Spatiotemporal evolution and driving factors of ecosystem services' transformation in the Yellow River basin, China.

The Yellow River basin (YRB) holds immense ecological significance in China, but it is currently undergoing profound transformations in its ecosystem services (ESs). To formulate appropriate environmental policies, it is vital to gain a comprehensive understanding of the characteristics and influential factors driving the ESs' transformation in the YRB. The spatiotemporal dynamics in ESs was evaluated using the InVEST model, and the modes of the ESs' transformation were summarized. The elements impacting ESs' transformation and their interactions were assessed using the optimal parameter-based geographical detector (OPGD). Over the period from 1980 to 2020, the water yield within the YRB exhibited an upward trajectory, with a distinctive spatial pattern characterized by higher values in the southern and eastern regions, in contrast to lower values observed in the northern and western regions. Similarly, soil conservation demonstrated a tendency to rise over the duration of the research, with southern and western regions consistently exhibiting higher values compared to the northern and eastern regions. In contrast, habitat quality decreased over time and was accompanied by a progressive spatial decline from the southeast regions to the northwest regions. The ESs' transformation in the YRB from 1980 to 2020 indicated three modes: (1) simultaneous increases, this mode was characterized by concurrent increases in water yield and soil conservation; (2) increase and decrease, in this mode, there was an increase in soil conservation accompanied by a decrease in habitat quality; and (3) increase and deterioration, the third mode entailed an increase in water yield but a simultaneous deterioration in habitat quality. The 45-km grid was the best spatial scale for the analysis in this study. Over the span of 2000 through 2020, the ESs' transformation in the YRB was subject to the influence of natural environmental, geographic location-related, socioeconomic, and policy factors. The determinants of the spatiotemporal heterogeneity in ESs' transformation in the YRB demonstrated double-factor and nonlinear enhancement effects. The counterchange with the most significant effects on ESs' transformation were those between economic density and annual mean precipitation, annual mean temperature and ecological restoration, and the per capita income of urban residents and vegetation index.

The dynamic patterns and driving factors of land use conflict in the Yellow River basin of China.

Land use conflict, as the spatial manifestation of conflicting human-land relationship, has a profound impact on sustainable use of regional land resources. Taking the Yellow River Basin (YRB) as an example, a land use conflict assessment model was constructed based on landscape pattern indices. The dynamic patterns and driving factors of land use conflict in the YRB and the corresponding driving factors were then assessed from 2000 to 2020 based on spatial autocorrelation analysis and the geodetector method. Significant spatial and temporal differences in land use conflict were observed in the YRB from 2000 to 2020. During this period, the area of stable controllable decreased by 3465 km2, whereas the areas of strong and extreme conflict increased by 34,964 and 13,057 km2, respectively. The expansion of areas with extreme and strong conflict mostly occurred in regions with high urbanization and human activity, including northern Shaanxi, Hetao Plain, and the Yellow River Delta. The distribution of land use conflict in the YRB from 2000 to 2020 was characterized by significant spatial agglomeration; high-value cluster conflict mainly extended from the midstream area to the upstream area, whereas low-value clusters tended to be concentrated in the upstream area of the Qinghai and Qilian Mountains. The spatial and temporal differentiation in land use conflict from 2000 to 2020 was influenced by factors related to the natural environment, geographic location, social economy, and regional policy in the YRB. The effects of elevation, distance to the nearest major river, population, economic density, and per capita disposable income of residents increased continuously during the study period, whereas the influences of mean annual precipitation and ecological retreat weakened. Analysis of the interactions between driving factors showed significant dual-factor and non-liner enhancement effects on the spatial and temporal differentiation in land use conflict. The findings provide a scientific reference for the comprehensive management of national land and ecological construction in the YRB.

Myxobolus xiushanensis n. sp. (Myxozoa: Myxobolidae) infecting the gill arches of Yellowhead Catfish Tachysurus fulvidraco from China.

OBJECTIVE: Myxosporidiosis of bagrid fishes has been a focus of aquaculture research in recent years. The purpose of this study is to characterize a novel myxobolid, named Myxobolus xiushanensis n. sp., infecting Yellowhead Catfish Tachysurus fulvidraco in China. METHODS: We used molecular biology, morphology, phylogeny, and histopathology in the present study. RESULT: Mature myxospores were circular to ellipsoidal in valve view, measuring 12.2 ± 0.4 µm (mean ± SD; range = 11.2-13.2 µm) in length and 10.6 ± 0.4 µm (9.5-11.1 µm) in width. Two oval polar capsules were equal in width (3.4 ± 0.2 µm; 3.0-3.8 µm) but slightly unequal in length: 5.6 ± 0.3 µm (5.3-6.1 µm) and 4.7 ± 0.2 µm (4.4-5.5 µm). The polar capsule was packed with five to seven spirals of polar tubules. Histopathological investigation demonstrated that the plasmodium under the cuticular layer of the gill arch only induced a local inflammatory response and did not cause serious damage to the gill arch's internal structure. The two small subunit (SSU) ribosomal DNA sequences of M. xiushanensis n. sp. showed 100% similarity and uniqueness, and the highest similarity with other myxosporean sequences in GenBank was 90.27% (query coverage = 94%). The secondary structures of the SSU ribosomal RNA revealed that the present species was distinctly different from related species in regions V4 and V7. Phylogenetic analysis showed that M. xiushanensis n. sp. clustered independently within a branch. CONCLUSION: These results enrich our understanding of the biodiversity of myxobolids infecting bagrid fishes and provide fundamental data for the diagnosis of myxosporidiosis.

The description of Myxobolus meijiangensis n. sp. (Myxozoa: Myxobolidae) and its pathogenicity to the gills of goldfish.

Myxobolus Bütschli, 1882 is the most speciose myxozoan genus, although some species have only been described according to the morphological characteristics of spores. In the present study, a new Myxobolus species infecting the gill lamellae of goldfish from Chongqing, China, was described using a comprehensive analysis of morphological, molecular, and histological data. Mature spores were flat-pear in valvular view with tapering anterior and rounded posterior ends, measuring 11.0 ± 0.4 (10.4-11.6) µm in length and 10.3 ± 0.3 (9.6-11.0) µm in width. Two equal-sized elongate pyriform polar capsules were 5.6 ± 0.6 (4.5-6.4) µm long and 3.5 ± 0.5 (2.4-4.1) µm wide. Polar tubules were coiled with 8 or 9 turns. The small-subunit ribosomal DNA gene sequence length of the present species was 1951 nt, and the highest similarity was 97.99% with M. pyramidis. Comparative analysis of the morphological and molecular data revealed that the present species was distinct from other known myxosporeans. Plasmodia were located at the interlamellar troughs nearing the top of the primary gills. Infection by the present species destroyed the original structure of gill lamellae and caused an inflammatory response, eventually leading to fish dyspnea. The morphological, molecular, and pathological data from the present study can be used for aquaculture since they provide guidance for easy detection and future control of this myxosporidiosis.

Characteristic Activity Parameters of Electron Donors and Electron Acceptors.

It is well-known that for an electron transfer reaction, the electron-donating ability of electron donors and the electron-accepting ability of electron acceptors can be quantitatively described by the oxidation potential of electron donors and the reduction potential of electron acceptors. However, for an electron transfer reaction, the electron-donating activity of electron donors and the electron-accepting activity of electron acceptors cannot be quantitatively described by a characteristic parameter of electron donors and a characteristic parameter of electron acceptors till now. In this paper, a characteristic activity parameter of electron donors and electron acceptors named as their thermo-kinetic parameter is proposed to quantify the electron-donating activity of electron donors and the electron-accepting activity of electron acceptors in electron transfer reactions. At the same time, the thermo-kinetic parameter values of 70 well-known electron donors and the corresponding 70 conjugated electron acceptors in acetonitrile at 298 K are determined. The activation free energies of 4900 typical electron transfer reactions in acetonitrile at 298 K are estimated according to the thermo-kinetic parameter values of 70 electron donors and 70 conjugated electron acceptors, and the estimated results have received good verification of the corresponding independent experimental measurements. The physical meaning of the thermo-kinetic parameter is examined. The relationship of the thermo-kinetic parameter with the corresponding redox potential as well as the relationship of the activation free energy with the corresponding thermodynamic driving force of electron transfer reactions is examined. The results show that the observed relationships between the thermo-kinetic parameters and the redox potentials as well as the observed relationships between the activation free energy and the thermodynamic driving force depend on the choice of electron donors and electron acceptors as well as the electron transfer reactions. The greatest contribution of this paper is to realize the symmetry and unification of kinetic equations and the corresponding thermodynamic equations of electron transfer reactions.

Comparison of the second-line treatments for patients with small cell lung cancer sensitive to previous platinum-based chemotherapy: A systematic review and Bayesian network analysis.

Objective: It remains unclear what the best second-line treatment is for patients with small-cell lung cancer sensitive to previous platinum-based chemotherapy. Methods: We systematically screened randomized controlled trials from several online databases. The primary outcome was objective response rate (ORR), and the secondary outcomes were disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and hematological complications graded 3 to 5. The efficacy of included treatments was ranked by surface under the cumulative ranking curve (SUCRA) value. Results: We included eleven trials involving 1560 patients in quantitative analysis. Triple chemotherapy containing platinum (TP, combination of cisplatin, etoposide, and irinotecan) was associated with favorable ORR (intravenous topotecan vs TP; odds ratio: 0.13, 95% CI:0.03-0.63; SUCRA, 0.94) and PFS (vs intravenous topotecan; hazard ratio, 0.5; 95% CI: 0.25-0.99; SUCRA, 0.90). Belotecan ranked highest for OS (SUCRA, 0.90), while intravenous topotecan plus Ziv-aflibercept ranked highest for DCR (SUCRA, 0.75). TP was more likely to cause anemia and thrombocytopenia while intravenous topotecan plus Ziv-aflibercept resulted in most neutrocytopenia. Conclusion: TP is the first recommendation for the second-line treatment of sensitive relapsed SCLC. TP achieved priority in ORR and PFS with the most frequent adverse effects in anemia and thrombocytopenia. For patients who cannot tolerate the hematological adverse effects of triple chemotherapy, amrubicin is an optional option. Amrubicin had relatively good ORR and PFS, accompanied by fewer hematological complications. The rechallenge of the platinum doublet is inferior to amrubicin in ORR, DCR, and PFS. Oral topotecan has a similar effect compared with IV topotecan, but oral topotecan was associated with slightly higher safety and less stress in nursing. Belotecan contributed to the best PFS with slightly better safety but was not ideal in other outcomes. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022358256.

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy.

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.

Montelukast Inhibits Lung Cancer Cell Migration by Suppressing Cysteinyl Leukotriene Receptor 1 Expression In vitro.

BACKGROUND: Lung cancer is a major threat to public health and remains difficult to treat. Repositioning of existing drugs has emerged as a therapeutic strategy in lung cancer. Clinically, low-dose montelukast has been used to treat asthma. OBJECTIVE: We evaluated the potential of using montelukast to treat lung cancer. METHODS: Migration was detected using wound-healing and Transwell assays, the expression of CysLT1 using western blotting, and subcellular localization of CysLT1 using immunofluorescence. CRISPR/Cas9 technology was used to further investigate the function of CysLT1. RESULTS: Subcellular localization staining showed that the CysLT1 distribution varied in murine and human lung cancer cell lines. Furthermore, montelukast suppressed CysLT1 expression in lung cancer cells. The treated cells also showed weaker migration ability compared with control cells. Knockout of CysLT1 using CRISPR/Cas9 editing in A549 cells further impaired the cell migration ability. CONCLUSION: Montelukast inhibits the migration of lung cancer cells by suppressing CysLT1 expression, demonstrating the potential of using CysLT1 as a therapeutic target in lung cancer.

Comparison of the Hydride-Donating Ability and Activity of Five- and Six-Membered Benzoheterocyclic Compounds in Acetonitrile.

In this work, we compared the hydride-donating ability of five-membered benzoheterocyclic compounds (FMB) and six-membered benzoheterocyclic compounds (SMB), isomers of DMBI and DMIZ and of DMPZ and DMPX, using detailed thermodynamic driving forces [ΔGo (XH)], kinetic intrinsic barriers (ΔG≠XH/X), and thermo-kinetic parameters [ΔG≠° (XH)]. For DMBI and DMIZ, the values of ΔGo (XH), ΔG≠XH/X, and ΔG≠° (XH) are 49.2 and 53.7 kcal/mol, 35.88 and 42.04 kcal/mol, and 42.54 and 47.87 kcal/mol, respectively. For DMPZ and DMPX, the values of ΔGo (XH), ΔG≠XH/X, and ΔG≠° (XH) are 73.2 and 79.5 kcal/mol, 35.34 and 25.02 kcal/mol, and 54.27 and 52.26 kcal/mol, respectively. It is easy to see that the FMB isomers are thermodynamically dominant and that the SMB isomers are kinetically dominant. Moreover, according to the analysis of ΔG≠° (XH), compared to the SMB isomers, the FMB isomers have a stronger hydride-donating ability in actual chemical reactions.

TET2 deficiency sensitizes tumor cells to statins by reducing HMGCS1 expression.

TET2 (ten-eleven-translocation) protein is a Fe(II)- and α-ketoglutarate-dependent dioxygenase that catalyzes DNA demethylation to regulate gene expression. While TET2 gene is frequently mutated in hematological cancer, its enzymatic activity is also compromised in various solid tumors. Whether TET2 deficiency creates vulnerability for cancer cells has not been studied. Here we reported that TET2 deficiency is associated with the change of lipid metabolism processes in acute myeloid leukemia (AML) patient. We demonstrate that statins, the inhibitors of ß-Hydroxy ß-methylglutaryl-CoA (HMG-CoA) reductase and commonly used cholesterol-lowering medicines, significantly sensitize TET2 deficient tumor cells to apoptosis. TET2 directly regulates the expression of HMG-CoA synthase (HMGCS1) by catalyzing demethylation on its promoter region, and conversely TET2 deficiency leads to significant down-regulation of HMGCS1 expression and the mevalonate pathway. Consistently, overexpression of HMGCS1 in TET2-deficient cells rescues statin-induced apoptosis. We further reveal that decrease of geranylgeranyl diphosphate (GGPP), an intermediate metabolite in the mevalonate pathway, is responsible for statin-induced apoptosis. GGPP shortage abolishes normal membrane localization and function of multiple small GTPases, leading to cell dysfunction. Collectively, our study reveals a vulnerability in TET2 deficient tumor and a potential therapeutic strategy using an already approved safe medicine.

Comparison between 1,2-Dihydropyridine and 1,4-Dihydropyridine on Hydride-Donating Ability and Activity.

In this paper, detailed comparisons of the driving force in thermodynamics and intrinsic force in the kinetics of 1,2-dihydropyridine and 1,4-dihydropyridine isomers of PNAH, HEH, and PYH in hydride transfer reactions are made. For 1,2-PNAH and 1,4-PNAH, the values of the thermodynamic driving forces, kinetic intrinsic barriers, and thermo-kinetic parameters are 60.50 and 61.90 kcal/mol, 27.92 and 26.34 kcal/mol, and 44.21 and 44.12 kcal/mol, respectively. For 1,2-HEH and 1,4-HEH, the values of the thermodynamic driving forces, kinetic intrinsic barriers, and thermo-kinetic parameters are 63.40 and 65.00 kcal/mol, 31.68 and 34.96 kcal/mol, and 47.54 and 49.98 kcal/mol, respectively. For 1,2-PYH and 1,4-PYH, the order of thermodynamic driving forces, kinetic intrinsic barriers, and thermo-kinetic parameters are 69.90 and 72.60 kcal/mol, 33.06 and 25.74 kcal/mol, and 51.48 and 49.17 kcal/mol, respectively. It is not difficult to find that thermodynamically favorable structures are not necessarily kinetically favorable. In addition, according to the analysis of thermo-kinetic parameters, 1,4-PNAH, 1,2-HEH, and 1,4-PYH have a strong hydride-donating ability in actual chemical reactions.

Plin2-mediated lipid droplet mobilization accelerates exit from pluripotency by lipidomic remodeling and histone acetylation.

Metabolic switch is critical for cell fate determination through metabolic functions, epigenetic modifications, and gene expression. However, the mechanisms underlying these alterations and their functional roles remain unclear. Here, we show that Plin2-mediated moderate lipid hydrolysis is critical for pluripotency of embryonic stem cells (ESCs). Upon exit from pluripotency, lipid droplet (LD)-associated protein Plin2 is recognized by Hsc70 and degraded via chaperone-mediated autophagy to facilitate LD mobilization. Enhancing lipid hydrolysis by Plin2 knockout promotes pluripotency exit, which is recovered by ATGL inhibition. Mechanistically, excessive lipid hydrolysis induces a dramatic lipidomic remodeling characterized by decreased cardiolipin and phosphatidylethanolamine, which triggers defects in mitochondrial cristae and fatty acid oxidation, resulting in reduced acetyl-CoA and histone acetylation. Our results reveal how LD mobilization is regulated and its critical role in ESC pluripotency, and indicate the mechanism linking LD homeostasis to mitochondrial remodeling and epigenetic regulation, which might shed light on development and diseases.

Morphological description and molecular identification of Myxobolus dajiangensis n. sp. (Myxozoa: Myxobolidae) from the gill of Cyprinus carpio in southwest China.

Background: Myxosporean diversity is a hot topic since they are difficult to accurately identify and classify. Many Myxobolus parasites have been named as Myxobolus koi because of their similar morphological features with the species originally reported. However, the distinctions in fine morphological features, host specificity, and molecular data have given rise to the attention of researchers. Methods: The classical morphometric and histological methods were used to describe the Myxobolus dajiangensis n. sp. in morphology. The common techniques in modern molecular biology and the methods of phylogenetic analyses were combined to identify the species. Results: Plasmodia of interlamellar-vascular type were found in the vascular network of gill lamellae. Mature myxospores of M. dajiangensis n. sp. were elongated and pyriform from the frontal view. The myxospores were 14.8 ± 0.4 (13.9-15.6) µm in length, 8.0 ± 0.5 (7.2-9.1) µm in width, and 5.5 µm in thickness. The two polar capsules were pyriform and slightly different in length. The length of the larger polar capsules was 8.0 ± 0.4 (7.1-8.8) µm, and it was 7.4 ± 0.4 (6.1-8.0) µm for the smaller ones. The width of both polar capsules was 2.5 ± 0.2 (2.0-3.2) µm. The polar filaments within the polar capsules were each coiled nine to 11 turns. Comparative analysis of both the morphological and molecular data between the present speices and other similar species revealed that the present species is a novel species, Myxobolus dajiangensis n. sp. Also, M. koi (FJ710800) was misidentified and the congener with M. dajiangensis n. sp., depending on the secondary structures of SSU rRNA and phylogenetic analysis. Moreover, the cryptic species existed in the M. koi parasites.

Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis.

BACKGROUND & AIMS: The liver is a metabolically active organ and is also 'tolerogenic', exhibiting sophisticated mechanisms of immune regulation that prevent pathogen attacks and tumorigenesis. How metabolism impacts the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains understudied. METHODS: We investigated the role of the metabolic regulator SIRT5 in HCC development by conducting metabolomic analysis, gene expression profiling, flow cytometry and immunohistochemistry analyses in oncogene-induced HCC mouse models and human HCC samples. RESULTS: We show that SIRT5 is downregulated in human primary HCC samples and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, via hypersuccinylation and increased BA biosynthesis in the peroxisomes of hepatocytes. BAs act as a signaling mediator to stimulate their nuclear receptor and promote M2-like macrophage polarization, creating an immunosuppressive TME that favors tumor-initiating cells (TICs). Accordingly, high serum levels of taurocholic acid correlate with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in HCC patient samples. Finally, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency in promoting M2-like polarized TAMs and liver tumor growth. CONCLUSIONS: This study uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC development. Our results also suggest a potential strategy of using clinically proven BA sequestrants for the treatment of patients with HCC, especially those with decreased SIRT5 and abnormally high BAs. LAY SUMMARY: Hepatocellular caricinoma (HCC) development is closely linked to metabolic dysregulation and an altered tumor microenvironment. Herein, we show that loss of the metabolic regulator Sirt5 promotes hepatocarcinogenesis, which is associated with abnormally elevated bile acids and subsequently an immunosuppressive microenvironment that favors HCC development. Targeting this mechanism could be a promising clinical strategy for HCC.

Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses.

As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.

Elevated nuclear localization of glycolytic enzyme TPI1 promotes lung adenocarcinoma and enhances chemoresistance.

Increased glycolysis is a hallmark of tumor, which can provide tumor cells with energy and building blocks to promote cell proliferation. Recent studies have shown that not only the expression of glycolytic genes but also their subcellular localization undergoes a variety of changes to promote development of different types of tumors. In this study, we performed a comprehensive analysis of glycolysis and gluconeogenesis genes based on data from TCGA to identify those with significant tumor-promoting potential across 14 types of tumors. This analysis not only confirms genes that are known to be involved in tumorigenesis, but also reveals a significant correlation of triosephosphate isomerase 1 (TPI1) with poor prognosis, especially in lung adenocarcinoma (LUAD). TPI1 is a glycolytic enzyme that interconverts dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP). We confirm the upregulation of TPI1 expression in clinical LUAD samples and an inverse correlation with the overall patient survival. Knocking down of TPI1 in lung cancer cells significantly reduced cell migration, colony formation, and xenograft tumor growth. Surprisingly, we found that the oncogenic function of TPI1 depends on its translocation to cell nucleus rather than its catalytic activity. Significant accumulation of TPI1 in cell nucleus was observed in LUAD tumor tissues compared with the cytoplasm localization in adjacent normal tissues. Moreover, nuclear translocation of TPI1 is induced by extracellular stress (such as chemotherapy agents and peroxide), which facilitates the chemoresistance of cancer cells. Our study uncovers a novel function of the glycolytic enzyme TPI1 in the LUAD.

Serum CCAT2 as a biomarker for adjuvant diagnosis and prognostic prediction of cervical cancer.

Growing evidence indicates that lncRNA colon cancer-associated transcript 2 (CCAT2) is associated with cancers. However, the clinical value of CCAT2 in cervical cancer (CC) remains unclear. In this study, serum CCAT2 level was detected by real-time quantitative PCR (RT-qPCR). Carbohydrate antigen 125 (CA125) and squamous-cell carcinoma antigen (SCC) were detected by electrochemiluminescence. A receiver operating characteristic (ROC) curve was utilized to estimate the diagnostic efficiency of CCAT2. Kaplan-Meier survival analysis and univariable and multivariable analyses were performed to assess the prognostic value of CCAT2. The relative expression level of CCAT2 in primary CC patients was significantly higher than that in cervical intraepithelial neoplasias (CIN) patients and healthy controls (both P < 0.001). CCAT2 relative expression was positively correlated with tumor Federation of Gynecology and Obstetrics (FIGO) stage, SCC-Ag and lymph node metastasis (LNM) (all P < 0.05). CCAT2 expression in recurrent/metastatic CC was significantly higher compared with primary CC (P < 0.0001) or operated CC (P < 0.0001) and during follow-up, CCAT2 expression was increased before surgery and decreased significantly after surgery (P < 0.0001). Furthermore, the overall survival rate of CC patients with high CCAT2 expression group markedly decreased as compared with that of low CCAT2 expression group (P = 0.026). Univariate analyses indicated that CCAT2 was a poor prognostic factor associated with overall survival (OS). Our study indicates that CCAT2 may be valuable in complementary diagnosis and monitoring of progression and prognosis of CC patients. Combined detection of CCAT2, CA125 and SCC can greatly improve the diagnostic efficiency of primary CC.

Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity.

DNA methyltransferases (DNMTs) catalyze DNA methylation, and their functions in mammalian embryonic development and diseases including cancer have been extensively studied. However, regulation of DNMTs remains under study. Here, we show that CCAAT/enhancer binding protein α (CEBPA) interacts with the long splice isoform DNMT3A, but not the short isoform DNMT3A2. CEBPA, by interacting with DNMT3A N-terminus, blocks DNMT3A from accessing DNA substrate and thereby inhibits its activity. Recurrent tumor-associated CEBPA mutations, such as preleukemic CEBPAN321D mutation, which is particularly potent in causing AML with high mortality, disrupt DNMT3A association and cause aberrant DNA methylation, notably hypermethylation of PRC2 target genes. Consequently, leukemia cells with the CEBPAN321D mutation are hypersensitive to hypomethylation agents. Our results provide insights into the functional difference between DNMT3A isoforms and the regulation of de novo DNA methylation at specific loci in the genome. Our study also suggests a therapeutic strategy for the treatment of CEBPA-mutated leukemia with DNA-hypomethylating agents.

Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer.

Background: DNA methylation is an important epigenetic modification, among which 5-methylcytosine methylation (5mC) is generally associated with tumorigenesis. Nonetheless, the potential roles of 5mC regulators in the tumor microenvironment (TME) remain unclear. Methods: The 5mC modification patterns of 1,374 lung adenocarcinoma samples were analyzed systematically. The correlation between the 5mC modification and tumor microenvironment cell infiltration was further assessed. The 5mCscore was developed to evaluate tumor mutation burden, immune check-point inhibitor response, and the clinical prognosis of individual tumors. Results: Three 5mC modification patterns were established based on the clinical characteristics of 21 5mC regulators. According to the differential expression of 5mC regulators, three distinct 5mC gene cluster were also identified, which showed distinct TME immune cell infiltration patterns and clinical prognoses. The 5mCscore was constructed to evaluate the tumor mutation burden, immune check-point inhibitor response, and prognosis characteristics. We found that patients with a low 5mCscore had significant immune cell infiltration and increased clinical benefit. Conclusion: This study indicated that the 5mC modification is involved in regulating TME infiltration remodeling. Targeting 5mC modification regulators might be a novel strategy to treat lung cancer.

Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK.

Obesity is an epidemic affecting 13% of the global population and increasing the risk of many chronic diseases. However, only several drugs are licensed for pharmacological intervention for the treatment of obesity. As a master regulator of metabolism, the therapeutic potential of AMPK is widely recognized and aggressively pursued for the treatment of metabolic diseases. We found that elaiophylin (Ela) rapidly activates AMPK in a panel of cancer-cell lines, as well as primary hepatocytes and adipocytes. Meanwhile, Ela inhibits the mTORC1 complex, turning on catabolism and turning off anabolism together with AMPK. In vitro and in vivo studies showed that Ela does not activate AMPK directly, instead, it increases cellular AMP/ATP and ADP/ATP ratios, leading to AMPK phosphorylation in a LKB1-dependent manner. AMPK activation induced by Ela caused changes in diverse metabolic genes, thereby promoting glucose consumption and fatty acid oxidation. Importantly, Ela activates AMPK in mouse liver and adipose tissue. As a consequence, it reduces body weight and blood glucose levels and improves glucose and insulin tolerance in both ob/ob and high-fat diet-induced obese mouse models. Our study has identified a novel AMPK activator as a candidate drug for the treatment of obesity and its associated chronic diseases.