tumor immunotherapies poses challenges for the tools used in cancer immunology research, highlighting the need for highly effective biomarkers and reproducible experimental models. Current immunotherapy biomarkers encompass surface protein markers such as PD-L1, genetic features such as microsatellite instability, tumor-infiltrating lymphocytes, and biomarkers in liquid biopsy such as circulating tumor DNAs. Experimental models, ranging from 3D in vitro cultures (spheroids, submerged models, air-liquid interface models, organ-on-a-chips) to advanced 3D bioprinting techniques, have emerged as valuable platforms for cancer immunology investigations and immunotherapy biomarker research. By preserving native immune components or coculturing with exogenous immune cells, these models replicate the tumor microenvironment in vitro. Animal models like syngeneic models, genetically engineered models, and patient-derived xenografts provide opportunities to study in vivo tumor-immune interactions. Humanized animal models further enable the simulation of the human-specific tumor microenvironment. Here, we provide a comprehensive overview of the advantages, limitations, and prospects of different biomarkers and experimental models, specifically focusing on the role of biomarkers in predicting immunotherapy outcomes and the ability of experimental models to replicate the tumor microenvironment. By integrating cutting-edge biomarkers and experimental models, this review serves as a valuable resource for accessing the forefront of cancer immunology investigation.

A novel non-invasive exhaled breath biopsy for the diagnosis and screening of breast cancer.

BACKGROUND: Early detection is critical for improving the survival of breast cancer (BC) patients. Exhaled breath testing as a non-invasive technique might help to improve BC detection. However, the breath test accuracy for BC diagnosis is unclear. METHODS: This multi-center cohort study consecutively recruited 5047 women from four areas of China who underwent BC screening. Breath samples were collected through standardized breath collection procedures. Volatile organic compound (VOC) markers were identified from a high-throughput breathomics analysis by the high-pressure photon ionization-time-of-flight mass spectrometry (HPPI-TOFMS). Diagnostic models were constructed using the random forest algorithm in the discovery cohort and tested in three external validation cohorts. RESULTS: A total of 465 (9.21%) participants were identified with BC. Ten optimal VOC markers were identified to distinguish the breath samples of BC patients from those of non-cancer women. A diagnostic model (BreathBC) consisting of 10 optimal VOC markers showed an area under the curve (AUC) of 0.87 in external validation cohorts. BreathBC-Plus, which combined 10 VOC markers with risk factors, achieved better performance (AUC = 0.94 in the external validation cohorts), superior to that of mammography and ultrasound. Overall, the BreathBC-Plus detection rates were 96.97% for ductal carcinoma in situ, 85.06%, 90.00%, 88.24%, and 100% for stages I, II, III, and IV BC, respectively, with a specificity of 87.70% in the external validation cohorts. CONCLUSIONS: This is the largest study on breath tests to date. Considering the easy-to-perform procedure and high accuracy, these findings exemplify the potential applicability of breath tests in BC screening.

Comparing management strategies for conserving communities of climate-threatened species with a stochastic metacommunity model.

Many species are shifting their ranges to keep pace with climate change, but habitat fragmentation and limited dispersal could impede these range shifts. In the case of climate-vulnerable foundation species such as tropical reef corals and temperate forest trees, such limitations might put entire communities at risk of extinction. Restoring connectivity through corridors, stepping-stones or enhanced quality of existing patches could prevent the extinction of several species, but dispersal-limited species might not benefit if other species block their dispersal. Alternatively, managers might relocate vulnerable species between habitats through assisted migration, but this is generally a species-by-species approach. To evaluate the relative efficacy of these strategies, we simulated the climate-tracking of species in randomized competitive metacommunities with alternative management interventions. We found that corridors and assisted migration were the most effective strategies at reducing extinction. Assisted migration was especially effective at reducing the extinction likelihood for short-dispersing species, but it often required moving several species repeatedly. Assisted migration was more effective at reducing extinction in environments with higher stochasticity, and corridors were more effective at reducing extinction in environments with lower stochasticity. We discuss the application of these approaches to an array of systems ranging from tropical corals to temperate forests. This article is part of the theme issue 'Ecological complexity and the biosphere: the next 30 years'.

miR-92b-3p Exerts Neuroprotective Effects on Ischemia/Reperfusion-Induced Cerebral Injury via Targeting NOX4 in a Rat Model.

The necessity to increase the efficiency of organ preservation has pushed researchers to consider the mechanisms to minimize cerebral ischemia/reperfusion (I/R) injury. Hence, we evaluated the role of the miR-92b-3p/NOX4 pathway in cerebral I/R injury. A cerebral I/R injury model was established by blocking the left middle cerebral artery for 2 h and reperfusion for 24 h, and a hypoxia/reoxygenation (H/R) model was established. Thereafter, cerebral I/R increased obvious neurobiological function and brain injury (such as cerebral infarction, apoptosis, and cell morphology changes). In addition, we noted a significant decrease in the expression of miR-92b-3p, as well as increases in apoptosis and oxidative stress and an increase in NOX4. Furthermore, overexpression of miR-92b-3p blocked the inhibitory effect of miR-92b-3p on the expression of NOX4 and the accumulation of oxygen-free radicals. Bioinformatics analysis found that NOX4 may be the target gene regulated by miR-92b-3p. In conclusion, the involvement of the miR-92b-3p/NOX4 pathway ameliorated cerebral I/R injury through the prevention of apoptosis and oxidative stress. The miR-92b-3p/NOX4 pathway could be considered a potential therapeutic target to alleviate cerebral I/R injury.

Evaluation of testicular spermatogenic function by ultrasound elastography in patients with varicocele-associated infertility.

OBJECTIVE: To investigate the application of ultrasound elastography and color Doppler ultrasound in the evaluation of testicular spermatogenic function in patients with varicocele (VC) associated infertility. METHODS: A total of 196 patients with VC-associated infertility treated in our hospital from January 2018 to January 2020 were included as the research subjects (VC group), and were classified into VC I group (66 cases), VC II group (60 cases), and VC III group (70 cases) according to the diameter of spermatic vein and the degree of reflux under ultrasound. 50 age-matched healthy subjects were included as the control group. Color ultrasound, ultrasound elastography and semen examination were performed on all patients. RESULTS: Compared with control group, a lower left testicular volume in VC group and a lower right testicular volume in VC III group were observed, and the left testicular volume was inversely proportional to VC grade (all P<0.05). Statistically significant differences in sperm viability, sperm density, peak systolic velocity (PSV), and MEAN values were determined among the 4 groups by one-way ANOVA, and between two groups by the independent-samples t test (all P<0.05). Pearson correlation analysis revealed that sperm viability and sperm density had no correlation with PSV, resistive index (RI) and pulsatility index (PI) of the left testicular artery in VC group, but were negatively correlated with the MEAN values of the testis. CONCLUSION: Ultrasound elastography can predict the semen quality in patients with VC-associated infertility. CLINICAL TRIAL REGISTRATION: This study was registered with the registration No. ChiCTR2010189 (URL: http://www.chictr.org.cn/showproj.aspx?proj=2018XE057-3).

Altered serum copper homeostasis suggests higher oxidative stress and lower antioxidant capability in patients with chronic hepatitis B.

Copper homeostasis can be altered by inflammation. This study aimed to investigate the alteration of serum copper homeostasis and to explore its clinical significance in patients with chronic hepatitis B (CHB).Thirty-two patients with CHB and 10 aged- and sex-matched healthy controls were recruited. Analyses included serum levels of total copper (TCu), copper ions (Cu), small molecule copper (SMC), ceruloplasmin (CP), Cu/Zn superoxide dismutase 1 (SOD1), urinary copper, and the activities of serum CP and SOD1.The serum TCu and urinary copper levels in patients with CHB were significantly higher than the controls (P = .04 and .003), while the serum Cu was lower than the controls (P = .0002). CP and SOD1 activities in the serum were significantly lower in patients with CHB compared to controls (P = .005) despite higher serum concentrations. In addition, serum alanine aminotransferase inversely correlated with serum CP activity (P = .0318, r = -0.4065).Serum copper homeostasis was altered in this cohort of patients with CHB. The results suggest increased oxidative stress and impaired antioxidant capability in patients with CHB, in addition to necroinflammation. These results may provide novel insights into the diagnosis and treatment of patients with CHB.

MYO18B promotes hepatocellular carcinoma progression by activating PI3K/AKT/mTOR signaling pathway.

BACKGROUND: MYO18B has been identified as a novel tumor suppressor gene in several cancers. However, its specific roles in the progression of hepatocellular carcinoma (HCC) has not been well defined. METHODS: We firstly identified the expression and prognostic values of MYO18B in HCC using TCGA cohort and our clinical data. Then, MYO18B knockdown by RNA inference was implemented to investigate the effects of MYO18B on HCC cells. Quantitative RT-PCR and Western blot were used to determine gene and protein expression levels. CCK-8 and colony formation assays were performed to examine cell proliferation capacity. Wound healing and transwell assays were used to evaluate the migration and invasion of HepG2 cells. RESULTS: MYO18B was overexpressed and correlated with poor prognosis in HCC. MYO18B expression was an independent risk factor for overall survival. Knockdown of MYO18B significantly inhibited the proliferation, migration and invasion of HepG2 cells. Meanwhile, MYO18B knockdown could effectively suppress the phosphorylation of PI3K, AKT, mTOR and P70S6K, suggesting that MYO18B might promote HCC progression by targeting PI3K/AKT/mTOR signaling pathway. CONCLUSIONS: MYO18B promoted tumor growth and migration via the activation of PI3K/AKT/mTOR signaling pathway. MYO18B might be a promising target for clinical intervention of HCC.