The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer.

The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.

Differences in the Immune Response of the Nonmetastatic Axillary Lymph Nodes between Triple-Negative and Luminal A Breast Cancer Surrogate Subtypes.

Breast cancer (BC) comprises four immunohistochemical surrogate subtypes of which triple-negative breast cancer (TNBC) has the highest risk of mortality. Axillary lymph nodes (ALNs) are the regions where BC cells first establish before distant metastasis, and the presence of tumor cells in the ALN causes an immune tolerance profile that contrasts with that of the nonmetastatic ALN (ALN-). However, few studies have compared the immune components of the ALNs- in BC subtypes. The present study aimed to determine whether differences between immune populations in the primary tumor and ALNs- were associated with the luminal A or TNBC subtype. We evaluated a retrospective cohort of 144 patients using paraffin-embedded biopsies. The TNBC samples tended to have a higher histologic grade and proliferation index and had higher levels of immune markers compared with luminal A in primary tumors and ALNs-. Two methods for validating the multivariate analysis found that histologic grade, intratumoral S100 dendritic cells, and CD8 T lymphocytes and CD57 natural killer cells in the ALNs- were factors associated with TNBC, whereas CD83 dendritic cells in the ALNs- were associated with the luminal A subtype. In conclusion, we found that intratumoral regions and ALNs- of TNBC contained higher concentrations of markers related to immune tolerance than luminal A. This finding partially explains the worse prognosis of patients with TNBC.

A Mix of Natural Bioactive Compounds Reduces Fat Accumulation and Modulates Gene Expression in the Adipose Tissue of Obese Rats Fed a Cafeteria Diet.

Scientists are focusing on bioactive ingredients to counteract obesity. We evaluated whether a mix containing grape seed proanthocyanidin extract (GSPE), anthocyanins, conjugated linoleic acid (CLA), and chicken feet hydrolysate (CFH) could reduce body fat mass and also determined which mechanisms in the white adipose tissue (WAT) and the brown adipose tissue (BAT) were affected by the treatment. The mix or vehicle (VH) were administered for three weeks to obese rats fed a cafeteria (CAF) diet. Biometric measures, indirect calorimetry, and gene expression in WAT and BAT were analyzed as was the histology of the inguinal WAT (IWAT). The individual compounds were also tested in the 3T3-L1 cell line. The mix treatment resulted in a significant 15% reduction in fat (25.01 ± 0.91 g) compared to VH treatment (21.19 ± 1.59 g), and the calorimetry results indicated a significant increase in energy expenditure and fat oxidation. We observed a significant downregulation of Fasn mRNA and an upregulation of Atgl and Hsl mRNA in adipose depots in the group treated with the mix. The IWAT showed a tendency of reduction in the number of adipocytes, although no differences in the total adipocyte area were found. GSPE and anthocyanins modulated the lipid content and downregulated the gene and protein levels of Fasn compared to the untreated group in 3T3-L1 cells. In conclusion, this mix is a promising treatment against obesity, reducing the WAT of obese rats fed a CAF diet, increasing energy expenditure and fat oxidation, and modifying the expression of genes involved in lipid metabolism of the adipose tissue.

Peritumoral immune infiltrates in primary tumours are not associated with the presence of axillary lymph node metastasis in breast cancer: a retrospective cohort study.

BACKGROUND: The axillary lymph nodes (ALNs) in breast cancer patients are the body regions to where tumoral cells most often first disseminate. The tumour immune response is important for breast cancer patient outcome, and some studies have evaluated its involvement in ALN metastasis development. Most studies have focused on the intratumoral immune response, but very few have evaluated the peritumoral immune response. The aim of the present article is to evaluate the immune infiltrates of the peritumoral area and their association with the presence of ALN metastases. METHODS: The concentration of 11 immune markers in the peritumoral areas was studied in 149 patients diagnosed with invasive breast carcinoma of no special type (half of whom had ALN metastasis at diagnosis) using tissue microarrays, immunohistochemistry and digital image analysis procedures. The differences in the concentration of the immune response of peritumoral areas between patients diagnosed with and without metastasis in their ALNs were evaluated. A multivariate logistic regression model was developed to identify the clinical-pathological variables and the peritumoral immune markers independently associated with having or not having ALN metastases at diagnosis. RESULTS: No statistically significant differences were found in the concentrations of the 11 immune markers between patients diagnosed with or without ALN metastases. Patients with metastases in their ALNs had a higher histological grade, more lymphovascular and perineural invasion and larger-diameter tumours. The multivariate analysis, after validation by bootstrap simulation, revealed that only tumour diameter (OR = 1.04; 95% CI [1.00-1.07]; p = 0.026), lymphovascular invasion (OR = 25.42; 95% CI [9.57-67.55]; p < 0.001) and histological grades 2 (OR = 3.84; 95% CI [1.11-13.28]; p = 0.033) and 3 (OR = 5.18; 95% CI [1.40-19.17]; p = 0.014) were associated with the presence of ALN metastases at diagnosis. This study is one of the first to study the association of the peritumoral immune response with ALN metastasis. We did not find any association of peritumoral immune infiltrates with the presence of ALN metastasis. Nevertheless, this does not rule out the possibility that other peritumoral immune populations are associated with ALN metastasis. This matter needs to be examined in greater depth, broadening the types of peritumoral immune cells studied, and including new peritumoral areas, such as the germinal centres of the peritumoral tertiary lymphoid structures found in extensively infiltrated neoplastic lesions.

Metabolomics Elucidates Dose-Dependent Molecular Beneficial Effects of Hesperidin Supplementation in Rats Fed an Obesogenic Diet.

Metabolic syndrome (MetS) is a global epidemic concern. Polyphenols are proposed as good candidates for its prevention, although their mechanisms are not fully understood. The gut microbiota seems to play a key role in polyphenol beneficial effects. Here, we assessed the effects of the citrus polyphenol hesperidin combining an untargeted metabolomics approach, which has an inherent potential to elucidate the host-microbiome interplay, with extensive anthropometric and biochemical characterizations and integrating metabolomics results with our previous 16S rRNA bacterial sequencing data. The rats were fed either a standard or an obesogenic cafeteria diet (CAF) for 17 weeks. After nine weeks, rats were supplemented with vehicle; low- (H1), or high- (H2) hesperidin doses. CAF animals developed MetS features. Hesperidin supplementation in CAF rats decreased the total cholesterol, LDL-C, and free fatty acids. The highest hesperidin dose also ameliorated blood pressure, insulin sensitivity, and decreased markers of arterial stiffness and inflammation. Metabolomics revealed an improvement of the lipidomic profile, decreases in circulating amino acids, and lower excretions of inflammation- and oxidative stress-related metabolites. Bacteroidaceae increases in the CAF-H2 group paralleled higher excretions of microbial-derived metabolites. Overall, our results provide detailed insights into the molecular effects of hesperidin on MetS and suggest that it is a promising prebiotic for the treatment of MetS and related conditions.

The Immune Response in Nonmetastatic Axillary Lymph Nodes Is Associated with the Presence of Axillary Metastasis and Breast Cancer Patient Outcome.

Tumor cells can modify the immune response in primary tumors and in the axillary lymph nodes with metastasis (ALN+) in breast cancer (BC), influencing patient outcome. We investigated whether patterns of immune cells in the primary tumor and in the axillary lymph nodes without metastasis (ALN-) differed between patients diagnosed without ALN+ (diagnosed-ALN-) and with ALN+ (diagnosed-ALN+) and the implications for clinical outcome. Eleven immune markers were studied using immunohistochemistry, tissue microarray, and digital image analysis in 141 BC patient samples (75 diagnosed-ALN+ and 66 diagnosed-ALN-). Two logistic regression models were derived to identify the clinical, pathologic, and immunologic variables associated with the presence of ALN+ at diagnosis. There are immune patterns in the ALN- associated with the presence of ALN+ at diagnosis. The regression models revealed a small subgroup of diagnosed-ALN+ with ALN- immune patterns that were more similar to those of the ALN- of the diagnosed-ALN-. This small subgroup also showed similar clinical behavior to that of the diagnosed-ALN-. Another small subgroup of diagnosed-ALN- with ALN- immune patterns was found whose members were more similar to those of the ALN- of the diagnosed-ALN+. This small subgroup had similar clinical behavior to the diagnosed-ALN+. These data suggest that the immune response present in ALN- at diagnosis could influence the clinical outcome of BC patients.

Immune response profile of primary tumour, sentinel and non-sentinel axillary lymph nodes related to metastasis in breast cancer: an immunohistochemical point of view.

Approximately 1.67 million new cases of breast cancer (BC) are diagnosed annually, and patient survival significantly decreases when the disease metastasizes. The axillary lymph nodes (ALNs) are the main doorway for BC tumoral cell escape, through which cells can disseminate to distant organs. The immune response, which principally develops in the lymph nodes, is linked to cancer progression, and its efficacy at controlling tumoral growth is compromised during the disease. Immunohistochemistry (IHC) is one of the most widely used research techniques for studying the immune response. It allows the measurement of the expression of particular markers related to the immune populations. This review focuses on the role of the immune populations in the primary tumour in the locoregional metastasis of the ALN, and the relationship of the immune response in these regions to distant metastasis. We considered only studies of immune cells using IHC techniques. In particular, lymphocytes, macrophages and dendritic cells all play important roles in BC and have been extensively studied. Although further research is needed, there is much evidence of their role in the invasion of the ALN and distant organs. Their association with tumoral growth or protection has not yet been demonstrated decisively and is very likely to be determined by a combination of factors. Moreover, even though IHC is a widely used technique in cancer diagnosis and research, there is still room for improvement, since its quantification needs to be properly standardized.

Seasonal consumption of polyphenol-rich fruits affects the hypothalamic leptin signaling system in a photoperiod-dependent mode.

Leptin has a central role in the maintenance of energy homeostasis, and its sensitivity is influenced by both the photoperiod and dietary polyphenols. The aim of this study was to investigate the effect of seasonal consumption of polyphenol-rich fruits on the hypothalamic leptin signaling system in non-obese and obese animals placed under different photoperiods. Non-obese and diet-induced obese male Fischer 344 rats were placed under either a short-day (SD) or long-day (LD) photoperiod and were supplemented with either 100 mg/kg of lyophilized red grapes or cherries. In non-obese animals, both fruits reduced energy balance independent of the photoperiod to which they were placed. However, the hypothalamic gene expression of Pomc was significantly up-regulated only in the SD photoperiod. In contrast, in obese animals only cherry significantly decreased the energy balance, although both fruits were able to counteract the diet-induced increase in hypothalamic AgRP mRNA levels when consumed during the SD photoperiod. In conclusion, the consumption of rich-polyphenol fruits may increase leptin sensitivity through the modulation of the hypothalamic leptin signal pathway mainly when consumed in the SD photoperiod. Therefore, fruit seasonality should be considered, as it can influence energy homeostasis and obesity.