Ulcerative colitis (UC) is associated with a substantial alteration of specific gut commensals, some of which may be involved in microbiota-mediated protection. In this study, microbiota cataloging of UC patients by 16S rRNA microbial profiling revealed a marked reduction of bifidobacteria, in particular the Bifidobacterium bifidum species, thus suggesting that this taxon plays a biological role in the aetiology of UC. We investigated this further through an in vivo trial by testing the effects of oral treatment with B. bifidum PRL2010 in a wild-type murine colitis model. TNBS-treated mice receiving 10(9) cells of B. bifidum PRL2010 showed a marked reduction of all colitis-associated histological indices as well as maintenance of mucosal integrity as it was shown by the increase in the expression of many tight junction-encoding genes. The protective role of B. bifidum PRL2010, as well as its sortase-dependent pili, appears to be established through the induction of an innate immune response of the host. These results highlight the importance of B. bifidum as a microbial biomarker for UC, revealing its role in protection against experimentally induced colitis.

IntroductionMultiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of malignant plasma cells within the bone marrow (BM). Despite treatment with alkylating agents, anthracyclines, corticosteroids, 1,2 and bortezomib 3 as well as high-dose therapy and stem cell transplantation, 4-6 MM remains an incurable disease because of the high resistance to apoptosis and both intrinsic and acquired drug resistance. [7][8][9][10][11][12] Therefore, new therapeutic strategies are needed to improve patient outcome.Preclinical in vitro and in vivo studies showed that arsenic trioxide (ATO) has antimyeloma effects both as a single agent [13][14][15][16] and in combination with glutathione-depleting agents [17][18][19] and/or other antimyeloma agents. 15,20,21 Moreover, the combined results of 3 phase 2 studies in patients with relapsed MM refractory to conventional chemotherapy showed only modest efficacy of ATO as single agent, [22][23][24][25][26][27][28] but combination therapies with ascorbic acid, melphalan, steroids, thalidomide, and bortezomib have shown promising results. [29][30][31][32][33][34] We have previously demonstrated that PD184352 (PD), a highly selective inhibitor of MEK phosphorylation and activation, strikingly enhances ATO-mediated apoptosis in acute myelogenous leukemia (AML) via multiple intrinsic apoptotic pathways activation. [35][36][37] MEK blockade efficiently and selectively sensitizes tumor cells to suboptimal doses of other apoptotic stimuli, including classic cytotoxic treatment (nucleoside analogs, microtubule-targeted drugs, ␥-irradiation), 38-43 biologicals (retinoids, interferons), 44,45 steroids, [46][47][48] and other signal transduction/apoptosis modulators (UCN-01, STI571, Bcl-2 antagonists, Bcl-2 antisense oligonucleotides). [49][50][51][52][53] In this study, we tested the apoptotic activity of ATO combined with MEK inhibitors in MM cells, and we were able to demonstrate that PD enhances ATO-induced cytotoxicity both in vitro and in vivo in a human plasmacytoma xenograft model, through a multiple modulation of apoptotic regulatory proteins, including p53 family proteins, TRAIL receptors, several Bcl-2 family proteins, and caspases, that depend on the functionality of the p53 pathway. MethodsApproval for the study was obtained from the Institutional Review Board of the Department of Clinical Sciences, University of Parma (Parma, Italy). ReagentsATO was purchased from Sigma-Aldrich (St Louis, MO). A 1 mM stock solution was obtained by dissolving ATO in phosphate-buffered saline.Submitted October 3, 2007; accepted June 12, 2008. Prepublished online as Blood First Edition paper, June 26, 2008; DOI 10.1182 DOI 10. /blood-2007 The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on April 27, 2019. by guest www.bloodj...

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Glioblastoma multiforme (GBM) is the most malignant brain tumor, showing high resistance to standard therapeutic approaches that combine surgery, radiotherapy, and chemotherapy. As opposed to healthy tissues, EphA2 has been found highly expressed in specimens of glioblastoma, and increased expression of EphA2 has been shown to correlate with poor survival rates. Accordingly, agents blocking Eph receptor activity could represent a new therapeutic approach. Herein, we demonstrate that UniPR1331, a pan Eph receptor antagonist, possesses significant in vivo anti-angiogenic and anti-vasculogenic properties which lead to a significant anti-tumor activity in xenograft and orthotopic models of GBM. UniPR1331 halved the final volume of tumors when tested in xenografts (p<0.01) and enhanced the disease-free survival of treated animals in the orthotopic models of GBM both by using U87MG cells (40 vs 24 days of control, p<0.05) or TPC8 cells (52 vs 16 days, p<0.01). Further, the association of UniPR1331 with the anti-VEGF antibody Bevacizumab significantly increased the efficacy of both monotherapies in all tested models. Overall, our data promote UniPR1331 as a novel tool for tackling GBM.

Abstract-The activation of the sympathetic nervous system is a common feature of arterial hypertension and other cardiovascular diseases. This activation might be dependent on an altered baroreflex control of vascular resistance of which the inhibitory response on sympathetic activity appears impaired. The aim of the study was to monitor during the natural course of arterial hypertension in spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats (5, 16, 30, and 54 weeks of age) the peripheral sympathetic activity expressed as interstitial norepinephrine (NE) release and as tyrosine hydroxylase (TH) activity, the rate-limiting enzyme of NE synthesis, in the differently baroreflexcontrolled subcutaneous adipose tissues and skeletal muscles. Blood pressure and plasma NE in SHR were similar to WKY at 5 weeks of age but increased at all other ages. Body weight was similar in both 5-week-old rats but reduced in SHR at all other ages. The interstitial NE levels were greater in both SHR tissues at all ages as compared with WKY. In adipose tissue of SHR, TH activity was higher at all ages as compared with WKY, whereas TH activity in skeletal muscle was higher only after the development of hypertension. These data show that in both SHR tissues, an increase of interstitial NE release is always present during its lifespan. This suggests that increased sympathetic activation in the SHR model is not specific to baroreflex-controlled tissues such as skeletal muscle but involves also subcutaneous adipose tissue, the sympathetic efferents of which are independent from baroreflexes.