FoxM1B regulates NEDD4-1 expression, leading to cellular transformation and full malignant phenotype in immortalized human astrocytes.

Our recent studies have shown that the FoxM1B transcription factor is overexpressed in human glioma tissues and that the level of its expression correlates directly with glioma grade. However, whether FoxM1B plays a role in the early development of glioma (i.e., in transformation) is unknown. In this study, we found that the FoxM1B molecule causes cellular transformation and tumor formation in normal human astrocytes (NHA) immortalized by p53 and pRB inhibition. Moreover, brain tumors that arose from intracranial injection of FoxM1B-expressing immortalized NHAs displayed glioblastoma multiforme (GBM) phenotypes, suggesting that FoxM1B overexpression in immortalized NHAs not only transforms the cells but also leads to GBM formation. Mechanistically, our results showed that overexpression of FoxM1B upregulated NEDD4-1, an E3 ligase that mediates the degradation and downregulation of phosphatase and tensin homologue (PTEN) in multiple cell lines. Decreased PTEN in turn resulted in the hyperactivation of Akt, which led to phosphorylation and cytoplasmic retention of FoxO3a. Blocking Akt activation with phosphoinositide 3-kinase/Akt inhibitors inhibited the FoxM1B-induced transformation of immortalized NHAs. Furthermore, overexpression of FoxM1B in immortalized NHAs increased the expression of survivin, cyclin D1, and cyclin E, which are important molecules for tumor growth. Collectively, these results indicate that overexpression of FoxM1B, in cooperation with p53 and pRB inhibition in NHA cells, promotes astrocyte transformation and GBM formation through multiple mechanisms

Breaking Glucose Transporter 1/Pyruvate Kinase M2 Glycolytic Loop Is Required for Cantharidin Inhibition of Metastasis in Highly Metastatic Breast Cancer

Aerobic glycolysis plays a decisive role in cancer growth. However, its role in cancer metastasis was rarely understood. Cantharidin a natural compound from an arthropod insect cantharis exerts potent anticancer activity. Here we found cantharidin possesses significant anti-metastatic activity on breast cancer dependent on inhibition of aerobic glycolysis. Cantharidin indicates significant inhibition on migration and invasion of breast cancer cells, angiogenesis in vitro, and inhibits breast cancer cells metastasizing to liver and lung in vivo. Subsequent results revealed that cantharidin decreases the extracellular acidification rates (ECAR) but increases the oxygen consumption rates (OCR) in high metastatic cells, leading to suppression of aerobic glycolysis. This was considered to be due to inhibiting the activity of pyruvate kinase (PK) and further blocking pyruvate kinase M2 (PKM2) translocation in nucleus. Fructose-1,6-bisphosphate (FBP) and L-cysteine can significantly reverse cantharidin inhibition on breast cancer cell migration, invasion, and PKM2 translocation. Furthermore, glucose transporter 1 (GLUT1) forming a metabolic loop with PKM2 is downregulated, as well as epidermal growth factor receptor (EGFR), the regulator of the glycolytic loop. Totally, cantharidin inhibits the PKM2 nuclear translocation and breaks GLUT1/PKM2 glycolytic loop, resulting in aerobic glycolysis transformation to oxidation and subsequent reversing the metastases in breast cancer. Based on inhibiting multi signals mediated aerobic glycolysis, cantharidin could be prospectively used for prevention of metastasis in breast cancer patients

Detecting the Candidate Gender Determinants by Bioinformatic Prediction of miRNAs and Their Targets from Transcriptome Sequences of the Male and Female Flowers in Salix suchowensis

MicroRNAs (miRNAs) belong to a class of small, noncoding, and endogenous single-stranded RNAs that negatively regulate gene expression at the posttranscriptional level. Potential miRNAs can be identified based on sequence homology since miRNAs are highly conserved in plants. In this study, we aligned the expressed sequence tags derived from flower buds of male and female S. suchowensis to miRNAs in the miRBase, which enable us to identify 34 potential miRNAs from flower buds of the alternate sexes. Among them, 11 were from the female and 23 were from the male. Analyzing sequence complementarity led to identification of 124 and 55 miRNA targets in the male and female flower buds, respectively. By mapping the target genes of the predicted miRNAs to the sequence assemblies of S. suchowensis, a miR156 mediated gene was detected at the gender locus of willow, which was a transcription factor involved in flower development. It is noteworthy that this target is not expressed in male flower, while it is expressed fairly highly in female flower based on the transcriptome data derived from the alternate sexes of willows. This study provides new bioinformatic clue for further exploring the genetic mechanism underlying gender determination in willows

The multi-staged “golden zones” of hydrocarbon exploration in superimposed petroliferous basins of onshore China and its significance

The hydrocarbon generation model proposed by Tissot et al. points out the temperature and depth of “liquid HC window”, which has become a “golden zone” for hydrocarbon exploration. It has been proved by exploration that multi-staged “golden zones” for hydrocarbon exploration is commonly developed in the superimposed petroliferous basins of onshore China. There are three factors for the formation of multi-staged “golden zones” of HC exploration in the superimposed basins: (1) source kitchens developed with multi-periods and multi-centers which have verified to lead multi-stages of HC generation with large scale, (2) multi-staged reservoirs develop with large scale, (3) hydrocarbon accumulations occur with the multi-periods and late effectiveness. The conventional source kitchens, dispersed liquid HC-cracking gas kitchens and effective reservoirs with large scale join together to control the distribution of “golden zones” in timing and space. Explorational “golden zones” have the characteristics of inherited stacking and lateral variation. Paleo-highs, paleo-slopes, paleo-platform margins, and multi-period inherited fault zones control the distribution of hydrocarbons in the explorational “golden zones”. The concept of multi explorational “golden zones” helps to deepen the knowledge of new hydrocarbon distributional regularity which revealed recently in China. It shows that there exist economic resources in the deep section of the superimposed basins of onshore China. The hydrocarbon discovery history in the superimposed petroliferous basins has the feature of multi-peaks of proven reserve increase and lasting a quite long, which indicates a huge potential for future exploration. Key words: superimposed basin, multi-staged HC exploration golden zone, conventional source kitchen, dispersed hydrocarbon- cracking gas kitchen, large scaled reservoir rock, multi-period hydrocarbon accumulation, deep section, China onshor

Petroleum geological features and exploration prospect of deep marine carbonate rocks in China onshore: A further discussion

Deep marine carbonate rocks have become one of the key targets of onshore oil and gas exploration and development for reserves replacement in China. Further geological researches of such rocks may practically facilitate the sustainable, steady and smooth development of the petroleum industry in the country. Therefore, through a deep investigation into the fundamental geological conditions of deep marine carbonate reservoirs, we found higher-than-expected resource potential therein, which may uncover large oil or gas fields. The findings were reflected in four aspects. Firstly, there are two kinds of hydrocarbon kitchens which were respectively formed by conventional source rocks and liquid hydrocarbons cracking that were detained in source rocks, and both of them can provide large-scale hydrocarbons. Secondly, as controlled by the bedding and interstratal karstification, as well as the burial and hydrothermal dolomitization, effective carbonate reservoirs may be extensively developed in the deep and ultra-deep strata. Thirdly, under the coupling action of progressive burial and annealing heating, some marine source rocks could form hydrocarbon accumulations spanning important tectonic phases, and large quantity of liquid hydrocarbons could be kept in late stage, contributing to rich oil and gas in such deep marine strata. Fourthly, large-scale uplifts were formed by the stacking of multi-episodic tectonism and oil and gas could be accumulated in three modes (i.e., stratoid large-area reservoir-forming mode of karst reservoirs in the slope area of uplift, back-flow type large-area reservoir-forming mode of buried hill weathered crust karst reservoirs, and wide-range reservoir-forming mode of reef-shoal reservoirs); groups of stratigraphic and lithologic traps were widely developed in the areas of periclinal structures of paleohighs and continental margins. In conclusion, deep marine carbonate strata in China onshore contain the conditions for widely and intensively preserving hydrocarbons, so large oil or gas fields are expected

Enantiomeric Separation and Determination of the Enantiomeric Impurity of Armodafinil by Capillary Electrophoresis with Sulfobutyl Ether-β-cyclodextrin as Chiral Selector

A selective capillary electrophoresis method using sulfobutyl ether-β-cyclodextrin as a chiral selector was developed and validated for the determination of the enantiomeric impurity of (R)-modafinil, i.e., armodafinil. Several parameters were optimized for a satisfactory enantioresolution, including the type and concentration of chiral selector and organic modifier, pH of background electrolyte (BGE), capillary temperature. The finally adopted condition was: 20 mmol/L phosphate buffer at pH 7.5, containing 20 mmol/L sulfobutyl ether-β-cyclodextrin and 20% methanol, at temperature of 25 °C. A good resolution of 3.3 for the two enantiomers of modafinil was achieved by applying the optimal conditions. The limit of detection (LOD) and limit of quantification (LOQ) of (S)-modafinil were 1.25 μg/mL and 2.50 μg/mL, respectively. The established method was also proven to display good selectivity, repeatability, linearity and accuracy. Finally, the method was used to investigate the enantiomeric purity of armodafinil in bulk samples

Seven cases of dermatitis caused by benzalkonium chloride disinfectant

Objective To analyze the clinical manifestations and histopathological features of 7 cases of dermatitis caused by benzalkonium chloride disinfectant, so as to enhance the understanding of this disease. Methods We retrospectively analyzed the clinical manifestations and pathological features of benzalkonium disinfectant-induced contact dermatitis in 7 cases who visited our clinic from August to November 2022. Results The clinical manifestations were repeated annular erythema and desquamation at the rubbing sites of the skin. The histopathological features of 4 cases were sponge formation, acanthosis and perivascular inflammation in the superficial dermis. Accumulation of neutrophils in the epidermis and the dermis was observed in 2 cases. Patients were treated with the systemic glucocorticoids and cyclosporine, and advised to avoid contact with benzalkonium chloride disinfectant. Conclusions Contact dermatitis caused by benzalkonium chloride disinfectant has specific manifestations and good response to the treatments. The skin patch test would be helpful to confirm the diagnosis