RBM15B Promotes Prostate Cancer Cell Proliferation via PCNA m6A Modification.

Prostate cancer (PC) is the most frequently occurring cancer in men, characterized by the abnormal proliferation of cells within the prostate gland. This study explores the role of RNA binding motif protein 15B (RBM15B) in PC. RBM15B expression levels in PC patients were predicted using the Starbase database. The expression of RBM15B and proliferating cell nuclear antigen (PCNA) expression in PC cells was detected. Following RBM15B knockdown, cell proliferation assays were conducted. N6-methyladenosine (m6A) levels in PC cells were quantified, and RNA immunoprecipitation was performed to analyze the binding of m6A and YTH N-methyladenosine RNA binding protein 1 (YTHDF1) on PCNA mRNA. The stability of PCNA mRNA was assessed after treatment with actinomycin D. An in vivo nude mouse xenograft model was created to validate the role of RBM15B. The findings revealed the upregulation of RBM15B in PC. RBM15B knockdown resulted in decreased proliferation, colony formation, and EdU-positive cells. Mechanical analysis showed that RBM15B facilitated m6A modification of PCNA mRNA, leading to increasing m6A methylation. YTHDF1 bound to these m6A sites on PCNA mRNA, thus stabilizing it. Furthermore, PCNA overexpression mitigated the effects of RBM15B knockdown on PC cell proliferation. In conclusion, RBM15B promotes PC cell proliferation by enhancing the stability of PCNA mRNA through YTHDF1-mediated m6A modification.

N6-methyladenosine modification-tuned lipid metabolism controls skin immune homeostasis via regulating neutrophil chemotaxis.

Disrupted N6-methyladenosine (m6A) modification modulates various inflammatory disorders. However, the role of m6A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m6A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m6A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m6A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m6A modulators to attenuate inflammatory skin diseases.

The applications of CT with artificial intelligence in the prognostic model of idiopathic pulmonary fibrosis.

TAKE HOME MESSAGE: The review summarizes the applications of CT and AI algorithms for prognostic models in IPF and procedures of model construction. It reveals the current limitations and prospects of AI-aid models, and helps clinicians to recognize the AI algorithms and apply them to more clinical work.

Helicase-assisted continuous editing for programmable mutagenesis of endogenous genomes.

Deciphering the context-specific relationship between sequence and function is a major challenge in genomics. Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited. Here we present a programmable platform for long-range, locus-specific hypermutation called helicase-assisted continuous editing (HACE). HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large (>1000-base pair) genomic intervals. We applied HACE to identify mutations in mitogen-activated protein kinase kinase 1 (MEK1) that confer kinase inhibitor resistance, to dissect the impact of individual variants in splicing factor 3B subunit 1 (SF3B1)-dependent missplicing, and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69. HACE provides a powerful tool for investigating coding and noncoding variants, uncovering combinatorial sequence-to-function relationships, and evolving new biological functions.

The role of gut microbiota in prostate inflammation and benign prostatic hyperplasia and its therapeutic implications.

Background: The gut microbiota thrives in a complex ecological environment and its dynamic balance is closely related to host health. Recent studies have shown that the occurrence of various diseases including prostate inflammation is related to the dysregulation of the gut microbiome. Objective: This review focus on the mechanisms by which the gut microbiota induces prostate inflammation and benign prostatic hyperplasia and its therapeutic implications. Materials and methods: Publications related to gut microbiota, prostate inflammation, and benign prostatic hyperplasia (BPH) until April 2023 were systematically reviewed. The research questions were formulated using the Problem, Intervention, Comparison/Control, and Outcome (PICO) frameworks. Results: Fifteen articles covering the relationship between the gut microbiota and prostate inflammation/BPH, the mechanisms by which the gut microbiota influences prostate inflammation and BPH, and potential therapeutic approaches targeting the gut microbiota for these conditions were included. Conclusion: Short-chain fatty acids (SCFAs), which are metabolites of the intestinal microbiota, protect the integrity of the intestinal barrier, regulate immunity, and inhibit inflammation. However, dysregulation of the gut microbiota significantly reduces the SCFA content in feces and impairs the integrity of the gut barrier, leading to the translocation of bacteria and bacterial components such as lipopolysaccharide, mediating the development of prostate inflammation through microbe-associated molecular patterns (MAMPs).

Actin like 6A is a prognostic biomarker and associated with immune cell infiltration in cancers.

PURPOSE: To investigate the role of Actin like 6 A (ACTL6A) in cancer and explore the potential mechanism of its function. METHODS: Differential expression of ACTL6A was analyzed using Oncomine and TIMER database. Then, we downloaded data sets from TCGA database. The correlation between ACTL6A expression and survival in pan-cancer were analyzed by "survival", "survminer" R package and PrognoScan database. STRING (v 11.0) and stringAPP for Cytoscape v3.7.2 were used to predict ACTL6A associated genes. Copy number and methylation alterations of ACTL6A were analyzed using cBioPortal and GSCALite. Transcription factors were downloaded from The Human Transcription Factors Database and analyzed using "limma" R package, JASPAR and PROMO database. Correlations analysis between ACTL6A and immune cells were performed using TIMER and GEPIA database. RESULTS: In our studies, we found that ACTL6A was widely upregulated in cancers, which might be attributed to its gene amplifications. Moreover, ACTL6A might regulated by transcription factors (TFs), including E2F1, YY1, CDX2 and HOXD10. In addition, high ACTL6A expression was associated with poor prognosis in most cancers. Meanwhile, ACTL6A was associated with the infiltration of immune cells, especially in liver hepatocellular carcinoma and brain lower grade glioma. CONCLUSION: Amplification of ACTL6A is correlated with poor prognosis and contribute to immune cells infiltration in LIHC and LGG, which may provide immune-related therapeutic targets to guide clinical strategies.

HER2 expression in upper tract urothelial carcinoma and the relationship with clinicopathological characteristics-an analysis of 155 patients in Southwest China.

OBJECTIVE: We aimed to evaluate the expression of HER2 in patients with upper tract urothelial carcinoma (UTUC) in Southwest China by using a relatively large cohort, and to determine the relationship between HER2 expression and clinicopathological characters. MATERIALS AND METHODS: We retrospectively enrolled the clinical data of 155 UTUC patients who have undergone radical nephroureterectomy (RNU) from March 2019 to September 2022. HER2 expression was assessed using immunohistochemistry and scored according to the HercepTest (Scores of 0 or 1 + were considered as negative and 2 + or 3 + as positive). Tumor molecular phenotype was classified by the panel of CK20, CK5/6, and CD44. RESULTS: HER2 was overexpressed in 55 (35.5%) patients. It was associated with pathologic characteristics such as grade (p = 0.017), tumor molecular phenotype (p < 0.001) and Ki-67 expression (p = 0.017). On univariate and multivariable logistic regression analysis, HER2 overexpression remained associated with higher grade (HR, 10.6; 95% CI 1.0-112.6; p = 0.050) and luminal molecular phenotype (HR, 8.0; 95% CI 1,6-38.4; p = 0.010). During disease progression after nephroureterectomy, the phenotype of the tumor might change and a switch phenomenon in phenotype after recurrence in the bladder was reported. CONCLUSION: According to our study, in Southwest China, one-third of UTUC patients overexpressed HER2. Tumors with high grade or luminal phenotype tended to be HER2 positive. HER2 may represent a promising target for therapy in UTUC.

Multiple effects of submerged plants on microplastics-heavy metals redistribution and combination in the hyporheic sediment.

Submerged plants (SP) in the hyporheic sediment (HS) dynamically alter the spatial distributions of heavy metals (HMs) and microplastics (MPs). In this study, we examined the redistribution and combination of HMs and MPs in the HS surrounding the SP (SSP) and non-nearby the SP (NSP) in the Weihe River Basin. The strong bioconcentration capacity of SP directly caused a decrease of HMs in the SSP (Bioconcentration Factors: SSP>NSP, 1.07 >1.00). Algal proliferation at high nutrient concentrations strengthened the interception of MPs by SP (SSP-MPs >NSP-MPs, 495 >315 items/kg). The significant correlation between SSP-HMs and SSP-MPs indicates the formation of MPs-HMs. The concentration of SSP-HMs was greater than NSP-HMs (Mn (462.95 >437.66 mg/kg)>Zn (63.46 >60.51 mg/kg)>V (53.98 >50.67 mg/kg)>Pb (21.98 >18.47 mg/kg)>As (18.36 >15.65 mg/kg). This finding implies that the MPs trapped by the SP indirectly contribute to elevating SSP-HMs, which showed higher pollution risk (Nemerow Pollution Index: 1.37 >1.22; Contamination Factor: V, 0.87 >0.82, Zn, 0.95 >0.90, As, 1.61 >1.41, Pb, 0.98 >0.88). Furthermore, SP can reduce NSP contamination by proactively collecting pollutants into SSP, endangering the integrity of rivers through the ingesting of hydrobiont. Our study provides theoretical suggestions for the application of SP to improve ecological health in the complex environment.

Influence of Immersion Orientation on Microstructural Evolution and Deformation Behavior of 40Cr Steel Automobile Front Axle during Oil Quenching.

This study employs the finite element method to investigate the microstructural evolution and deformation behavior of a 40Cr steel automobile front axle during the quenching process. By establishing a multi-physics field coupling model, the study elucidates the variation patterns of the microstructure field in the quenching process of the front axle under different immersion orientations. It is found that along the length direction, the bainite and martensite structures decrease from the center to the edge region, while the ferrite structure shows an increasing trend. Additionally, the influence of immersion orientation on the hardness of the front axle's microstructure and deformation behavior is thoroughly discussed. The results indicate that, firstly, when quenched horizontally, the hardness difference among different regions of the front axle is approximately 8.2 HRC, whereas it reaches 10.3 HRC when quenched vertically. Considering the uniformity of the microstructure, the horizontal immersion method is preferable. Secondly, due to the different immersion sequences in different regions of the front axle leading to varying heat transfer rates, as well as the different amounts of martensite structures obtained in different regions, the deformation decreases along the length direction from the center to the edge region. Horizontal immersion quenching, compared to vertical immersion, results in a reduction of approximately 56.2% and 48.9% in deformation on the representative central cross-section (A-A) and the total length of the front axle, respectively. Therefore, considering aspects such as microstructure uniformity and deformation, the horizontal immersion quenching orientation is more favorable.

[Analysis of Spatiotemporal Differences and Influencing Factors of Land Use Carbon Emissions in Ningxia].

Analyzing the spatiotemporal differences in land use carbon emissions systematically and exploring their influencing factors for the rational allocation of land resources is of great importance and promoting collaborative emission reduction in this region. Based on the calculation of land use carbon emissions in Ningxia and its prefecture-level cities from 2000 to 2021, the regional differences in carbon emissions, economic efficiency, and carbon sink capacity were reflected through the difference index, carbon emission intensity, economic contribution rate, and carbon sink ecological carrying capacity. The results were as follows： ① From 2000 to 2021, the land use carbon emissions in Ningxia showed a significant increase by 110 919 400 t. Construction land was the main carbon source land, accounting for 99.57% of the total carbon emissions in 2021, and forest land was the main type of carbon absorption, accounting for 79.22% of the total carbon absorption in 2021. ② During the research period, the carbon emission difference among prefecture-level cities showed a trend of first rising and then slightly falling, with the gap reaching the maximum in 2016. ③ Although the overall difference in carbon emission intensity among prefecture-level cities showed a trend of narrowing and convergence, the economic contribution coefficient and carbon sink ecological carrying coefficient had significant differences, and the economic contribution rate and carbon emission contribution rate were both in a relatively unbalanced state, with obvious regional differences. ④ Land use carbon emission intensity, land use structure, economic development level, and population all played a promoting role in land use carbon emission, with contribution rates of 56.48%, 41.27%, 85.20%, and 9.29%, respectively. The contribution value of land use carbon intensity per unit GDP was negative, which inhibited the increase of land use carbon emission.

A Global Database of Pitted Cones on Mars for Research on Martian Volcanism.

This study presents a global database of pitted cones on Mars. This database was created using an active deep-learning approach based on a global mosaic of Mars Context Camera (CTX) images, followed by extensive manual verification. The global database contains 250,547 pitted cones along with their central coordinates and diameters. 94.2% of the pitted cones have diameters ranging from 100 m to 1 km. Most of them are in the northern lowlands, while some are scattered in the southern highlands. Systematic evaluation of the extracted pitted cones is performed in Isidis Planitia, Acidalia Planitia, and Cerberus Palus on Mars. The results reveal that the precision ranges from 79.2% to 85.6%, and the recall rate ranges from 62.4% to 87.7%, indicating a varying among regions but satisfactory performance. Manual digitizing evaluation indicates that over 94.1% of manual labels by different annotators have a differentiation rate of 10%, showing promising precision and consistency. This global database can facilitate further research on the origin and evolution of pitted cones on Mars.

Highly efficient removal of aqueous phosphate via iron-manganese fabricated biochar: Performance and mechanism.

Biochar (BC) has emerged as a potential solution to phosphate removal from wastewater primarily resulting from global overuse of fertilizers. Further modification by embedment of iron (Fe)-manganese (Mn) oxides on BC can enhance phosphate removal; however, the modification method serves as a vital factor underlying distinctive removal performances and mechanisms, which have yet been systematically examined. Herein, two Fe-Mn modified BC, Fe/MnBC (comprised of Fe3O4 and MnO2) and Fe-MnBC (comprised of MnFe2O4), were comprehensively investigated for gaining insights into the unsolved perspectives. The results indicated that Fe-MnBC exhibited a markedly greater maximum phosphate adsorption capacity of 135.88 mg g-1 than that of Fe/MnBC with 17.93 mg g-1. The comparative results based on microstructure and spectroscopic analyses suggested that different Fe and Mn oxides were successfully loaded, which played a distinctive role in phosphate removal. Further characterizations unveiled that the key mechanisms for phosphate removal by Fe/MnBC are inner-sphere complexation and precipitation, while electrostatic interaction and outer-sphere complexation are the dominant mechanisms underlying the notable performance of Fe-MnBC. The delicately designed Fe-MnBC with special structure and property also enabled a superior regeneration capacity, which presented a promisingly high phosphate removal efficacy of over 81.34% after five cycles. These results enhance comprehension regarding the impact of biochar modification techniques on phosphate removal, offering positive indications for the remediation of excessive phosphate and other pollutant-containing water through feasible design and green chemicals.

Network pharmacology-based exploration of molecular mechanisms underlying therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure with spleen Qi deficiency syndrome.

BACKGROUND: Chronic heart failure is a complex clinical syndrome. The Chinese herbal compound preparation Jianpi Huatan Quyu recipe has been used to treat chronic heart failure; however, the underlying molecular mechanism is still not clear. AIM: To identify the effective active ingredients of Jianpi Huatan Quyu recipe and explore its molecular mechanism in the treatment of chronic heart failure. METHODS: The effective active ingredients of eight herbs composing Jianpi Huatan Quyu recipe were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target genes of chronic heart failure were searched in the Genecards database. The target proteins of active ingredients were mapped to chronic heart failure target genes to obtain the common drug-disease targets, which were then used to construct a key chemical component-target network using Cytoscape 3.7.2 software. The protein-protein interaction network was constructed using the String database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed through the Metascape database. Finally, our previously published relevant articles were searched to verify the results obtained via network pharmacology. RESULTS: A total of 227 effective active ingredients for Jianpi Huatan Quyu recipe were identified, of which quercetin, kaempferol, 7-methoxy-2-methyl isoflavone, formononetin, and isorhamnetin may be key active ingredients and involved in the therapeutic effects of TCM by acting on STAT3, MAPK3, AKT1, JUN, MAPK1, TP53, TNF, HSP90AA1, p65, MAPK8, MAPK14, IL6, EGFR, EDN1, FOS, and other proteins. The pathways identified by KEGG enrichment analysis include pathways in cancer, IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, calcium signaling pathway, cAMP signaling pathway, NF-kappaB signaling pathway, AMPK signaling pathway, etc. Previous studies on Jianpi Huatan Quyu recipe suggested that this Chinese compound preparation can regulate the TNF-α, IL-6, MAPK, cAMP, and AMPK pathways to affect the mitochondrial structure of myocardial cells, oxidative stress, and energy metabolism, thus achieving the therapeutic effects on chronic heart failure. CONCLUSION: The Chinese medicine compound preparation Jianpi Huatan Quyu recipe exerts therapeutic effects on chronic heart failure possibly by influencing the mitochondrial structure of cardiomyocytes, oxidative stress, energy metabolism, and other processes. Future studies are warranted to investigate the role of the IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, and other pathways in mediating the therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure.

LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.

Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.

Bruton tyrosine kinase inhibitor-related atrial fibrillation and its implications in the treatment of B-cell lymphoma.

Adverse events of atrial fibrillation (AF) have been commonly reported in lymphoma patients in treating Bruton's tyrosine kinase inhibitors (BTKi). The incidence rate of AF can vary depending on the specific types of BTKi and the patient population. Totally 45 published studies have revealed that the overall incidence rate of AF is 5% (95% CI 4%-7%). By performing a subtype single-rate analysis, the second-generation BTKi shows a lower AF incidence rate and lower cardiovascular toxicity. In the subtype single-rate analysis, we conclude the different AF incidence rates of Ibrutinib (10%, 95% CI 7%-13%), Acalabrutinib (4%, 95% CI 1%-6%), Orelabrutinib (0%, 95% CI 0%-1%), and Zanubrutinib (0%, 95% CI 0%-1%). The comprehensive analysis of AF inspires us to better predict and manage AF and other cardiovascular events in treating lymphoma. Meticulous evaluation, collaboration between cardiologists and hematologists, and discovery of new biomarkers are essential for its management.

Degradation Behaviors of Polylactic Acid, Polyglycolic Acid, and Their Copolymer Films in Simulated Marine Environments.

Poly(lactic acid) (PLA) and poly(glycolic acid) (PGA) are extensively studied biodegradable polymers. However, the degradation behavior of their copolymer, poly(lactic-co-glycolic acid) (PLGA), in marine environments has not yet been confirmed. In this study, the changes in macroscopic and microscopic morphology, thermal properties, aggregation, and chemical structure of PLA, PGA, PLGA-85, and PLGA-75 (with 85% and 75% LA content) in simulated marine environments were investigated. Results revealed that degradation occurred through hydrolysis of ester bonds, and the degradation rate of PGA was faster than that of PLA. The amorphous region degraded preferentially over the crystalline region, leading to cleavage-induced crystallization and decreased thermal stability of PLA, PLGA-85, and PLGA-75. The crystal structures of PLGAs were similar to those of PLA, and the higher GA content, the faster was the degradation rate. This study provides a deeper understanding of the seawater degradation behaviors of PLA, PGA, and their copolymers, and provides guidance for the preparation of materials with controllable degradation performance.

Liposomes Loaded with 5-Fluorouracil Can Improve the Efficacy in Pathological Scars.

Introduction: Pathological scars, such as hypertrophic scars and keloids, are characterized by the proliferation of fibroblasts and the deposition of collagen that often cause pruritus, pain, and disfigurement. Due to their high incidence and deformity, pathological scars have resulted in severe physical and psychological trauma for patients. Intralesional injection of 5-fluorouracil (5-Fu) is a recommended option for treating pathological scars. However, the efficacy of 5-Fu injection was limited and unstable due to limited drug penetration and short retention time. Methods: Liposomes are promising carriers that have advantages, such as high biocompatibility, controlled release property, and enhanced clinical efficacy. Here, we constructed a transdermal 5-Fu-loaded liposome (5-Fu-Lip) to provide a more effective and safer modality to scar treatment. Results: Compared to 5-Fu, 5-Fu-Lip showed superior ability in inhibiting primary keloid fibroblasts proliferation, migration, and collagen deposition, and also significantly inhibited human umbilical vein endothelial cells (HUVECs) proliferation and microvessel construction. In vivo experiments demonstrated that 5-Fu-Lip can significantly reduce the severity of hypertrophic scars in a rabbit ear wounding model. Discussion: 5-Fu-Lip provides a promising strategy to improve drug efficacy, which has great potential in the treatment of pathological scars.

Exploring genetic diversity and population structure in Cinnamomum cassia (L.) J.Presl germplasm in China through phenotypic, chemical component, and molecular marker analyses.

Cinnamomum cassia (L.) J.Presl, a tropical aromatic evergreen tree belonging to the Lauraceae family, is commonly used in traditional Chinese medicine. It is also a traditional spice used worldwide. However, little is currently known about the extent of the genetic variability and population structure of C. cassia. In this study, 71 individuals were collected from seven populations across two geographical provinces in China. Nine morphological features, three chemical components, and single nucleotide polymorphism (SNP) markers were used in an integrated study of C. cassia germplasm variations. Remarkable genetic variation exists in both phenotypic and chemical compositions, and certain traits, such as leaf length, leaf width, volatile oil content, and geographic distribution, are correlated with each other. One-year-old C. cassia seedling leaf length, leaf width, elevation, and volatile oil content were found to be the main contributors to diversity, according to principal component analysis (PCA). Three major groupings were identified by cluster analysis based on the phenotypic and volatile oil data. This was in line with the findings of related research using 1,387,213 SNP markers; crucially, they all demonstrated a substantial link with geographic origin. However, there was little similarity between the results of the two clusters. Analysis of molecular variance (AMOVA) revealed that the genetic diversity of C. Cassia populations was low, primarily among individuals within populations, accounting for 95.87% of the total. Shannon's information index (I) varied from 0.418 to 0.513, with a mean of 0.478 (Na=1.860, Ne =1.584, Ho =0.481, He =0.325, and PPB =86.04%). Genetic differentiation across populations was not significant because natural adaptation or extensive exchange of seeds among farmers between environments, thus maintaining the relationship. Following a population structure analysis using the ADMIXTURE software, 71 accessions were found to be clustered into three groups, with 38% of them being of the pure type, a finding that was further supported by PCA. Future breeding strategies and our understanding of the evolutionary relationships within the C. cassia population would benefit greatly from a thorough investigation of phenotypic, chemical, and molecular markers.

DNA methylation urine test in the diagnosis of upper tract urothelial carcinoma: a systematic review and meta-analysis.

OBJECTIVE: The DNA methylation urine test, a non-invasive early detection method for upper tract urothelial carcinoma (UTUC), is currently in full swing. This study aimed to systematically assess its diagnostic performance on UTUC. MATERIALS AND METHODS: PubMed, Scopus, Embase, and Cochrane were our main databases when searching articles published from January 2000 to December 2023. Sensitivity and specificity were study primary endpoints. I2 was used to evaluated heterogeneity, meanwhile subgroup and meta-regression analyses were adopted to investigated the source of heterogeneity. Sensitivity analysis was performed to evaluate the result robustness, while Deeks' funnel plot asymmetry test was for the publication bias. RESULTS: Nine studies with 1326 patients were included. The pooled sensitivity was 0.89 (95% confidence interval (CI), 0.83-0.93) and specificity were 0.91 (95% CI, 0.83-0.96). The area under the receiver operating characteristic curve was 0.96 (95% CI, 0.93-0.97). Substantial heterogeneity was found during the data synthesis, whereas the pooled results remained robust in the sensitivity analysis. None of the potential covariates-urine sample collection method, population, country, methylation test method, or tumor grade-could account for the heterogeneity. CONCLUSION: DNA methylation urine test is a promising method with high efficiency for UTUC early detection. Nevertheless, owing to the significant heterogeneity, more well-organized studies are warranted to further explore its diagnostic efficiency and application context.

CREB3 suppresses hepatocellular carcinoma progression by depressing AKT signaling through competitively binding with insulin receptor and transcriptionally activating RNA-binding motif protein 38.

cAMP responsive element binding protein 3 (CREB3), belonging to bZIP family, was reported to play multiple roles in various cancers, but its role in hepatocellular carcinoma (HCC) is still unclear. cAMP responsive element binding protein 3 like 3 (CREB3L3), another member of bZIP family, was thought to be transcription factor (TF) to regulate hepatic metabolism. Nevertheless, except for being TFs, other function of bZIP family were poorly understood. In this study, we found CREB3 inhibited growth and metastasis of HCC in vitro and in vivo. RNA sequencing indicated CREB3 regulated AKT signaling to influence HCC progression. Mass spectrometry analysis revealed CREB3 interacted with insulin receptor (INSR). Mechanistically, CREB3 suppressed AKT phosphorylation by inhibiting the interaction of INSR with insulin receptor substrate 1 (IRS1). In our study, CREB3 was firstly proved to affect activation of substrates by interacting with tyrosine kinase receptor. Besides, CREB3 could act as a TF to transactivate RNA-binding motif protein 38 (RBM38) expression, leading to suppressed AKT phosphorylation. Rescue experiments further confirmed the independence between the two functional manners. In conclusion, CREB3 acted as a tumor suppressor in HCC, which inhibited AKT phosphorylation through independently interfering interaction of INSR with IRS1, and transcriptionally activating RBM38.