Analytical Solution for Predicting the Elastic Modulus of a Cement Slurry System with the Effect of Calcium Dissolution.

The dissolution of calcium ions in concrete in a low-alkalinity environment is an important factor causing a significant increase in the porosity of internal concrete, leading to a deterioration in its mechanical properties and affecting the durability of the concrete structure. In order to improve the reliability of concrete durability design and significantly increase the service life of concrete structures located in soft water environments, it is crucial to establish an analytical method to predict the elastic modulus (Edc) of cement slurry systems suffering from calcium dissolution. Firstly, the hydrated cement particles are regarded as a three-phase composite sphere composed of unhydrated cement particles (UC), a high-density hydrated layer (H-HL), and a low-density hydrated layer (L-HL). By introducing the equivalent inclusion phase (EQ) composed of UC and H-HL, the three-phase composite sphere model can be simplified into an equivalent hydrated cement particle model composed of EQ and L-HL. Finally, the Edc of the two-phase composite sphere composed of the equivalent hydrated cement particles and the porosity of the dissolved cement slurry system are solved by using elasticity theory. The effectiveness of the developed analytical method is verified by comparing it with third-party numerical results. Based on this method, the effects of hydration degree, volume ratio of calcium hydroxide (CH) to hydrated calcium silicate (C-S-H), and volume ratio of inner C-S-H to outer C-S-H on the Edc of the dissolved cement slurry system are analyzed. The parameter analysis indicates that among the three influencing parameters, the hydration degree has the greatest effect on the Edc of the dissolved cement slurry system. This study provides an analytical method for predicting Edc, which can provide some references for the durability design of concrete after calcium dissolution.

Impact of CYP2C19 and CYP2C9 gene polymorphisms on sodium valproate plasma concentration in patients with epilepsy.

BACKGROUND: Valproic acid (VPA) is a broad spectrum anticonvulsant drug, which could be partially metabolised by cytochrome P450 (CYP) 2C9 and 2C19 enzymes. This study was designed to investigate the relationship between CYP2C19 and CYP2C9 gene polymorphisms and the plasma concentrations of VPA in subjects with epilepsy. METHODS: Eighty-three subjects with epilepsy aged 18-92 years were enrolled in this study. All were treated with sustained-release VPA monotherapy. Based on the genotypes of CYP2C19 and the ability to metabolise substrates, the subjects were divided into poor metabolisers, intermediate metabolisers and extensive metabolisers. Sanger sequencing was used to detect the genotypic and allelic frequencies of CYP2C19 (*1, *2 and *3) and CYP2C9 (*13) of the patients. Automatic immunity analysis was used to find steady-state trough plasma concentrations of VPA. By adjusting the plasma concentrations of VPA with body weight and total daily dose of VPA, the concentration-to-dose ratio of VPA (CDRV) was obtained. Data were analysed using SPSS software. RESULTS: The genetic frequencies of CYP2C19*2, CYP2C19*3 and CYP2C9*13 were 33.1%, 3.0% and 5.4%, respectively, among patients with epilepsy from Yunnan province, China who used VPA therapy. The CDRV was significantly lower in the CYP2C19 extensive metabolisers (3.33±1.78) than it was in the CYP2C19 intermediate metabolisers (4.45±1.42) and the CYP2C19 poor metabolizers (6.64±1.06). The CYP2C19*2 and CYP2C19*3 alleles were correlated with the plasma VPA concentration, while the CYP2C9*13 allele had no effect on the plasma VPA concentration (p=0.809). CONCLUSIONS: The genetic polymorphisms of CYP2C19 significantly affect the VPA plasma concentration, and the dosage of VPA for intermediate and poor metabolisers could be lower than for extensive metabolisers. CYP2C9*13 carrier was not closely related to plasma concentrations of VPA in patients with epilepsy.

Anti-androgen enzalutamide enhances prostate cancer neuroendocrine (NE) differentiation via altering the infiltrated mast cells → androgen receptor (AR) → miRNA32 signals.

The recently developed anti-androgen enzalutamide also known as (MDV3100) has the advantage to prolong by 4.8 months the survival of castration resistant prostate cancer (CRPC) patients. However, the mechanisms behind the potential side effects involving the induction of the prostate cancer (PCa) neuroendocrine (NE) differentiation remain unclear. Here we found PCa cells could recruit more mast cells than normal prostate epithelial cells, and enzalutamide (or casodex) treatment could further increase such recruitment that resulted in promoting the PCa NE differentiation. Mechanism dissection found infiltrated mast cells could function through positive feedback to enhance PCa to recruit more mast cells via modulation of the androgen receptor (AR) â†’ cytokines IL8 signals, and interruption by AR-siRNA or neutralizing anti-IL8 antibody could partially reverse the recruitment of mast cells. Importantly, targeting the PCa androgens/AR signals with AR-siRNA or enzalutamide (or casodex) also increased PCa NE differentiation via modulation of the miRNA32 expression, and adding miRNA32 inhibitor reversed the AR-siRNA- or enzalutamide-enhanced NE differentiation. Together, these results not only identified a new signal via infiltrated mast cells â†’ PCa AR â†’ miRNA32 to increase PCa NE differentiation, it also pointed out the potential unwanted side effects of enzalutamide (or casodex) to increase PCa NE differentiation. Targeting these newly identified signals, including AR, IL8, or miRNA32, may help us to better suppress PCa NE differentiation that is induced during ADT with anti-androgen enzalutamide (or casodex) treatment.

Infiltrating mast cells enhance prostate cancer invasion via altering LncRNA-HOTAIR/PRC2-androgen receptor (AR)-MMP9 signals and increased stem/progenitor cell population.

Early studies indicated that selective inflammatory immune cells in the prostate tumor microenvironment might be able to influence prostate cancer (PCa) progression. Here we found treating PCa cells with androgen deprivation therapy (ADT) results in the recruitment of more mast cells, which might then increase PCa cell invasion via down-regulation of AR signals in 4 different PCa cell lines. Mechanism dissection revealed infiltrating mast cells could decrease AR transcription via modulation of the PRC2 complex with LncRNA-HOTAIR at the AR 5' promoter region in PCa cells. The consequences of suppressing AR may then increase PCa cell invasion via increased MMP9 expression and/or increased stem/progenitor cell population. The in vivo mouse model with orthotopically xenografted PCa CWR22Rv1 cells with/without mast cells also confirmed that infiltrating mast cells could increase PCa cell invasion via suppression of AR signals. Together, our results provide a new mechanism for the ADT-enhanced PCa metastasis via altering the infiltrating mast cells to modulate PCa AR-MMP9 signals and/or AR-stem/progenitor cell population. Targeting these newly identified inflammatory mast cells-AR signals may help us to better suppress PCa metastasis at the castration resistant stage.

Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-ß1/Smad/MMP9 signals.

High fat dietary intake may increase the risk of prostate cancer (PCa). Pre-adipocytes, one of the basic components in the tumor microenvironment (TME), are capable of differentiating into adipose tissues and play key roles to affect PCa progression. Here we found the pre-adipocytes could be recruited more easily to PCa than its surrounding normal prostate tissue. In vitro co-culture system also confirmed PCa has a better capacity than normal prostate to recruit pre-adipocytes. The consequences of recruiting more pre-adipocytes may then increase PCa cell invasion. Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-ß1/Smad/MMP9 signals. The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling. Together, our results reveal a new mechanism showing pre-adipocytes in the prostate TME can be recruited to PCa to increase PCa metastasis via modulation of the miR-301a/AR/TGF-ß1/Smad/MMP9 signals. Targeting this newly identified signaling may help us to better inhibit PCa metastasis.