Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary

There has been considerable investigation of the potential for soyfoods to reduce risk of cancer, and in particular cancer of the breast. Most interest in this relationship is because soyfoods are essentially a unique dietary source of isoflavones, compounds which bind to estrogen receptors and exhibit weak estrogen-like effects under certain experimental conditions. In recent years the relationship between soyfoods and breast cancer has become controversial because of concerns – based mostly on in vitro and rodent data – that isoflavones may stimulate the growth of existing estrogen-sensitive breast tumors. This controversy carries considerable public health significance because of the increasing popularity of soyfoods and the commercial availability of isoflavone supplements. In this analysis and commentary we attempt to outline current concerns regarding the estrogen-like effects of isoflavones in the breast focusing primarily on the clinical trial data and place these concerns in the context of recent evidence regarding estrogen therapy use in postmenopausal women. Overall, there is little clinical evidence to suggest that isoflavones will increase breast cancer risk in healthy women or worsen the prognosis of breast cancer patients. Although relatively limited research has been conducted, and the clinical trials often involved small numbers of subjects, there is no evidence that isoflavone intake increases breast tissue density in pre- or postmenopausal women or increases breast cell proliferation in postmenopausal women with or without a history of breast cancer. The epidemiologic data are generally consistent with the clinical data, showing no indication of increased risk. Furthermore, these clinical and epidemiologic data are consistent with what appears to be a low overall breast cancer risk associated with pharmacologic unopposed estrogen exposure in postmenopausal women. While more research is required to definitively allay concerns, the existing data should provide some degree of assurance that isoflavone exposure at levels consistent with historical Asian soyfood intake does not result in adverse stimulatory effects on breast tissue

Editorial: what can be done when infliximab stops working in ulcerative colitis?

Currently the clinician managing secondary loss of anti‐tumour necrosis factor (TNF)‐α response in ulcerative colitis (UC) is faced with a difficult dilemma. Should he/she escalate the anti‐TNFα dose, switch to an alternative anti‐TNFα or biological (e.g. vedolizumab), initiate a thiopurine (if naïve to this) or a course of glucocorticosteroids or consider surgery as a curative option? In a progressively unwell individual with a severe flare, the window for decision‐making is narrow. More broadly, what is the threshold for anti‐TNFα (or any biologic) in UC and what is the long‐term exit strategy of those maintained on anti‐TNFα therapies if they are stable in remission or experience a flare, and what is the most cost‐effective approach? </p

Controversies in inflammatory bowel disease: exploring clinical dilemmas using Cochrane Reviews

A symposium organized by the Cochrane IBD Group and presented at the 2017 Digestive Disease Week annual meeting reviewed the recent literature on several controversial topics in inflammatory bowel disease (IBD) management including the efficacy of oral aminosalicylates for induction and maintenance of Crohn's disease (CD), the feasibility of drug withdrawal in patients with quiescent CD, and strategies for detecting colon cancer in patients with IBD. This article summarizes the data presented at that session

Mitochondrial DNA is a pro-inflammatory damage-associated molecular pattern released during active IBD

BackgroundDue to common evolutionary origins, mitochondrial DNA (mtDNA) shares many similarities with immunogenic bacterial DNA. MtDNA is recognized as a pro-inflammatory damage-associated molecular pattern (DAMP) with a pathogenic role in several inflammatory diseases. We hypothesised that mtDNA is released during active disease, serving as a key pro-inflammatory factor in inflammatory bowel disease (IBD).MethodsBetween 2014 and 2015, we collected plasma separated within 2 hours of sampling from 97 prospectively recruited IBD patients (67 ulcerative colitis [UC] and 30 Crohn’s disease [CD]) and 40 non-IBD controls. We measured circulating mtDNA using quantitative polymerase chain reaction (amplifying mitochondria COXIII/ND2 genes) and also in mouse colitis induced by dextran sulfate-sodium (DSS). We used a mass spectometry approach to detect free plasma mitochondrial formylated peptides. Furthermore, we examined for mitochondrial damage using electron microscopy (EM) and TLR9 expression, the target for mtDNA, in human intestinal IBD mucosa.ResultsPlasma mtDNA levels were increased in UC and CD (both P ≺ 0.0001) compared with non-IBD controls. These levels were significantly correlated to blood (C-reactive protein, albumin, white cell count), clinical and endoscopic markers of severity, and disease activity. In active UC, we identified 5 mitochondrial formylated peptides (the most abundant being fMMYALF with known chemoattractant function) in plasma. We observed mitochondrial damage in inflamed UC mucosa and significantly higher fecal MtDNA levels (vs non-IBD controls [P ≺ 0.0001]), which supports gut mucosal mitochondrial DAMP release as the primary source. In parallel, plasma mtDNA levels increased during induction of acute DSS colitis and were associated with more severe colitis (P ≺ 0.05). In active IBD, TLR9+ lamina propria inflammatory cells were significantly higher in UC and CD compared with controls (P ≺ 0.05).ConclusionWe present the first evidence to show that mtDNA is released during active IBD. MtDNA is a potential mechanistic biomarker, and our data point to mtDNA-TLR9 as a therapeutic target in IBD.</p

Single-molecule FRET reveals the energy landscape of the full-length SAM-I riboswitch

S-adenosyl-L-methionine (SAM) ligand binding induces major structural changes in SAM-I riboswitches, through which gene expression is regulated via transcription termination. Little is known about the conformations and motions governing the function of the full-length Bacillus subtilis yitJ SAM-I riboswitch. Therefore, we have explored its conformational energy landscape as a function of Mg^2+ and SAM ligand concentrations using single-molecule Förster resonance energy transfer (smFRET) microscopy and hidden Markov modeling analysis. We resolved four conformational states both in the presence and the absence of SAM and determined their Mg^2+-dependent fractional populations and conformational dynamics, including state lifetimes, interconversion rate coefficients and equilibration timescales. Riboswitches with terminator and antiterminator folds coexist, and SAM binding only gradually shifts the populations toward terminator states. We observed a pronounced acceleration of conformational transitions upon SAM binding, which may be crucial for off-switching during the brief decision window before expression of the downstream gene