Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.

Benign prostatic hyperplasia (BPH), a common disease in elderly males, is accompanied by non-malignant growth of prostate tissues, subsequently causing hypoxia and angiogenesis. Although VEGF-related angiogenesis is one of the therapeutic targets of prostate cancer, there is no previous study targeting angiogenesis for treatment of BPH. Dihydrotestosterone (DHT)-induced expressions of vascular endothelial growth factor (VEGF) in prostate epithelial RWPE-1 cells and human umbilical vascular endothelial cells (HUVECs). Conditioned media (CM) from DHT-treated RWPE-1 cells were transferred to HUVECs. Then, 6SL inhibited proliferation, VEGFR-2 activation, and tube formation of HUVECs transferred with CM from DHT-treated RWPE-1 cells. In the rat BPH model, 6SL reduced prostate weight, size, and thickness of the prostate tissue. Formation of vessels in prostatic tissues were also reduced with 6SL treatment. We found that 6SL has an ameliorative effect on in vitro and in vivo the BPH model via inhibition of VEGFR-2 activation and subsequent angiogenesis. These results suggest that 6SL might be a candidate for development of novel BPH drugs.

Studies on acetone–butanol–ethanol (ABE) fermentation of sugars from lignocellulosic biomass have been actively carried out in recent years, and recombinant strains have been developed to efficiently coutilize glucose and xylose, which are the dominant sugar types in most lignocellulosic biomass. However, there is a lack of mathematical models for describing and predicting the simultaneous utilization of glucose and xylose in ABE fermentation, particularly for the purpose of supporting optimization and control of the process. This study proposes a kinetic model for ABE fermentation with coutilization of glucose and xylose by recombinant Clostridium acetobutylicum. The model is developed based on unstructured models, that is, the Monod equation and the Luedeking–Piret model, and a modified concentration-dependent weighting factor is suggested to describe the simultaneous utilization of glucose and xylose based on the experimental analysis. A systematic identification approach is employed to obtain reliable estimates of model parameters for the cofermentation process, which involves highly nonlinear and correlated kinetics. The glucose- and xylose-associated parameter groups are sequentially estimated using single substrate- and cofermentation data, respectively, and in the combined model, a subset of the parameters is selected through an identifiability analysis for further refinement. The developed model is shown to accurately predict the dynamics of the cofermentation of glucose and xylose in ABE production at various glucose-to-xylose ratios, feeding rates, and feed concentrations.

Background: B3 breast lesions identified on core needle biopsy have uncertain malignant potential. Traditional management of these lesions has been surgical excision, but there is growing interest in less invasive and more cost-effective alternatives such as vacuumassisted excisional biopsy (VAEB). Determining the rate of malignant upgrade for B3 lesions is important as it may identify low-risk lesions where VAEB could be considered. Methods: A retrospective study was conducted of women undergoing an elective excisional biopsy for a B3 lesion identified on core needle biopsy at a tertiary Australian breast centre. The pre-operative biopsy diagnosis and subsequent excisional biopsy diagnosis were used to calculate the proportion of cases where the diagnosis was upgraded to malignancy. Results: A total of 299 eligible patients were identified. Pre-operative diagnosis of papillary lesion with atypia was associated with the highest upgrade rate (50%, n = 12). The next highest upgrade rates occurred in those with flat epithelial atypia (37.50%, n = 8); atypical ductal hyperplasia (24.71%, n = 85); lobular carcinoma in situ (LCIS)/atypical lobular hyperplasia with calcification (17.65%, n = 17); and papillary lesion without atypia (4.72%, n = 106). Patients with radial scar (n = 51), classical LCIS without calcification (n = 7) and mucocoele-like lesion (n = 8) had a 0% upgrade rate. Conclusion: VAEB may be appropriate for low malignant risk lesions such as papillary lesion without atypia, mucocoele-like lesion and radial scar lesion without atypia. Opensurgical-excisional biopsy remains appropriate for high upgrade lesions such as atypical ductal hyperplasia, papillary lesion with atypia, flat epithelial atypia and classical LCIS with calcification. Long-term prospective randomized multicentre studies and continuing multidisciplinary approach is recommended for future clinical implementation.