Improving whole tomato transformation for prostate health: benign prostate hypertrophy as an exploratory model

It is well-established that the beneficial properties of single phytonutrients can be better attained when they are taken with the complex of the molecules present in their natural milieu. Tomato, the fruit providing the most comprehensive complex of prostate-health-preserving micronutrients, has been shown to be superior to its single-nutrient counterparts in decreasing the incidence of age-related prostate diseases. Herein, we describe a novel tomato food supplement enriched with olive polyphenols, containing cis-lycopene concentrations far exceeding those present in industry-produced tomato commodities. The supplement, endowed with antioxidant activity comparable to that of N-acetylcysteine, significantly reduced, in experimental animals, the blood levels of prostate-cancer-promoting cytokines. In prospective, randomized, double-blinded, placebo-controlled studies performed on patients affected by benign prostatic hyperplasia, its uptake significantly improved urinary symptoms and quality of life. Therefore, this supplement can complement and, in some cases, be an alternative to current benign prostatic hyperplasia management. Furthermore, the product suppressed carcinogenesis in the TRAMP mouse model of human prostate cancer and interfered with prostate cancer molecular signaling. Thus, it may offer a step forward in exploring the potential of tomato consumption to delay or prevent the onset of age-related prostate diseases in high-risk individuals

Effects of Dietary Supplementation of Carnosine on Mitochondrial Dysfunction, Amyloid Pathology, and Cognitive Deficits in 3xTg-AD Mice

BACKGROUND: The pathogenic road map leading to Alzheimer's disease (AD) is still not completely understood; however, a large body of studies in the last few years supports the idea that beside the classic hallmarks of the disease, namely the accumulation of amyloid-β (Aβ) and neurofibrillary tangles, other factors significantly contribute to the initiation and the progression of the disease. Among them, mitochondria failure, an unbalanced neuronal redox state, and the dyshomeostasis of endogenous metals like copper, iron, and zinc have all been reported to play an important role in exacerbating AD pathology. Given these factors, the endogenous peptide carnosine may be potentially beneficial in the treatment of AD because of its free-radical scavenger and metal chelating properties. METHODOLOGY: In this study, we explored the effect of L-carnosine supplementation in the 3xTg-AD mouse, an animal model of AD that shows both Aβ- and tau-dependent pathology. PRINCIPAL FINDINGS: We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits. CONCLUSIONS AND SIGNIFICANCE: Our data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD

Vav1 is ectopically expressed in breast tumors in which reduces the efficiency of the metastatic process

Vav1, normally restricted to hematopoietic cells, results ectopically expressed in solid tumors, including breast cancer (Sebban et al., 2013) in which, contrarily to other neoplasias, seems to be higher in tumors from patients who remained diseasefree than in patients who developed recurrence (Lane et al., 2008). The significance of Vav1 expression in breast tumors was evaluated by immunohistochemical analysis on TMAs containing invasive breast tumors from patients without lymph node involvement. Our findings indicate that Vav1 is expressed in almost all investigated cancers and shows a peculiar localization inside the nucleus of tumor cells. High amounts of nuclear Vav1 positively correlates with low incidence of relapse, regardless phenotype and molecular subtype of the neoplasia. Experiments performed with breast tumor-derived cells showing different morphology, immunoprofile and invasive properties indicated that Vav1 negatively modulates their invasiveness in vitro and their metastatic efficiency in vivo, possibly by affecting the expression of genes involved in invasion and/or metastasis of breast cancer. Since the high heterogeneity of breast tumors makes difficult to predict the evolution of early neoplasias, the evaluation of nuclear Vav1 levels may help in profiling and management of early breast cancer patients. In addition, Vav1 may serve as a target for new therapies designed to prevent breast cancer progression

epcam expression is an indicator of increased incidence of relapse in p53 positive breast cancer

Originally identified as Trop1, epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that received great attention because of its putative involvement in metastatic spread of several solid tumors including breast cancer. Experimental evidence indicated that EpCAM is a key transcriptional target of p53 tumor suppressor, due to the presence of specific p53 response elements within EPCAM gene promoter. Aim of present study was to investigate the joined prognostic significance of p53 and EpCAM in a cases series of 640 breast cancers with long-term follow-up. In addition, considering the role of EpCAM in modulating cell-cell interaction by decreasing the cytoskeleton-anchored fraction of E-cadherin, when feasible, we evaluated also E-cadherin expression. Results indicated that EpCAM overexpression was associated with a high incidence of relapse and that, when in association with p53 status, EpCAM was able to identify, within p53-positive cases, those with the highest incidence of relapse. Conversely, E-cadherin overexpression was associated with a low incidence of relapse. Overall, these findings are of particular clinical relevance taking into account the biological link between p53 activity and EPCAM gene expression and the functional relationship between EpCAM and E-cadherin in mediating cell-to-cell adhesion

Secreted Gal-3BP is a novel promising target for non-internalizing Antibody–Drug Conjugates

Abstract Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice. ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues

The Insulin Receptor Substrate 1 (Irs1) in Intestinal Epithelial Differentiation and in Colorectal Cancer

Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P<0.01) and colonic epithelium (P<0.01). Primary and metastatic CRCs, compared to colonic epithelium, contained significantly higher numbers of IRS1-positive cells (P = 0.013 and P = 0.014, respectively). Pathologic correlations in 163 primary CRCs revealed that diffuse IRS1 staining was associated with tumors combining differentiated phenotype and aggressive markers (high Ki67, p53, and ß-catenin). In Caco 2 IRS1 and InsR were maximally expressed after polarization, while IGF1R was highest in pre-polarized cells. No nuclear IRS1 was detected, while, with polarization, phosphorylated IRS1 (pIRS1) shifted from the lateral to the apical plasma membrane and was expressed in surface cells only. In HT29, that carry mutations constitutively activating survival signaling, IRS1 and IGF1R decreased with polarization, while pIRS1 localized in nuclear spots throughout the course. Overall, these data provide evidence that IRS1 is modulated according to CRC differentiation, and support a role of IRS1 in CRC progression and liver metastatization

Lymph Node Micrometastases Do Influence Breast Cancer Outcome.

In summary, stage IB patients consistently seem to be at significantly greater risk of experiencing disease relapse than stage IA patients when treatment effect is taken into account. As Mittendorf et al1 argue, distinct biologic contexts10 do modulate the benefit of adjuvant therapy. At the same time, though, stage IB consistently remains one of the key, predictive parameters of response from systemic therapy.5 Hence, it correspondingly remains important to rigorously identify patients with stage IB breast cancer to provide them with effective therapeutic procedures

Vav1 downmodulates Akt in different breast cancer subtypes: A new promising chance to improve breast cancer outcome

Targeting different members of the Akt pathways is a promising therapeutic chance in solid tumors including breast cancer. The variable expression levels of Akt isoforms with opposite effects on tumor growth and metastasis, however, make it difficult to select the inhibitors to be used for specific breast tumor subtypes. Using in vitro and in vivo models, we demonstrated here that Vav1, ectopically expressed in invasive breast tumors derived cells, downmodulates Akt acting at expression and/or activation levels depending on tumor subtype. The decreased p-Akt1 (Ser473) levels are a common effect of Vav1 upmodulation, suggesting that, in breast tumor-derived cells and independently of their phenotype, Vav1 interferes with signaling pathways ended to specifically recruit Akt1. Only in ER-negative cell lines, the silencing of Vav1 induced the expression but not the activation of Akt2. A retrospective analysis of early invasive breast tumors allowed to establish the prognostic significance of the p-Akt/Vav1 relationship. In particular, low Vav1 levels negatively influence the follow-up of patients with low p-Akt in their primary tumors and subjected to adjuvant chemotherapy. As the use of specific or pan Akt inhibitors may not be sufficient or may even be detrimental, increasing the levels of Vav1 could be a new approach to improve breast cancer outcomes. This might be particularly relevant for tumors with a triple-negative phenotype, for which target-based therapies are not currently available

Expression of hMSH2 and hMLH1 proteins of the human DNA mismatch repair system in salivary gland tumors.

BACKGROUND: The human DNA mismatch repair (hMMR) system plays an important role in reducing mutation and maintaining genomic stability. The MMR system in human cells is composed of at least six genes (hMSH2, hMLH1, hMSH3, hPMS1, hPMS2 and GTBP/hMSH6). In particular, hMSH2 and hMLH1 are expressed in cells undergoing rapid renewal; their reduced expression has been reported in several tumors. METHODS: We examined the expression of hMSH2 and hMLH1 by immunohistochemistry in tumor specimens from 43 patients with primary tumors. RESULTS: All carcinomas (n = 20) expressed these proteins. In addition, when compared to pleomorphic adenomas, malignant tumors contained significantly (P < 0.01) higher proportions of hMSH2 (56.1 +/- 31.5 vs. 31.1 +/- 22.6) and hMLH1 (27.9 +/- 26.0 vs. 14.0 +/- 12.6) positive cells. Warthin's tumors showed no specific nuclear staining of tumor cells for both hMSH2 and hMLH1. CONCLUSIONS: These data suggest a minor, if any, role for a defect in the hMMR system in the pathogenesis of malignant salivary gland tumors