Enhancement of anti-tumour immunity by transduction with a <i>Mycobacterium tuberculosis</i> gene

As a strategy to enhance immune response against tumours by a "danger signal", the Mycobacterium tuberculosis Ag38 gene encoding an highly immunogenic protein has been transduced in tumour cells. The gene was stably expressed on tumour cell surface by using a retroviral vector modified to express the leader and transmembrane sequences of the Nerve Growth Factor Receptor. Transduced cells have been used as a cellular vaccine in syngeneic mice and their ability to elicit an anti-tumour response has been evaluated against both a transplanted tumour model and against a spontaneous tumour model. In the transplanted melanoma model, vaccination with transduced cells induced a significant protection against subcutaneous or intravenous challenge with non transduced cells. In Ag38-transduced vaccinated mice a preferential Thl response was observed. Moreover, after challenge, a high titre of antibodies directed against tumour cells was detected in protected mice. Most of these antibodies were directed against endogenously expressed viral antigens, while no reactivity against melanocyte lineage specific antigens was observed. In the HER2/Neu transgenic mice model, which spontaneously develop stochastic mammary tumours after a long latency period, the onset of tumour development was significantly delayed in mice vaccinated with Ag38-transduced cells. The delay in tumour development was increased when mice were vaccinated with the Ag38 transduced vaccine plus ·a systemic administration of IL-12 at . ~ low dose. Consistent with melanoma model, a preferential Thl profile was observed in mice in response to vaccination with Ag38-transduced cells and a CD3+CD8+ population able to respond to the tumour with IFN-y production was derived from these mice. No humoral response was induced in protected mice, while an activated CD4+ T cell population producing IL-4 was obtained from long-survived mice

Polyphenols&ndash;Gut&ndash;Heart: An Impactful Relationship to Improve Cardiovascular Diseases

A healthy gut provides the perfect habitat for trillions of bacteria, called the intestinal microbiota, which is greatly responsive to the long-term diet; it exists in a symbiotic relationship with the host and provides circulating metabolites, hormones, and cytokines necessary for human metabolism. The gut&ndash;heart axis is a novel emerging concept based on the accumulating evidence that a perturbed gut microbiota, called dysbiosis, plays a role as a risk factor in the pathogenesis of cardiovascular disease. Consequently, recovery of the gut microbiota composition and function could represent a potential new avenue for improving patient outcomes. Despite their low absorption, preclinical evidence indicates that polyphenols and their metabolites are transformed by intestinal bacteria and halt detrimental microbes&rsquo; colonization in the host. Moreover, their metabolites are potentially effective in human health due to antioxidant, anti-inflammatory, and anti-cancer effects. The aim of this review is to provide an overview of the causal role of gut dysbiosis in the pathogenesis of atherosclerosis, hypertension, and heart failure; to discuss the beneficial effects of polyphenols on the intestinal microbiota, and to hypothesize polyphenols or their derivatives as an opportunity to prevent and treat cardiovascular diseases by shaping gut eubiosis

Degranulation of Paneth Cells via Toll-Like Receptor 9

The release of antimicrobial peptides and growth factors by Paneth cells is thought to play an important role in protecting the small intestine, but the mechanisms involved have remained obscure. Immunohistochemistry and immunofluorescence showed that Paneth cells express Toll-like receptor 9 (TLR9) in the granules. Injection of mice with oligonucleotides containing CpG sequence (CpG-ODNs) led to a down-modulation of TLR9 and a striking decrease in the number of large secretory granules, consistent with degranulation. Moreover CpG-ODN treatment increased resistance to oral challenge with virulent Salmonella typhimurium. Moreover, our findings demonstrate a sentinel role for Paneth cells through TLR9

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer

While the results thus far demonstrate the clinical benefit of trastuzumab in breast cancer (BC), some patients do not respond to this drug. HER2 mRNA, alone or combined with other genes/biomarkers, has been proven to be a powerful predictive marker in several studies. Here, we provide evidence of the association between HER2 mRNA levels and the response to anti-HER2 treatment in HER2-positive BC patients treated with adjuvant trastuzumab and show that this association is independent of estrogen receptor (ER) tumor positivity. While HER2 mRNA expression was significantly correlated with HER2 protein levels in ER-negative tumors, no correlation was found in ER-positive tumors, and HER2 protein expression was not associated with relapse risk. Correlation analyses in the ER-positive subset identified ER activity as the pathway inversely associated with HER2 mRNA. Associations between HER2 levels and oncogene addiction, as well as between HER2 activation and trastuzumab sensitivity, were also observed in vitro in HER2-positive BC cell lines. In ER-positive but not ER-negative BC cells, HER2 transcription was increased by reducing ligand-dependent ER activity or inducing ER degradation. Accordingly, HER2 mRNA levels in patients were found to be inversely correlated with blood levels of estradiol, the natural ligand of ER that induces ER activation. Moreover, low estradiol levels were associated with a lower risk of relapse in HER2-positive BC patients treated with adjuvant trastuzumab. Overall, we found that HER2 mRNA levels, but not protein levels, indicate the HER2 dependency of tumor cells and low estrogen-dependent ER activity in HER2-positive tumors