Protumor Steering of Cancer Inflammation by p50 NF-κB Enhances Colorectal Cancer Progression.

Although tumor-associated macrophages (TAM) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer, both TAM polarization and its impact remain controversial. We investigated the role of the M2-polarizing p50 NF-κB subunit in orchestrating TAM phenotype, tumor microenvironment composition, and colorectal cancer progression. We first demonstrated, by parallel studies in colitis-associated cancer (CAC) and in genetically driven ApcMin mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supported colorectal cancer development. In accordance with these studies, p50-/- mice displayed exacerbated CAC with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development in vivo The inflammatory profile supporting tumor resistance in colons from p50-/- tumor bearers correlated inversely with TAM load and positively with both recruitment of NK, NKT, CD8+ T cells and number of apoptotic tumor cells. In agreement, myeloid-specific ablation of p50 promoted tumor resistance in mice, whereas in colorectal cancer patients, a high number of p50+ TAMs at the invasive margin was associated with decreased IL12A and TBX21 expression and worse postsurgical outcome. Our findings point to p50 involvement in colorectal cancer development, through its engagement in the protumor activation of macrophages, and identify a candidate for prognostic and target therapeutic intervention. Cancer Immunol Res; 6(5); 578-93. ©2018 AACR.

Intracellular lactate-mediated induction of estrogen receptor beta (ERß) in biphasic malignant pleural mesothelioma cells.

Biphasic malignant pleural mesothelioma (MPM) is the second most common histotype of MPM. It is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter associated with worse prognosis. In this report we describe that silencing of AKT1 in spindle-shaped biphasic MPM cells promotes the shift toward an epithelioid phenotype. Furthermore, AKT1 silencing resulted in decreased expression of the lactate/H+ symporter MCT4 and its chaperone CD147/Basigin, and in the induction of estrogen receptor ß (ERß) expression. We provide evidence that ERß expression is induced by increased intracellular lactate concentration. Spheroid culturing and tumor growth of ERß negative biphasic MPM in nude mice resulted in the induction of ERß expression and response to the selective agonist KB9520. In both models, the treatment with the ERß agonist results in reduced cell proliferation, decreased expression of MCT4 and CD147/Basigin and increased acetylation and inactivation of AKT1. Collectively, in response to metabolic changes, ERß expression is induced and exerts an anti-tumor effect through selective agonist activation. The possibility to reverse the more aggressive biphasic mesothelioma histotype by targeting ERß with a selective agonist could represent a new effective treatment strategy.

Agonist activation of estrogen receptor beta (ERß) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity.

BACKGROUND: Estrogen receptor (ER) ß acts as a tumor suppressor in malignant mesotheliomas. METHODS: Here we explored the anti-proliferative and anti-tumorigenic efficacy of the selective ERß agonist, KB9520, in human mesothelioma cell lines in vitro and in a mesothelioma mouse model in vivo. RESULTS: KB9520 showed significant anti-proliferative effect in ERß positive human malignant pleural mesothelioma cells in vitro. Selective activation of ERß with KB9520 sensitized the cells to treatment with cisplatin, resulting in enhanced growth inhibition and increased apoptosis. Furthermore, in CD1 nude mice mesothelioma tumor growth was significantly inhibited when KB9520 was added on top of the standard of care chemo combination cisplatin/pemetrexed, as compared to the cisplatin/pemetrexed alone group. Importantly, KB9520 exerted a protective effect to cisplatin toxicity in the non-malignant mesothelium derived MET5A cells. CONCLUSIONS: Together, the data presented suggest that selective targeting of ERß may be an efficacious stand-alone treatment option and/or become an important add-on to existing malignant mesothelioma therapy.

Characterization of Muscat wines aroma evolution using comprehensive gas chromatography followed by a post-analytic approach to 2D contour plots comparison.

This study presents the application of a headspace solid-phase microextraction (HS-SPME) method on the analysis of Muscat-based wines volatiles by comprehensive two-dimensional gas chromatography (GC×GC) and Time-Of-Flight mass spectrometry (TOF-MS). The aroma patterns were established for different samples of Asti Spumante and Moscato d'Asti wines, stored in bottles for 6 months at different temperatures. Wines stored at 5 °C for 6 months did not show significant changes in flavor; otherwise, the samples stored at 15 and 25 °C, showed a significant decrease in linalool, ß-damascenone, ethyl hexanoate, and ethyl octanoate levels. In these last samples, α-terpineol, hotrienol, nerol oxide, furanic linalool oxides A/B and rose oxide concentrations significantly increased. A mathematical approach was developed and applied to raw data exported after the chromatographic course, in order (i) to normalise different 2D chromatograms, permitting their direct comparison and (ii) to automatically identify and calculate from pixel-to-pixel re-designed 2D chromatograms any differences among key volatile compounds.

MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications.

MicroRNAs (miRNAs) post-transcriptionally regulate the expression of target genes, and may behave as oncogenes or tumor suppressors. Human malignant mesothelioma is an asbestos-related cancer, with poor prognosis and low median survival. Here we report, for the first time, a cross-evaluation of miRNA expression in mesothelioma (MPP-89, REN) and human mesothelial cells (HMC-telomerase reverse transcriptase). Microarray profiling, confirmed by real-time quantitative RT-PCR, revealed a differential expression of miRNAs between mesothelioma and mesothelial cells. In addition, a computational analysis combining miRNA and gene expression profiles allowed the accurate prediction of genes potentially targeted by dysregulated miRNAs. Several predicted genes belong to terms of Gene Ontology (GO) that are associated with the development and progression of mesothelioma. This suggests that miRNAs may be key players in mesothelioma oncogenesis. We further investigated miRNA expression on a panel of 24 mesothelioma specimens, representative of the three histotypes (epithelioid, biphasic, and sarcomatoid), by quantitative RT-PCR. The expression of miR-17-5p, miR-21, miR-29a, miR-30c, miR-30e-5p, miR-106a, and miR-143 was significantly associated with the histopathological subtypes. Notably, the reduced expression of two miRNAs (miR-17-5p and miR-30c) correlated with better survival of patients with sarcomatoid subtype. Our preliminary analysis points at miRNAs as potential diagnostic and prognostic markers of mesothelioma, and suggests novel tools for the therapy of this malignancy.

Effects of raloxifene and continuous combined hormone therapy on haemostasis variables: a multicenter, randomized, double-blind study.

INTRODUCTION: Hormone replacement therapy is known to increase the risk of thromboembolic events. We compared the effects of HRT and raloxifene on some haemostasis variables. MATERIALS AND METHODS: In a multicenter, double-blind study, 54 healthy postmenopausal women were randomized to receive either continuous treatment with 2 mg 17beta-estradiol plus 1 mg norethisterone acetate (n=30) or 60 mg raloxifene (n=24) daily for 12 months. Blood samples were collected at baseline and at 3, 6 and 12 months to evaluate therapy effects on some haemostasis variables (factor VII, factor VIII, prothrombin fragments 1 and 2, protein C, protein C activity, protein S, thrombin-antithrombin complex, D-dimer, antithrombin, fibrinogen and plasminogen activator inhibitor). RESULTS: Both raloxifene and continuous combined hormone therapy modified the haemostasis variables toward a more prothrombotic profile. Factor VIII (p<0.01) and fibrinogen (p<0.05) plasma levels significantly increased at 6 months, prothrombin fragments 1 and 2 (p<0.05) significantly increased at 12 months, whereas protein C activity (p<0.001) and antithrombin (p<0.01) significantly decreased at 12 months in both groups. CONCLUSIONS: Our results demonstrate that raloxifene and continuous combined hormone therapy exhibit the same prothrombotic profile. Both treatments induced an increase in procoagulant parameters at 6 months and a decrease in anticoagulant parameters at 12 months.

Neutral effect of prolonged transdermal hormone therapy on liver function of postmenopausal women with chronic active hepatitis.

OBJECTIVE: To test whether transdermal hormone therapy can be safely administered to postmenopausal women with chronic viral hepatitis B and/or C. DESIGN: Eighty-one postmenopausal women with chronic viral hepatitis B and/or C and with severe vasomotor symptoms were treated for 5 years with transdermal estradiol (50 microg/day) continuously and with transdermal norethisterone (250 microg/day) for 14 days of every 28-day cycle. Another 95 women with viral chronic hepatitis but without climacteric symptoms were used as controls. Liver enzymes (glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, gamma-glutamine-transferase, and alkaline phosphatase) were measured every year. RESULTS: At baseline, liver enzymes were similar in the two groups, with the exception of gamma-GT, which was slightly higher in untreated women (P < 0.01). Liver enzymes did not significantly vary with time in hormone-treated and untreated women. No significant difference was observed between the two groups. CONCLUSIONS: Transdermal estradiol and norethisterone can be safely administered for a prolonged period to postmenopausal women with chronic viral B and/or C hepatitis.

Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries.

OBJECTIVE: To determine the effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the vascular reactivity of uterine and cerebral arteries. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Sixty-two postmenopausal women aged 45-60 years attending the Outpatient Menopause Clinic of our gynecological departments. INTERVENTION(S): The patients were administered 72 mg of soy-derived isoflavones or placebo under double-blind conditions. The daily number of hot flushes was recorded in a diary. Endometrial thickness was measured by means of transvaginal ultrasound; the uterine, internal carotid, and middle cerebral arteries were evaluated using Doppler ultrasound. MAIN OUTCOME MEASURE(S): The daily number of hot flushes, endometrial thickness, and arterial pulsatility index (PI). RESULT(S): Both treatments led to a 40% reduction in the number of hot flushes. Soy-derived isoflavones had no effect on endometrial thickness or the PI of the uterine and cerebral arteries. CONCLUSION(S): The daily administration of 72 mg of soy-derived isoflavones is no more effective than placebo in reducing hot flushes in postmenopausal women. It also has no effect on endometrial thickness or the PI of the uterine and cerebral arteries.