International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Evaluation of the antiangiogenic and angiopreventive activity of nature-based compounds.

Several studies demonstrated that angiogenesis is a limiting process for tumour growth and progression. Consequently it is at the same time a potential target for both preventive and therapeutic interventions. Angiogenesis is a multi-step phenomenon that involves different cell types; in particular endothelial cells, tumour cells and immune cells, which orchestrate an intricate network of stimuli aiming to render tumour microenvironment suitable for malignant progression. Here we have demonstrated the anti-angiogenic activity of three compounds derived from naturalling occurring sources: hyperforin (from Saint John\u2019s Wort), methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) and 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), both synthetic compounds based on oleanolic acids found in citrus fruits. These compounds could be suitable chemoprevention approaches, and the CDDO derivatives are under study for chemotherapeutic application

Effects of diet-derived molecules on the tumor microenvironment

It is now widely accepted that tumors are a complex tissue composed, in addition to the cancer cells, by endothelial cells and their precursors, stromal cells, pericytes, smooth muscle cells, fibroblasts, myofibroblasts. Inflammatory and immune cells such as macrophages, neutrophils, granulocytes, mast cells, B and T cells, natural killer (NK) and dendritic cells also infiltrate the tumor to constitute the microenvironment. All these players interact with each other and with tumor cells through specific molecular pathways resulting in the production of an intricate network of molecular mediators, cytokines and growth factors providing the proper conditions for tumor maintenance, growth and propagation. Several pathways of cell-cell interactions within the microenvironment have been previously investigated and extensively studied in physiological and pathological scenarios. Some of these pathways can be targeted with therapeutic drugs during tumor progression. However, a more efficacious approach would be to halt tumor-host interactions before a cancer develops or metastasizes. Many phytochemicals and diet derivatives are able to act as chemopreventive agents, targeting the tumor microenvironment and in particular inflammatory angiogenesis, in a new discipline that we named "angioprevention". In this review we analyze some of the potential phytochemical drugs, natural or synthetic, that seem to owe part of their chemopreventive potential to their action on the tumor microenvironment. In particular, we provide an overview of the pathways regulated by chemopreventive microenvironment-active substances: oleanic acid triterpenoids (CDDOs), resveratrol, epigallocathechin gallate (EGCG), xanthohumol and curcumin

SANIST: A rapid mass spectrometric SACI/ESI data acquisition and elaboration platform for verifying potential candidate biomarkers

10nononeRationale Surface-Activated Chemical Ionization/Electrospray Ionization mass spectrometry (SACI/ESI-MS) is a technique with high sensitivity and low noise that allows accurate biomarker discovery studies. We developed a dedicated SACI/ESI software, named SANIST, for both biomarker fingerprint data acquisition and as a diagnostic tool, using prostate cancer (PCa) as the disease of interest. Methods Liquid chromatography (LC)/SACI/ESI-MS technology was employed to detect a potential biomarker panel for PCa disease prediction. Serum from patients with histologically confirmed or negative prostate biopsies for PCa was employed. The biomarker data (m/z or Thompson value, retention time and extraction mass chromatogram peak area) were stored in an ascii database. SANIST software allowed identification of potential biomarkers. A Bayesian scoring algorithm developed in house allowed sample separation based on comparison with samples in the database. Results Biomarker candidates from the carnitine family were detected at significantly lower levels in patients showing histologically confirmed PCa. Using these biomarkers, the SANIST scoring algorithm allowed separation of patients with PCa from biopsy negative subjects with high accuracy and sensitivity. Conclusions SANIST was able to rapidly identify and perform a preliminary evaluation of the potential diagnostic efficiency of potential biomarkers for PCa.noneAlbini, Adriana; Briga, Daniela; Conti, Matteo; Bruno, Antonino; Farioli, Daniela; Canali, Sara; Sogno, Ilaria; D'Ambrosio, Gioacchino; Consonni, Paolo; Noonan, DouglasAlbini, Adriana; Briga, Daniela; Conti, Matteo; Bruno, Antonino; Farioli, Daniela; Canali, Sara; Sogno, Ilaria; D'Ambrosio, Gioacchino; Consonni, Paolo; Noonan, Dougla

Prevention and Treatment of Experimental Estrogen Receptor–Negative Mammary Carcinogenesis by the Synthetic Triterpenoid CDDO-Methyl Ester and the Rexinoid LG100268

PURPOSE: To test whether the triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and the rexinoid LG100268 (268) prevent the formation of estrogen receptor (ER) – negative mammary tumors or either arrest the growth or cause regression of established tumors in MMTV-neu mice. EXPERIMENTAL DESIGN: For prevention, mice were fed control diet, CDDO-Me (60 mg/kg diet), 268 (20 mg/kg diet), or the combination for 45 weeks. For treatment, mice with established tumors at least 4 mm in diameter were fed control diet, CDDO-Me (100 mg/kg diet), 268 (60 mg/kg diet), or the combination for 4 weeks. RESULTS: CDDO-Me and 268 significantly delayed the development of ER-negative tumors, with a 14- and 24-week delay, respectively, compared with the control group for the time required to reach 50% tumor incidence. The combination of CDDO-Me and 268 was significantly more potent than the individual drugs, as only one tumor was found in the combination group, after 45 weeks on diet, at which time all control animals had tumors. Treating established tumors with CDDO-Me arrested the growth of 86% of the tumors, and 268 induced tumor regression in 85% of tumors. CDDO-Me and 268 target different signaling pathways and cell types. CDDO-Me inhibited constitutive STAT3 phosphorylation and the degradation of IKBα in ER-negative breast cancer cells, whereas 268 blocked IKBα degradation and the release of interleukin-6 in RAW264.7 macrophage-like cells, inhibited the ability of endothelial cells to organize into networks, and blocked angiogenesis in vivo. CONCLUSIONS: CDDO-Me and 268 are useful as individual drugs to prevent ER-negative mammary tumorigenesis and to treat established tumors. They synergize when used in combination for prevention

Exome coverage and target coverage statistics of ten CHI probands.

<p>Exome coverage and target coverage statistics of ten CHI probands.</p

Whole-exome sequencing identification of non-synonymous SNP variants of 10 CHI patients.

*<p>Mutation reported in Human Genome Mutation Database( HGMD).</p><p>PolyPhen/SIFT: (−) benign or tolerated; (+) possibly damaging/DAMAGING Low confidence;</p><p>(++) probably damaging/DAMAGING.</p><p>In bold known causative genes.</p