AI-based digital pathology provides newer insights into lifestyle intervention-induced fibrosis regression in MASLD: An exploratory study.

BACKGROUND AND AIMS: Lifestyle intervention is the mainstay of therapy for metabolic dysfunction-associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention-induced fibrosis changes in MASH. METHODS: We examined unstained sections from paired liver biopsies (baseline and end-of-intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions. RESULTS: About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI-induced liver fibrosis regression was concentrated in the periportal region. CONCLUSION: Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle-induced fibrosis regression and placebo responses, which is not captured by conventional histological staging.

Clinical characteristics and molecular mechanisms underlying bladder cancer in individuals with spinal cord injury: a systematic review.

BACKGROUND: Patients with spinal cord injury have a relatively high risk for bladder cancer and often complicated with bladder cancer in advanced stages, and the degree of aggressiveness of malignancy is high. Most of the literature is based on disease clinical features while, our study reviews the clinical characteristics and molecular mechanisms of spinal cord injury patients with bladder cancer, so that it might help clinicians better recognize and manage these patients. METHOD: We searched PubMed, Web of Science and Embase, using retrieval type like ("Neurogenic Lower Urinary Tract Dysfunction" OR "Spinal cord injury" OR "Spinal Cord Trauma") AND ("bladder cancer" OR "bladder neoplasm" OR "bladder carcinoma" OR "Urinary Bladder Neoplasms" OR "Bladder Tumor"). In Web of Science, the retrieval type was searched as "Topic", and in PubMed and Embase, as "All Field". The methodological quality of eligible studies and their risk of bias were assessed using the Newcastle-Ottawa scale. This article is registered in PROSPERO with the CBD number: CRD42024508514. RESULT: In WOS, we searched 219 related papers, in PubMed, 122 and in Embase, 363. Thus, a total of 254 articles were included after passing the screening, within a time range between 1960 and 2023. A comprehensive analysis of the data showed that the mortality and incidence rates of bladder cancer in spinal cord injury patients were higher than that of the general population, and the most frequent pathological type was squamous cell carcinoma. In parallel to long-term urinary tract infection and indwelling catheterization, the role of molecules such as NO, MiR 1949 and Rb 1. was found to be crucial pathogenetically. CONCLUSION: This review highlights the risk of bladder cancer in SCI patients, comprehensively addressing the clinical characteristics and related molecular mechanisms. However, given that there are few studies on the molecular mechanisms of bladder cancer in spinal cord injury, further research is needed to expand the understanding of the disease.

Biological roles of microRNA-140 in tumor growth, migration, and metastasis of osteosarcoma in vivo and in vitro.

The objective of this study was to explore the biological roles of microRNA-140 (miR-140) in tumor growth, migration, and metastasis of osteosarcoma (OS) in vivo and in vitro. Between 2007 and 2014, 47 cases of OS samples and normal bone tissue samples adjacent to OS were selected from our hospital. Tissue biopsies from OS patients were used to measure miR-140 levels to obtain a correlation between clinicopathological features and miR-140 expression. In vitro, MG63 human osteosarcoma cells were divided into four groups: blank group, miR-140 mimic group, miR-140 inhibitor group, and negative control (NC; empty plasmid) group. qRT-PCR was used to detect miR-140 expression, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell proliferation, flow cytometry was used to detect cell cycle distribution, and scratch migration assay was used to detect cell migration. In vivo, the relative expression of miR-140 level in OS tissue was lower than that in the adjacent normal bone tissue. miR-140 expression is inversely correlated with tumor size, Enneking stage, and tumor metastasis. In vitro, compared with blank group and NC group, relative miR-140 expression was increased, cell proliferation was inhibited, cell population in G0/G1 phase was increased, cell population in G2/M phase and S phases and proliferation index (PI), and cell migration distance were decreased in the miR-140 mimic group, but the relative expression and all the cell indexes were found opposite trend in the miR-140 inhibitor group. In conclusion, in vivo and vitro findings provided evidence that miR-140 could inhibit the growth, migration, and metastasis of OS cells.

Potential effects of Ag ion on the host by changing the structure of its gut microbiota.

Silver (Ag) can change the structure of the gut microbiota (GM), but how such change may affect host health is unknown. In this study, mice were exposed to silver acetate daily for 120 days. During this period, Ag accumulation in the liver was measured, its effects on GM structure were analyzed, and potential metabolic changes in liver and serum were examined. Although Ag accumulation remained unchanged in most treatments, the ratio of Firmicutes to Bacteroidetes at the phylum level increased and changes in the relative abundance of 33 genera were detected, suggesting that Ag altered the energy metabolism of mice via changes in the gut GM. In serum and liver, 34 and 72 differentially expressed metabolites were identified, respectively. The KEGG pathways thus enriched mainly included those involving the metabolism of amino acids, organic acids, lipids, and purine. Strong correlations were found between 33 % of the microorganisms with altered relative abundances and 46 % of the differentially expressed metabolites. The resulting clusters yielded two communities responsible for host inflammation and energy metabolism. Overall, these results demonstrate potential effects of Ag on the host, by changing its GM structure, and the need to consider them when evaluating the health risk of Ag.

Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression.

BACKGROUND: Urinary bladder cancer (UBC) is a common malignancy of the urinary tract; however, the mechanism underlying its high recurrence and responses to immunotherapy remains unclear, making clinical outcome predictions difficult. Epigenetic alterations, especially DNA methylation, play important roles in bladder cancer development and are increasingly being investigated as biomarkers for diagnostic or prognostic predictions. However, little is known about hydroxymethylation since previous studies based on bisulfite-sequencing approaches could not differentiate between 5mC and 5hmC signals, resulting in entangled methylation results. METHODS: Tissue samples of bladder cancer patients who underwent laparoscopic radical cystectomy (LRC), partial cystectomy (PC), or transurethral resection of bladder tumor (TURBT) were collected. We utilized a multi-omics approach to analyze both primary and recurrent bladder cancer samples. By integrating various techniques including RNA sequencing, oxidative reduced-representation bisulfite sequencing (oxRRBS), reduced-representation bisulfite sequencing (RRBS), and whole exome sequencing, a comprehensive analysis of the genome, transcriptome, methylome, and hydroxymethylome landscape of these cancers was possible. RESULTS: By whole exome sequencing, we identified driver mutations involved in the development of UBC, including those in FGFR3, KDMTA, and KDMT2C. However, few of these driver mutations were associated with the down-regulation of programmed death-ligand 1 (PD-L1) or recurrence in UBC. By integrating RRBS and oxRRBS data, we identified fatty acid oxidation-related genes significantly enriched in 5hmC-associated transcription alterations in recurrent bladder cancers. We also observed a series of 5mC hypo differentially methylated regions (DMRs) in the gene body of NFATC1, which is highly involved in T-cell immune responses in bladder cancer samples with high expression of PD-L1. Since 5mC and 5hmC alternations are globally anti-correlated, RRBS-seq-based markers that combine the 5mC and 5hmC signals, attenuate cancer-related signals, and therefore, are not optimal as clinical biomarkers. CONCLUSIONS: By multi-omics profiling of UBC samples, we showed that epigenetic alternations are more involved compared to genetic mutations in the PD-L1 regulation and recurrence of UBC. As proof of principle, we demonstrated that the combined measurement of 5mC and 5hmC levels by the bisulfite-based method compromises the prediction accuracy of epigenetic biomarkers.

[A comparative study of macular thickness and function before and after idiopathic macular epiretinal membrane surgery].

OBJECTIVE: To compare the thickness and functional changes of the macula after idiopathic macular epiretinal membrane (IEM) surgery. METHODS: A retrospective study. Thirty-seven patients (37 eyes) received surgical treatment of IEM. All patients received standard three-port vitrectomy as well as epiretinal membrane peeling. The best corrected visual acuity (BCVA, LogMAR) were recorded and optical coherence tomography (OCT) were used to evaluate central foveal thickness (CFT). Microperimetry (MP)-1 was used for the mean sensitivity (MS) of central 10° macula area. SPSS13.0 was used for statistical analysis. Rank and testing methods were used to compare the preoperative and postoperative BCVA, paired t testing method was used to compare the preoperative and postoperative CFT and MS values. Correlation analysis was used to study the BCVA, CFT, and MS. Pearson correlation analysis was applied to analyze measurement data and Spearman rank correlation analysis was used to analyze rating data. RESULTS: Postoperatively, the BCVA (0.1 - 0.7, median 0.4) was significantly better (Z = -4.97, P < 0.05) than the preoperative one (0.3 - 1.3, median 0.7). The CFT (246.2 ± 60.4) µm was significantly thinner (t = 15.86, P < 0.05) than the preoperative one (482.2 ± 101.8)µm. The MS of central 10° macula area (18.6 ± 1.8) dB was significantly higher (t = -9.20, P < 0.05) than the preoperative one (14.1 ± 3.4) dB. Thicker preoperative CFT was associated with a lower preoperative BCVA (r(s) = 0.91, P < 0.05), a lower MS of central 10° macula area (r = -0.82, P < 0.05) and a lower postoperative BCVA level (r(s) = 0.63, P < 0.05). But with a significant postoperative CFT reduce (r = 0.81, P < 0.05) and a significant postoperative BCVA increase (r(s) = 0.71, P < 0.05). CONCLUSIONS: Vitrectomy combined with macular epiretinal membrane removal can effectively promote the recovery of macular thickness and function in patients with IEM. Examination and analysis of preoperative CFT, BCVA and MS of macula area may help to predict the recovery of CFT and function objectively in patients of IEM.

Changes in Gut Microbiota Structure: A Potential Pathway for Silver Nanoparticles to Affect the Host Metabolism.

Silver nanoparticles (AgNPs) are one of the most widely used NPs. Their adverse effects on either the host or its gut microbiota (GM) have been examined. Nevertheless, whether the GM plays any role in AgNP toxicity to the host remains unclear. In the present study, AgNPs were administered to mice by oral gavage once a day for 120 days. A significant dose-dependent accumulation of Ag in the liver was observed, with a steady state reached within 21 days. The AgNPs changed the structure of the GM, mainly with respect to microorganisms involved in the metabolism of energy, amino acids, organic acids, and lipids, as predicted in a PICRUST analysis. Effects of the AgNPs on liver metabolism were also demonstrated, as a KEGG pathway analysis showed the enrichment of pathways responsible for the metabolism of amino acids, purines and pyrimidine, lipids, and energy. More interestingly, the changes in GM structure and liver metabolism were highly correlated, evidenced by the correlation between ∼23% of the differential microorganisms at the genus level and ∼60% of the differential metabolites. This implies that the metabolic variations in liver as affected by AgNPs were partly attributable to NP-induced changes of GM structure. Therefore, our results demonstrate the importance of considering the roles of GM in the toxicity of NPs to the host in evaluations of the health risks of NPs.

Identification and analysis of microRNA editing events in recurrent bladder cancer based on RNA sequencing: MicroRNA editing level is a potential novel biomarker.

Background: With the continued advancement of RNA-seq (RNA-sequencing), microRNA (miRNA) editing events have been demonstrated to play an important role in different malignancies. However, there is yet no description of the miRNA editing events in recurrent bladder cancer. Objective: To identify and compare miRNA editing events in primary and recurrent bladder cancer, as well as to investigate the potential molecular mechanism and its impact on patient prognosis. Methods: We examined the mRNA and miRNA transcriptomes of 12 recurrent bladder cancer cases and 13 primary bladder cancer cases. The differentially expressed mRNA sequences were analyzed. Furthermore, we identified the differentially expressed genes (DEGs) in recurrent bladder cancer. The Gene Ontology (GO) functional enrichment analyses on DEGs and gene set enrichment analysis were performed. The consensus molecular subtype (CMS) classification of bladder cancer was identified using the Consensus MIBC package in R (4.1.0); miRNA sequences were then further subjected to differentially expressed analysis and pathway enrichment analysis. MiRNA editing events were identified using miRge3.0. miRDB and TargetScanHuman were used to predict the downstream targets of specific differentially edited or expressed miRNAs. The expression levels of miR-154-5p and ADAR were validated by RT-qPCR. Finally, survival and co-expression studies were performed on the TCGA-BLCA cohort. Results: First, the mRNA expression levels in recurrent bladder cancer changed significantly, supporting progression via related molecular signal pathways. Second, significantly altered miRNAs in recurrent bladder cancer were identified, with miR-154-5p showing the highest level of editing in recurrent bladder cancer and may up-regulate the expression levels of downstream targets HS3ST3A1, AQP9, MYLK, and RAB23. The survival analysis results of TCGA data revealed that highly expressed HS3ST3A1 and RAB23 exhibited poor prognosis. In addition, miR-154 editing events were found to be significant to CMS classification. Conclusion: MiRNA editing in recurrent bladder cancer was detected and linked with poor patient prognosis, providing a reference for further uncovering the intricate molecular mechanism in recurrent bladder cancer. Therefore, inhibiting A-to-I editing of miRNA may be a viable target for bladder cancer treatment, allowing current treatment choices to be expanded and individualized.

[Macular retinal function detected by MP-1 microperimetry in normal subjects of middle and old age].

OBJECTIVE: To investigate the macular retinal sensitivity and fixation stability rates in normal subjects of middle and old age by using the MP-1 microperimetry. METHODS: This was a normal value test which enrolled 60 healthy subjects aging from 41 to 70 years old. It detected the retinal function of the central 10 degrees of the macular by using the MP-1 microperimetry. Sixty subjects were divided into three groups according to their ages: group A from 41 to 50, group B from 51 to 60 and group C from 61 to 70. Rank and testing methods were used to compare the mean retinal sensitivity (MS) within the central 10 degrees of the macular among the three groups, and P < 0.017 was used for statistical significance. Rank and testing methods were used to compare MS of different locations in the macular fovea, and P < 0.025 was used for statistical significance. Correlation analysis was used to analyze the correlation between the age and retinal MS values. RESULTS: The retinal MS within the central 10 degrees of the macular in 60 eyes of the 60 subjects was (19.7833 ± 0.4906) dB, and were (19.5117 ± 1.1044), (19.8542 ± 0.4099) and (19.9183 ± 0.3895) dB at 5 degrees, 3 degrees and 1 degree from the center of the macular, respectively. The mean fixation stability rates within 2 degrees and 4 degrees were (88.4667 ± 9.9600)% and (97.2000 ± 3.9091)%, respectively. There was statistical significance between retinal MS at 5 degrees and at 3 degrees from the center of the macular (Z = -2.943, P < 0.025); there was also statistical significance between retinal MS at 3 degrees and at 1 degree from the center of the macular (Z = -2.367, P < 0.025). CONCLUSIONS: MP-1 microperimetry examination could be used to evaluate the macular retinal function. There is no difference in the retinal MS within the central 10 degrees of the macular among the three groups of normal subjects of different ages. The retinal MS difference is statistically significant with different distances from the center of the macular; but there is no correlation between the age and the retinal sensitivities in normal subjects of middle and old age.

Seroprevalence and Genetic Characterization of Toxoplasma gondii In Naturally Infected Synanthropic Rodents In Yunnan Province, Southwestern China.

Rodents play an important role in the transmission of Toxoplasma gondii; however, little is known about the seroprevalence and genetic diversity of T. gondii infection in rodents in Yunnan Province, China. In this study, we examined the seroprevalence and genetically characterized T. gondii infection in naturally infected rodents in Yunnan Province between March and July 2016. In total, 261 serum samples were collected from rodents in the Jingha district, Xishuangbanna Dai Autonomous Prefecture, Yunnan Province, and examined for T. gondii antibodies by modified agglutination test (MAT) at a 1:20 cut-off, with titers of 1:20 in 24 samples, 1:40 in 10, 1:80 in 10, and 1:160 in 4. Thirty-two of 261 (12.26%) serum samples were positive for T. gondii by MAT. In total, 751 rodent brain samples were examined by semi-nested PCR; 46 (6.13%) were positive for the T. gondii B1 gene, 2 of which showed complete genotyping results for all 11 polymorphic loci (SAG1, SAG2, alt.SAG2, SAG3, BTUB, GRA6, L358, PK1, C22-8, C29-2, and Apico). The 2 samples were characterized to represent ToxoDB#137 ( http://toxodb.org/toxo/ ). These findings enriched the epidemiological and genetic diversity of T. gondii in China and have implications for the better prevention and control of T. gondii infection in humans and animals.

[Image analysis of avulsion fracture, permanent osteoepiphyte, sesamoid and accessory bones].

OBJECTIVE: To investigate a method to distinguish avulsion fracture from sesamoid, accessory bone, and permanent osteoepiphyte. METHODS: Fourteen cases of suspicious avulsion fractures of articular portion of tubular bones were reviewed. Direct/indirect signs and the injury mechanism of avulsion fractures were analyzed and compared with permanent osteoepiphyte, sesamoid and accessory bones for their morphological characteristics. RESULTS: There are two cases of permanent osteoepiphytes, three cases of sesamoids, and three cases of accessory bones. These cases were characterized by smooth edges, contiguous bony cortex, without swelling of the surrounding soft tissue or obvious image changes after consecutive radiography. CONCLUSION: It is fundamental in image analysis to distinguish avulsion fracture from physiological small osteoepiphyte, sesamoid bone, and aberrant accessory bone.

Sequestration of Guest Intermediates by Dalesconol Bioassembly Lines in Daldinia eschscholzii.

Microbial constructions of secondary metabolites are generally biosynthetic gene cluster (BGC)-based, and the forging of different BGC-sourced intermediates tends to be overlooked. Here, we show that the dalesconol bioassembly lines in Daldinia eschscholzii can sequester guest intermediates (i.e., building blocks produced outside the dalesconol biosynthetic gene cluster) to form arrays of skeletally undescribed molecules such as (+)-dalescone A, a potent inhibitor against the NLRP3 inflammasome activation.

Selesconol, a Fungal Polyketide That Induces Stem Cell Differentiation.

Owing to the negligible or acceptable immunogenicity, small molecules capable of inducing the differentiation of undifferentiated stem cells into organ-specific cell types are particularly promising in developing replacement therapy, but such compounds with undescribed architectures are extremely rare. Selesconol (1) is discovered from the culture of Daldinia eschscholzii IFB-TL01 as a skeletally unprecedented inducer for the differentiation of rat bone marrow mesenchymal stem cells into neural cells, with its unique framework clarified to derive from the intermediate tautomerization of the dalesconol A biosynthetic pathway.

Identification and genetic effect of haplotype in the bovine BMP7 gene.

Bone morphogenetic proteins (BMPs) are peptide growth factors belonging to the transforming growth factor-beta (TGF-ß) superfamily, and some members of the BMP family support white adipocyte differentiation. In this study, we focused on the BMP7 which singularly promotes the differentiation of brown preadipocytes. Haplotypes involving 5 single nucleotide polymorphism (SNP) sites in the bovine BMP7 gene were identified and their effect on body weight was analyzed. 16 haplotypes and 18 combined haplotypes were revealed and the linkage disequilibrium was assessed in the cattle population with 602 individuals representing three main cattle breeds from China. The results showed that haplotypes 3, 10 and 14 were predominant and accounted for 75.64%, 69.85%, and 83.36% in Nanyang, Qinchuan and Jiaxian cattle breeds, respectively. The statistical analyses indicated that the SNP 1, 4, and 5 are associated with the body weight, body length, and heart girth at 12 and 24 months in Nanyang cattle population (P<0.05), whereas there is no significant association between their 16 haplotypes and 18 combined haplotypes. Our results provide evidence that some SNPs and haplotypes in BMP7 are associated with growth traits, and may be utilized as a genetic marker in marker-assisted selection for beef cattle breeding programs.

Apelin supports primary rat retinal Müller cells under chemical hypoxia and glucose deprivation.

Müller cells support the integrity of the blood-retinal barrier, whereas their dysfunction under pathological conditions may contribute to retinal edema formation. The apelin peptide, as the endogenous ligand of G protein-coupled receptor APJ, participates in numbers of physiological and pathological processes. Recent studies highlight its emerging role against ischemic injury. Our study aimed to investigate the potential neuroprotection of apelin for primary rat retinal Müller cells under hypoxia or glucose-deprivation (GD) by cell viability, migration and apoptosis, as well as apelin/APJ immunofluorescence labeling and mRNA expression. The results showed that exogenous apelin significantly stimulated Müller cells viability and migration under normal, hypoxic and glucose-free condition, also prevented apoptosis. Apelin immunoreactivities represented weak and diffuse staining in the cytoplasm, along with restricted nuclear APJ expression. They both appeared stronger immunoreactivities after 12h hypoxia. Under hypoxic stress, apelin mRNA expression began to increase at 6h (9.97 folds, p<0.01), and APJ mRNA also up-regulated (2h 6.50 folds, p<0.05; 4h 2.25 folds, p<0.05; 6h 14 folds, p<0.01), whereas they both down-regulated during 4-12h GD. Our results suggested that apelin induced the tolerance of Müller cells to hypoxia and GD. Its administration might be a promising protection for blood-retinal barrier to ischemia.

Association of interaction between smoking and CYP 2C19*3 polymorphism with coronary artery disease in a Uighur population.

OBJECTIVES: Cytochrome P450 (CYP) 2C19 is expressed in vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which are potent endogenous vasodilators and inhibitors of vascular inflammation. The purpose of this study is to explore the relationship between the interaction of CYP2C19*3 polymorphism and smoking and coronary artery disease (CAD) in a Uighur population. METHODS: In a Chinese Uighur case-control study of patients with CAD (n = 336) and healthy controls (n = 370), we investigated the roles of polymorphism in the CYP2C19 gene by the use of polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: The CYP2C19*3 AG + AA genotype was significantly more prevalent in patients with CAD (6.25.0% vs 2.96%; P = .03). Multiple logistic regression analysis showed 4 independent risk factors: the interaction of CYP2C19*3 and smoking (OR 7.22, 95% confidence interval [CI] 2.32-10.23; P = .009), smoking (OR 3.23, 95% CI 1.72-5.44; P = .003), blood sugar (OR 2.12, 95% CI 1.03-4.21; P < .01), and hypertension (OR 1.74, 95% CI 0.98-2.34; P = .013). CONCLUSIONS: The CYP2C19*3 polymorphism and CAD were synergistically and significantly associated in Chinese Uighur patients.