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Embryonic stem cells (ESCs) favor glycolysis over oxidative phosphorylation for energy production, and glycolytic metabolism is critical for pluripotency establishment, maintenance, and exit. However, an understanding of how glycolysis regulates the self-renewal and differentiation of ESCs remains elusive. Here, we demonstrated that protein lactylation, regulated by intracellular lactate, contributes to the self-renewal of ESCs. We further showed that Esrrb, an orphan nuclear receptor involved in pluripotency maintenance and extraembryonic endoderm stem cell (XEN) differentiation, is lactylated on K228 and K232. The lactylation of Esrrb enhances its activity in promoting ESC self-renewal in the absence of the LIF and XEN differentiation of ESCs by increasing its binding at target genes. Our studies reveal the importance of protein lactylation in the self-renewal and XEN differentiation of ESCs, and the underlying mechanism of glycolytic metabolism regulating cell fate choice. [ABSTRACT FROM AUTHOR]

Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development. [ABSTRACT FROM AUTHOR]

Background and Aim. Although a strong antitumor effect of lenvatinib has been noted for patients with unresectable hepatocellular carcinoma (HCC), its efficacy requires improvement. It is imperative to seek therapeutic strategies that combine Lenvatinib with other anticancer agents. In this study, we investigated the anticancer effect of combining lenvatinib with alisertib, aurora A kinase (AURKA) target drug, against HCC in vitro and in vivo. Methods. Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. Results. AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all P s < 0.01). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 μM vs. lenvatinib 1 μM + alisertib 0.1 μM 8.84 ± 0.84 vs. 34.0 ± 1.54 , P < 0.001). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all P s < 0.01). Conclusions. Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes. [ABSTRACT FROM AUTHOR]

We systematically investigate the scaling property of mesons (pions and kaons) and baryons (protons, Λ , Ξ and Ω) transverse momentum ( p T ) spectra at different centrality classes (0–5 % , 5–10 % , 10–20 % , 20–40 % , 40–60 % , 60–80 % and 80–100 %) in proton-lead collisions with center of mass energy per nucleon pair 5.02 TeV. In the low p T region with p T ≤ 3. 9   (3. 1 , 2. 5 , 2. 7 , 2. 4   and   2. 8) GeV/c, a universal scaling independent of the centrality is observed in the pion (kaon, proton, Λ , Ξ and Ω) spectra when a dilatation, p T → p T / K , is applied. Here, K is a scaling parameter depending on the centrality class. We find that the rates at which ln K changes with the logarithmic value of the average value of the number of participating nucleons, ln 〈 N part 〉 , are stronger for baryons than those for mesons. In the high p T region, there is a deviation from the scaling. The more peripheral the collisions are, the more obvious the violation of the scaling is. In the framework of the color string percolation (CSP) model, we show that mesons and baryons are generated from the decay of clusters formed by strings overlapping in the transverse plane with the same size dispersion but with different mean size. The mean size of clusters for baryons is smaller than that of mesons. For the same hadrons at different centrality classes, the mean size of clusters decreases with the increase of centrality. The fragmentation functions for cluster decay are different for different hadrons, while they are universal for the same hadrons at different centrality classes. The universal scaling of the meson and baryon spectra in the low p T region can be quantitatively understood with the CSP model at the same time. [ABSTRACT FROM AUTHOR]

Melanoma is an extremely rare tumor in Asia. This retrospective study aimed to identify the clinical characteristics and prognostic factors of metastatic melanoma patients at Tianjin Medical University Cancer Hospital over the last 30 years. Survival analysis was performed with Kaplan-Meier, log-rank test, and multivariate Cox regression method using SPSS 19.0 software. The 1-, 2-, and 5-year survival rates of metastatic melanoma patients were 52, 32, and 16 %, respectively. Median overall survival (OS) was 13.5 months, median progression-free survival (PFS) 9.0 months, and median disease-free survival 20.3 months. Furthermore, patients with a single metastatic site achieved better OS and PFS than those with two or more metastatic lesions (OS 21.6 vs. 8.9 months, P < 0.001; PFS 11.3 vs. 7.1 months, P < 0.001). Survival times of patients with visceral metastases were the shortest (OS 8.5 months; PFS 7.5 months). Specifically, patients with primary mucosal lesions had a worse OS (9.7 months) and PFS (6.8 months) than those with acral (19.2 and 15.6 months, respectively) or non-acral primary lesions (11.8 and 11.1 months, respectively). The treatment of advanced melanoma was unitary, and prognoses of patients with metastatic melanoma in China were poor. Visceral metastasis, multiple metastatic sites, and primary mucosal lesions were significant predictors of survival of patients with metastatic melanoma. Those with primary mucosal lesions had significantly worse survivals than those with primary cutaneous lesions. More active involvement in clinical studies and more feedback on various treatment options are required. [ABSTRACT FROM AUTHOR]

Among different winter precipitation types, freezing rain is the most dangerous and the most difficult to forecast. Nearly 84% of total freezing rain days in China occur over Guizhou province. Statistical analysis indicates that the frequency distribution of freezing rain over Guizhou is correlated to its topography. In this article, a typical freezing rain case from 2011 is selected to explore the impact of Guizhou topography on the distribution of freezing rain. Synoptic analysis shows that this event is dominated by two cold currents below 800 hPa and a warm, moist southwesterly at 700 hPa, which contribute to an overlaying surface cold layer and a warm layer aloft in central Guizhou. Freezing rain is developed through a 'warm rain process' under the mid-lower tropospheric warm layer. Contrasting numerical terrain experiments demonstrate that Guizhou terrain plays an essential role in the formation of freezing rain by influencing the set-up of the surface cold layer, warm layer and precipitation. Except for the effect of altitude, the vertical distance between the cold centre in the cold flow and the surface height also impacts on the formation of the surface cold layer. The intensities of the warm layer and inversion change after altering terrain height. The number of rainwater particles reaching the surface layer decreases as the surface temperature increases in the lowered terrain experiment, whereas the block of steeper windward slope results in an increase of surface precipitation in the heightened terrain experiment. The regions experiencing freezing rain shrink after reducing the terrain but spread southeastwards after raising the terrain. The unique topography of Guizhou including its elevation and distribution contributes to the highest frequency of freezing rain in China. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) is one of the major diseases of the urinary system in elderly men. Tanshinone IIA (Tan IIA) is the active ingredient extracted from the traditional Chinese medicine Salvia, and it has effects of anti-oxidation, anti-inflammation, vascular smooth muscle relaxation and tumour growth inhibition. The present study aimed to investigate the therapeutic potential of Tan IIA in the prevention and treatment of BPH. In a rat model of oestradiol/testosterone-induced BPH, Tan IIA inhibited the increase in the thickness of the peri-glandular smooth muscle layer, suppressed the expression of proliferating cell nuclear antigen (PCNA) in both prostate epithelial cells and stromal cells, downregulated the expression of androgen receptor (AR), oestrogen receptor α (ERα), cyclin B1 (CCNB1) and cyclin D1 (CCND1), and effectively prevented the development of the disorder. In vitro , Tan IIA inhibited the proliferation of human prostate stromal cell line WPMY-1 and epithelial cell line RWPE-1 in a dose- and time-dependent manner. In WPMY-1 cells, Tan IIA treatment arrested the cell cycle at the G2/M phase and downregulated the expression of CCNB1. However, in RWPE-1 cells, Tan IIA treatment arrested cell cycle at the G0/G1 phase and reduced the expression of CCND1. Tan IIA also reduced the expression of ERα and AR in WPMY-1 and RWPE-1 cells. These results suggest that Tan IIA can inhibit the growth of prostate stromal and epithelial cells both in vivo and in vitro by a mechanism that may involve arresting the cell cycle and downregulating ERα and AR expression. [ABSTRACT FROM AUTHOR]

Abstract: Mesenchymal to epithelial transition (MET) in carcinomas has been proposed to promote the growth of epithelial tumour cells at distant sites during metastasis. MET has also been suggested as an important biological and clinical process in mesenchymal tumors, sarcomas. Here we review studies on MET in sarcomas, including molecular markers, signalling mechanisms, regulation by micro RNAs and therapeutic implications. Accumulating evidences suggest that deeper investigation and understanding of MET in sarcomas would shed light on the pathogenesis of sarcomas and might lead to identification of potential clinical biomarkers for prognosis and targets for sarcoma therapeutics. [Copyright &y& Elsevier]

In early January 2011, southern China experienced another severe wintertime storm as in the winter of 2008. The storm consisted of a narrow east-west-oriented freezing rain band over central Guizhou with an extensive area of snow to the north and a rain swath to the south. This study investigates this event using conventional surface and radiosonde data as well as final (FNL) analyses data from the US National Center for Atmospheric Research/National Centers for Environmental Prediction(NCAR/NCEP). The results show that forcing by geostrophic and diabatic heating built up a positive direct secondary circulation perpendicular to the quasi-stationary front beneath 700 hPa to maintain the surface cold layer and warm layer aloft through surface cold advection and warm advection aloft. In addition, turbulence induced by strong wind shear in the middle and lower stratiform clouds with a low concentration of ice nuclei plays an important role in the growth of cloud drops and the enhancement of supercool raindrop precipitation over Guizhou. Copyright © 2011 Royal Meteorological Society [ABSTRACT FROM AUTHOR]

Food safety is one of the most important and widespread research topics worldwide. The development of relevant analytical methods or devices for detection of unsafe factors in foods is necessary to ensure food safety and an important aspect of the studies of food safety. In recent years, developing high-performance sensors used for food safety analysis has made remarkable progress. The combination of carbon-based nanomaterials with excellent properties is a specific type of sensor for enhancing the signal conversion and thus improving detection accuracy and sensitivity, thus reaching unprecedented levels and having good application potential. This review describes the roles and contributions of typical carbon-based nanomaterials, such as mesoporous carbon, single- or multi-walled carbon nanotubes, graphene and carbon quantum dots, in the construction and performance improvement of various chemo- and biosensors for various signals. Additionally, this review focuses on the progress of applications of this type of sensor in food safety inspection, especially for the analysis and detection of all types of toxic and harmful substances in foods. [ABSTRACT FROM AUTHOR]

As a complementary study to that performed on the transverse momentum (pT) spectra of charged pions, kaons and protons in proton-proton (pp) collisions at LHC energies 0.9, 2.76 and 7TeV, we present a scaling behaviour in the pT spectra of strange particles (KS0, Λ, Ξ and ϕ) at these three energies. This scaling behaviour is exhibited when the spectra are expressed in a suitable scaling variable z=pT/K, where the scaling parameter K is determined by the quality factor method and increases with the center of mass energy (s). The rates at which K increases with lns for these strange particles are found to be identical within errors. In the framework of the colour string percolation model, we argue that these strange particles are produced through the decay of clusters that are formed by the colour strings overlapping. We observe that the strange mesons and baryons are produced from clusters with different size distributions, while the strange mesons (baryons) KS0 and ϕ (Λ and Ξ) originate from clusters with the same size distributions. The cluster’s size distributions for strange mesons are more dispersed than those for strange baryons. The scaling behaviour of the pT spectra for these strange particles can be explained by the colour string percolation model in a quantitative way. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma is a highly genetically unstable tumor with poor prognosis. We performed microarray-based comparative genomic hybridization (aCGH), transcriptome sequencing (RNA-seq), and pathway analysis to gain a systemic view of the pathway alterations of osteosarcoma.Methods: aCGH experiments were carried out on 10 fresh osteosarcoma samples. The output data (Gene Expression Omnibus Series accession number GSE19180) were pooled with published aCGH raw data (GSE9654) to determine recurrent copy number changes. These were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify altered pathways in osteosarcoma. Transcriptome sequencing of six osteosarcomas was performed to detect the expression profile of Wnt signaling pathway genes. Protein expression of WNT1, β-catenin, c-myc, and cyclin D1 in the Wnt pathway was detected by immunohistochemistry (IHC) in an independent group of 46 osteosarcoma samples.Results: KEGG pathway analysis identified frequent deletions of Wnt and other Wnt signaling pathway genes. At the mRNA level, transcriptome sequencing found reduced levels of mRNA expression of Wnt signaling pathway transcripts. While WNT1 protein expression was detected by IHC in 69.6% (32/46) of the osteosarcomas, no β-catenin protein was detected in the nucleus. β-catenin protein expression was, however, detected in the membrane and cytoplasm of 69.6% (32/46) of the osteosarcomas. c-myc protein expression was detected in only 47.8% (22/46) and cyclin D1 protein expression in 52.2% (24/46) of osteosarcoma samples. Kaplan-Meier survival analysis showed that WNT1-negative patients had a trend towards longer disease free survival than WNT1-positive patients. Interestingly, in WNT1-negative patients, those who were also cyclin D1-negative had significantly longer disease free survival than cyclin D1-positive patients. However, there was no significant association between any of the investigated proteins and overall survival of human osteosarcoma patients.Conclusions: Frequent deletions of Wnt and other Wnt signaling pathway genes suggest that the Wnt signaling pathway is genetically inactivated in human osteosarcoma. [ABSTRACT FROM AUTHOR]

Abstract: Recent reports indicate prostaglandin E2 (PGE2) can modulate tumor environment and promote angiogenesis through induction of stromal cell-derived factor 1 (SDF-1) production. We investigated the mechanism of PGE2-induced SDF-1 regulation in human prostate stromal cell and analyzed the effects in a stromal–epithelial interaction model. PGE2 stimulation increased SDF-1 expression in the prostate stromal cell lines WPMY-1 and NAF. We revealed signaling through the PGE2 receptor EP3 and activation of protein kinase A (PKA) are required. The EP3 agonist sulprostone and the cAMP analog forskolin mimicked and the EP3 siRNA, antagonist L798106 and the PKA inhibitor H89 abrogated the effect of PGE2 on SDF-1 expression. SDF-1 promoter truncation experiments demonstrated a 254bp (from nt −219 to nt +34) SDF-1 proximal promoter fragment containing 5 putative transcription factor Sp1 binding motifs is sufficient for PGE2 induction. CHIP assays confirmed binding and PGE2 induced recruitment of Sp1 to the SDF-1 promoter. Sp1 motif mutation identified Sp1 motifs −140/−133 and −9/+1 as the crucial elements responsible for PGE2 induction. Moreover, SDF-1 was up- or down-regulated by Sp1 over-expression or knock-down. We also demonstrate stimulation of migration of prostate cancer cell lines PC3 and DU145 with conditioned media collected from WPMY-1 or NAF cells stimulated with PGE2 and blockade of enhanced migration by a SDF-1 neutralizing antibody. In conclusion, we provide evidence for a paracrine prostate stromal–epithelial interaction induced by upregulation of expression of SDF-1 by PGE2. Our research provides new insights into the mechanism promoting metastasis of prostate carcinoma via stromal–epithelial interaction. [Copyright &y& Elsevier]

Castration-resistant prostate cancer (CRPC) following androgen deprivation therapy remains a major obstacle advanced prostate cancer management. Aromatase catalyzes estrogen from androgens, yet the role of aromatase-generated endogenous estrogen in CRPC is poorly understood. In this study, we assessed the expression and function of aromatase in CRPC. We found that aromatase expression was significantly increased in CRPC tissues and cell lines. In some prostate cancer cell lines, aromatase was predominantly expressed in CD44+ subsets. Bicalutamide treatment significantly increased aromatase expression, and CYP19A1 expression positively correlated with estrogen responses and epithelial-mesenchymal transition. Aromatase knockdown in PC3 cells reduced invasiveness and decreased metastasis-related gene expression. The aromatase inhibitor, letrozole, attenuated tumour metastasis in castrated PC3-xenograft mice. Mechanistically, aromatase-induced endogenous estrogen promoted estrogen receptor-α (ERα) binding to matrix metalloproteinase 12 (MMP12) promoter estrogen response element (ERE). MMP12 co-localized with CD44 on the cell membrane and MMP12 knockdown significantly reduced estradiol-induced PC3 invasion. Taken together, our findings indicated that increased endogenous estrogen, catalysed by elevated aromatase levels, enhanced MMP12 expression via ERα, participated in CRPC progression and promoted tumour metastasis. Thus, aromatase represents a potential novel therapeutic target for CRPC. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) is one of the major disorders of the urinary system in elderly men. Docosahexaenoic acid (DHA) is the main component of n-3 polyunsaturated fatty acids (n-3 PUFAs) and has nerve protective, anti-inflammatory and tumour-growth inhibitory effects. Here, the therapeutic potential of DHA in treating BPH was investigated. Seal oil effectively prevented the development of prostatic hyperplasia induced by oestradiol/testosterone in a rat model by suppressing the increase of the prostatic index (PI), reducing the thickness of the peri-glandular smooth muscle layer, inhibiting the proliferation of both prostate epithelial and stromal cells, and downregulating the expression of androgen receptor (AR) and oestrogen receptor α (ERα). An in vitro study showed that DHA inhibited the growth of the human prostate stromal cell line WPMY-1 and the epithelial cell line RWPE-1 in a dose- and time-dependent manner. In both cell lines, the DHA arrested the cell cycle in the G2/M phase. In addition, DHA also reduced the expression of ERα and AR in the WPMY-1 and RWPE-1 cells. These results indicate that DHA inhibits the multiplication of prostate stromal and epithelial cells through a mechanism that may involve cell cycle arrest and the downregulation of ERα and AR expression. [ABSTRACT FROM AUTHOR]