Over-the-scope clip as first-line treatment of peptic ulcer bleeding: a multicenter randomized controlled trial (TOP Study).

BACKGROUND: First-line over-the-scope (OTS) clip treatment has shown higher efficacy than standard endoscopic therapy in acute nonvariceal upper gastrointestinal bleeding (NVUGIB) from different causes. We compared OTS clips with through-the-scope (TTS) clips as first-line mechanical treatment in the specific setting of peptic ulcer bleeding. METHODS: We conducted an international, multicenter randomized controlled trial on consecutive patients with suspected NVUGIB. Patients with Forrest Ia-IIb gastroduodenal peptic ulcer were randomized 1:1 to OTS clip or TTS clip treatment. The primary outcome was the rate of 30-day rebleeding after successful initial hemostasis. Secondary outcomes included the rates of successful initial hemostasis and overall clinical success, defined as the composite of successful initial hemostasis and no evidence of 30-day rebleeding. RESULTS: 251 patients were screened and 112 patients were randomized to OTS (n = 61) or TTS (n = 51) clip treatment. The 30-day rebleeding rates were 1.6% (1/61) and 3.9% (2/51) in patients treated with OTS clips and TTS clips, respectively (Kaplan-Meier log-rank, P = 0.46). Successful initial hemostasis rates were 98.4% (60/61) in the OTS clip group and 78.4% (40/51) in the TTS clip group (P = 0.001). Overall clinical success rates were 96.7% (59/61) with OTS clips and 74.5% (38/51) with TTS clips (P = 0.001). CONCLUSIONS: Low rates of 30-day rebleeding were observed after first-line endoscopic treatment of acute peptic ulcer bleeding with either OTS or TTS clips. However, OTS clips showed higher efficacy than TTS clips in achieving successful initial hemostasis and overall clinical success.

Efficient Oligomerization of Aromatic Amino Acids Induced by Gaps in Four-Helix Bundles of DNA or RNA.

The formation of peptides from amino acids is one of the processes associated with life. Because of the dominant role of translation in extant biology, peptide-forming processes that are RNA induced are of particular interest. We have previously reported the formation of phosphoramidate-linked peptido RNAs as the products of spontaneous condensation reactions between ribonucleotides and free amino acids in aqueous solution. We now asked whether four-helix bundle (4HB) DNA or RNA folding motifs with a single- or double-nucleotide gap next to a 5'-phosphate can act as reaction sites for phosphoramidate formation. For glycine, this was found to be the case, whereas phenylalanine and tryptophan showed accelerated formation of peptides without a covalent link to the nucleic acid. Free peptides with up to 11 tryptophan or phenylalanine residues were found in precipitates forming in the presence of gap-containing DNA or RNA 4HBs. Control experiments using motifs with just a nick or primer alone did not have the same effect. Because folded structures with a gap in a double helix are likely products of hybridization of strands formed in statistically controlled oligomerization reactions, our results are interesting in the context of prebiotic scenarios. Independent of a putative role in evolution, our findings suggest that for some aromatic amino acids an RNA-induced pathway for oligomerization exists that does not have a discernable link to translation.

Safety of a novel 1L-polyethylene glycol-ascorbate solution for colonoscopy cleansing (REAL Study).

BACKGROUND AND AIM: Very low-volume bowel preparation (BP) for colonoscopy with 1-liter polyethylene glycol plus ascorbate (1L-PEG-Asc) has displayed high tolerability and quality of bowel cleansing. Concerns have been raised regarding its safety. We aimed to evaluate the incidence of adverse events (AEs) following BP with 1L-PEG-Asc or 2L-PEG-Asc. PATIENTS AND METHODS: From January 2019 to September 2020, data from all consecutive adult outpatients who underwent colonoscopy in Our Unit were collected. AEs were assessed by reviewing the clinical and laboratory data of patients who attended the Emergency Department (ED) of Modena District Hospitals in the 7 days following the colonoscopy, and were classified as "BP-related" or "BP-unrelated". RESULTS: During the study, 4069 (68.03%) and 1912 (31.97%) patients underwent colonoscopy after taking 2L-PEG-Asc or 1L-PEG-Asc, respectively. Regarding AEs, 77 (1.29%) patients attended ED, 53 (53/4069, 1.30%) and 24 (24/1912, 1.25%) after taking 2L-PEG-Asc and 1L-PEG-Asc. BP-related AEs were observed in 5 (5/4069, 0.12%) and 4 (4/1912, 0.21%) patients, respectively. The most frequent BP-related AEs were tachyarrhythmias (6/5981, 0.10%). CONCLUSION: The incidence rate of clinically relevant BP-related AEs is extremely low. This strongly suggests that 1L-PEG-Asc colonoscopy BP is as safe as 2L-PEG-Asc BP in a real-life clinical setting of unselected patients.

Perioperative intensity-modulated brachytherapy for refractory orbital rhabdomyosarcomas in children.

PURPOSE: To evaluate the feasibility and toxicity of perioperative intensity-modulated brachytherapy (IMBT) as well as functional outcome in children with therapy-refractory orbital rhabdomyosarcomas (RMS). PATIENTS AND METHODS: Since 1993, children with therapy-refractory orbital RMS have been treated by a multidisciplinary approach combining function-preserving, mostly R1 tumor resection and perioperative IMBT at the University Hospital of Schleswig-Holstein, Germany. All children with orbital RMS, who were enrolled in this multidisciplinary treatment protocol between 1993 and 2002, were prospectively assessed with respect to evaluation of side effects and functional outcome. RESULTS: Ten children (six boys, four girls) were included. Median age was 6.5 years (range, 1-19 years) at the beginning of our treatment and 6.0 years (range 1-17 years) at diagnosis. All children were in Intergroup Rhabdomyosarcoma Study Group (IRSG) group III and had embryonal subtype. Estimated 5-year survival was 62% +/- 18%. There was no radiation-related toxicity grade 3 or 4 observed. The eyes were primarily preserved in all cases. One child underwent secondary orbital exenteration 10 months after completion of IMBT. Visual acuity could be preserved apart from one child developing significant visual deterioration due to radiation cataract grade 2. The cosmetic results were good or very good in eight and moderate in two children. Four children died of their disease. CONCLUSION: This interdisciplinary, individually tailored and function-preserving treatment procedure has proven to be a well-tolerated therapeutic option in cases with refractory orbital RMS. It provides both improvement of local tumor control and quality of life.

Stabilizing DNA nanostructures through reversible disulfide crosslinking.

Designed DNA nanostructures can be generated in a wide range of sizes and shapes and have the potential to become exciting tools in material sciences, catalysis and medicine. However, DNA nanostructures are thermally labile assemblies of delicate biomacromolecules, and the lability hampers the use in many applications. Disulfide crosslinking is nature's successful approach to stabilize folded proteins against denaturation. It is therefore interesting to ask whether similar approaches can be used to stabilize DNA nanostructures. Here we report the synthesis of two 2'-deoxynucleoside phosphoramidites and two nucleosides linked to controlled pore glass that can be used to prepare oligodeoxynucleotides with protected thiol groups via automated DNA synthesis. Strands with one, two, three or four thiol-bearing nucleotides were prepared. One nicked duplex and three different nanostructures were assembled, the protected thiols were liberated under non-denaturing conditions, and disulfide crosslinking was induced with oxygen. Up to 19 crosslinks were thus placed in folded DNA structures up to 1456 nucleotides in size. The crosslinked structures had increased thermal stability, with UV-melting points 9-50 °C above that of the control structure. Disulfides were converted back to free thiols under reducing conditions. The redox-dependent increase in stability makes crosslinked DNA nanostructures attractive for the construction of responsive materials and biomedical applications.

A four-helix bundle DNA nanostructure with binding pockets for pyrimidine nucleotides.

Designed DNA nanostructures of impressive size have been described, but designed structures of the size of protein enzymes that bind organic ligands with high specificity are rare. Here we report a four-helix motif consisting of three synthetic strands with 65 base pairs and 165 nucleotides in total that folds well. Furthermore, we show that in the interior of this small folded DNA nanostructure, cavities can be set up that bind pyrimidine nucleotides with micromolar affinity. Base-specific binding for both thymidine and cytidine derivatives is demonstrated. The binding affinity depends on the position in the structure, as expected for recognition beyond simple base pairing. The folding motif reported here can help to expand DNA nanotechnology into the realm of selective molecular recognition that is currently dominated by protein-based enzymes and receptors.