Characterization of genome-wide p53-binding sites upon stress response

The tumor suppressor p53 is a sequence-specific transcription factor, which regulates the expression of target genes involved in different stress responses. To understand p53's essential transcriptional functions, unbiased analysis of its DNA-binding repertoire is pivotal. In a genome-wide tiling ChIP-on-chip approach, we have identified and characterized 1546 binding sites of p53 upon Actinomycin D treatment. Among those binding sites were known as well as novel p53 target sites, which included regulatory regions of potentially novel transcripts. Using this collection of genome-wide binding sites, a new high-confidence algorithm was developed, p53scan, to identify the p53 consensus-binding motif. Strikingly, this motif was present in the majority of all bound sequences with 83% of all binding sites containing the motif. In the surrounding sequences of the binding sites, several motifs for potential regulatory cobinders were identified. Finally, we show that the majority of the genome-wide p53 target sites can also be bound by overexpressed p63 and p73 in vivo, suggesting that they can possibly play an important role at p53 binding sites. This emphasizes the possible interplay of p53 and its family members in the context of target gene binding. Our study greatly expands the known, experimentally validated p53 binding site repertoire and serves as a valuable knowledgebase for future research

Evaluation and Treatment of Iron Deficiency Anemia: A Gastroenterological Perspective

A substantial volume of the consultations requested of gastroenterologists are directed towards the evaluation of anemia. Since iron deficiency anemia often arises from bleeding gastrointestinal lesions, many of which are malignant, establishment of a firm diagnosis usually obligates an endoscopic evaluation. Although the laboratory tests used to make the diagnosis have not changed in many decades, their interpretation has, and this is possibly due to the availability of extensive testing in key populations. We provide data supporting the use of the serum ferritin as the sole useful measure of iron stores, setting the lower limit at 100 μg/l for some populations in order to increase the sensitivity of the test. Trends of the commonly obtained red cell indices, mean corpuscular volume, and the red cell distribution width can provide valuable diagnostic information. Once the diagnosis is established, upper and lower gastrointestinal endoscopy is usually indicated. Nevertheless, in many cases a gastrointestinal source is not found after routine evaluation. Additional studies, including repeat upper and lower endoscopy and often investigation of the small intestine may thus be required. Although oral iron is inexpensive and usually effective, there are many gastrointestinal conditions that warrant treatment of iron deficiency with intravenous iron

Evaluation and Treatment of Iron Deficiency Anemia: A Gastroenterological Perspective

A substantial volume of the consultations requested of gastroenterologists are directed towards the evaluation of anemia. Since iron deficiency anemia often arises from bleeding gastrointestinal lesions, many of which are malignant, establishment of a firm diagnosis usually obligates an endoscopic evaluation. Although the laboratory tests used to make the diagnosis have not changed in many decades, their interpretation has, and this is possibly due to the availability of extensive testing in key populations. We provide data supporting the use of the serum ferritin as the sole useful measure of iron stores, setting the lower limit at 100 μg/l for some populations in order to increase the sensitivity of the test. Trends of the commonly obtained red cell indices, mean corpuscular volume, and the red cell distribution width can provide valuable diagnostic information. Once the diagnosis is established, upper and lower gastrointestinal endoscopy is usually indicated. Nevertheless, in many cases a gastrointestinal source is not found after routine evaluation. Additional studies, including repeat upper and lower endoscopy and often investigation of the small intestine may thus be required. Although oral iron is inexpensive and usually effective, there are many gastrointestinal conditions that warrant treatment of iron deficiency with intravenous iron

Randomized Controlled Trial of Over-the-Scope Clip as Initial Treatment of Severe Nonvariceal Upper Gastrointestinal Bleeding

Background and aimsNo prior randomized controlled trial (RCT) has reported patient outcomes of large over-the-scope clip (OTSC) compared to standard hemostasis as initial endoscopic treatment of severe NVUGIB. This was our study aim.MethodsPatients with bleeding ulcers or Dieulafoy's lesions and major stigmata of hemorrhage - SRH (active spurting bleeding, visible vessel, or clot) - or lesser SRH (oozing bleeding or flat spots - with arterial blood flow by Doppler probe) were randomized to OTSC or standard endoscopic hemostasis (with hemoclips or multipolar electrocoagulation - MPEC). Patients and their healthcare providers were blinded to treatments and made all post-randomization management decisions. Ulcer patients received high dose intravenous infusions of proton pump inhibitors (PPI) for 3 days, then 27 days of oral PPI. 30 day outcomes were prospectively recorded; data management was with SAS; and data analysis was by a statistician.Results53 patients (25 OTSC, 28 Standard) were randomized, with similar baseline risk factors. However, there were significant differences in OTSC vs. Standard groups in rates of rebleeding (4% vs. 28.6%; p = .017; relative risk 0.10, 95% confidence intervals 0.01, 0.91; number needed to treat 4); severe complications (0 % vs. 14.3%); and post-randomization units of red cell transfusions (0.04 vs. 0.68). All rebleeds occurred in patients with major SRH and none with lesser SRH.Conclusion1. OTSC significantly reduced rates of rebleeding, severe complications, and post-randomization red cell transfusions. 2. Patients with major stigmata benefited significantly from hemostasis with OTSC, but those with lesser stigmata did not. (ClinicalTrials.gov, Number: NCT03065465)