The human ether-à-go-go channel (hEag1 or KV10.1) is a cancer-relevant voltage-gated potassium channel that is overexpressed in a majority of human tumors. Peptides that are able to selectively ...inhibit this channel can be lead compounds in the search for new anticancer drugs. Here, we report the activity-guided purification and electrophysiological characterization of a novel KV10.1 inhibitor from the sea anemone Anthopleura elegantissima. Purified sea anemone fractions were screened for inhibitory activity on KV10.1 by measuring whole-cell currents as expressed in Xenopus laevis oocytes using the two-microelectrode voltage clamp technique. Fractions that showed activity on Kv10.1 were further purified by RP-HPLC. The amino acid sequence of the peptide was determined by a combination of MALDI- LIFT-TOF/TOF MS/MS and CID-ESI-FT-ICR MS/MS and showed a high similarity with APETx1 and APETx3 and was therefore named APETx4. Subsequently, the peptide was electrophysiologically characterized on KV10.1. The selectivity of the toxin was investigated on an array of voltage-gated ion channels, including the cardiac human ether-à-go-go-related gene potassium channel (hERG or Kv11.1). The toxin inhibits KV10.1 with an IC50 value of 1.1 μM. In the presence of a similar toxin concentration, a shift of the activation curve towards more positive potentials was observed. Similar to the effect of the gating modifier toxin APETx1 on hERG, the inhibition of Kv10.1 by the isolated toxin is reduced at more positive voltages and the peptide seems to keep the channel in a closed state. Although the peptide also induces inhibitory effects on other KV and NaV channels, it exhibits no significant effect on hERG. Moreover, APETx4 induces a concentration-dependent cytotoxic and proapoptotic effect in various cancerous and noncancerous cell lines. This newly identified KV10.1 inhibitor can be used as a tool to further characterize the oncogenic channel KV10.1 or as a scaffold for the design and synthesis of more potent and safer anticancer drugs.
To determine prognostic factors in patients with systemic rheumatic diseases admitted to the intensive care unit (ICU) and to examine whether the observed mortality rate is predicted using the Acute ...Physiology And Chronic Health Assessment II (APACHE II) score.
Retrospective study with historical controls in a 31-bed medicosurgical ICU at a university hospital.
Seventy-one patients admitted to the ICU for an acute illness related to a systemic rheumatic disease and/or its treatment and 353 ICU control patients.
Systemic rheumatic diseases were mainly rheumatoid arthritis and vasculitides. In-hospital mortality rate was 28/71 (39%), including 23 patients who died in the ICU. Multivariable logistic regression showed that poor prior health status (Berdit's classification), APACHE II score, and admission for infection were associated with mortality, whereas prior use of immunosuppressive agents was not. APACHE II score at admission was higher in nonsurvivors (22+/-9) than in survivors (17+/-5) (p<0.01). The standard mortality ratio, i.e., the ratio between observed and predicted mortality, was 1.7 in the 71 study patients and 1.0 in the 353 control patients (p<0.0001).
In patients with systemic rheumatic diseases admitted to the ICU for at least 48 h, poor prior chronic health status, APACHE II score, and infection were prognostic factors for in-hospital mortality. SMR was higher than in a control ICU population.
Part of the documentary ensemble: IconMUS1
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A search for long-lived particles was performed with data corresponding to an integrated luminosity of 2.6 fb$^{−1}$ collected at a center-of-mass energy of 13 TeV by the CMS experiment in 2015. The ...analysis exploits two customized topological trigger algorithms, and uses the multiplicity of displaced jets to search for the presence of a signal decay occurring at distances between 1 and 1000 mm. The results can be interpreted in a variety of different models. For pair-produced long-lived particles decaying to two b quarks and two leptons with equal decay rates between lepton flavors, cross sections larger than 2.5 fb are excluded for proper decay lengths between 70–100 mm for a long-lived particle mass of 1130 GeV at 95% confidence. For a specific model of pair-produced, long-lived top squarks with R-parity violating decays to a b quark and a lepton, masses below 550–1130 GeV are excluded at 95% confidence for equal branching fractions between lepton flavors, depending on the squark decay length. This mass bound is the most stringent to date for top squark proper decay lengths greater than 3 mm.
Results are presented from a search for supersymmetry in events with a single electron or muon and hadronic jets. The data correspond to a sample of proton–proton collisions at $\sqrt{s}$=13TeV with ...an integrated luminosity of 35.9 fb$^{−1}$ , recorded in 2016 by the CMS experiment. A number of exclusive search regions are defined according to the number of jets, the number of b -tagged jets, the scalar sum of the transverse momenta of the jets, and the scalar sum of the missing transverse momentum and the transverse momentum of the lepton. Standard model background events are reduced significantly by requiring a large azimuthal angle between the direction of the lepton and of the reconstructed W boson, computed under the hypothesis that all of the missing transverse momentum in the event arises from a neutrino produced in the leptonic decay of the W boson. The numbers of observed events are consistent with the expectations from standard model processes, and the results are used to set lower limits on supersymmetric particle masses in the context of two simplified models of gluino pair production. In the first model, where each gluino decays to a top quark–antiquark pair and a neutralino, gluino masses up to 1.8 TeV are excluded at the 95% CL. The second model considers a three-body decay to a light quark–antiquark pair and a chargino, which subsequently decays to a W boson and a neutralino. In this model, gluinos are excluded up to 1.9 TeV.
With the advent of device-assisted enteroscopy (DAE) in the early 2000s, endoscopic access to the entire small bowel is possible nowadays (1). And yet, there is still room for improvement. Total ...enteroscopy remains a time-consuming procedure, often combining the antegrade (oral) and retrograde (anal) approach with only a reasonable chance to obtain complete endoscopy of the entire small bowel (2). Therefore, the aim is to go faster, deeper and to perform more advanced therapeutic interventions within the long and tortuous small bowel. Moreover, DAE was also shown to be effective to perform endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomy and to complete colonoscopy in patients with previously incomplete conventional colonoscopy due to long dolichocolon (3). The latest DAE development is Motorized Spiral Enteroscopy (MSE), initially conceptualized as a manually driven rotational spiral overtube by Paul A. Akerman, and further developed and commercialized as a motorized spiral overtube by the Olympus Medical Systems Corporation (4). Initial feasibility trials have shown that MSE can compete with already available DAE techniques (single- and double-balloon enteroscopy) with regard to diagnostic yield and endotherapy within the small bowel (5,6). However, being a short type enteroscope of 168 cm (as compared to the 200 cm long single- and double-balloon enteroscopes), MSE appears to be even more effective in obtaining deep and total enteroscopy with a relatively short procedural duration (2,6). In addition, the working channel diameter is increased to 3.2 mm (as compared to 2.8 mm) with an extra irrigation channel, facilitating therapeutic interventions within the small bowel. This faster and deeper (but more aggressive) enteroscopy technique comes with the price of an increased risk of mucosal injuries (ranging from superficial bruising to laceration and even perforation) within the oesophagus and the small bowel, luckily remaining asymptomatic most of the time without any clinical consequence (6). So far, this promising new technique has the potential of becoming a gamechanger in the still evolving field of deep enteroscopy.
Motorized spiral enteroscopy is proven to be effective in antegrade and retrograde enteroscopy. Nevertheless, little is known about its use in less common indications. The aim of this study was to ...identify new indications for the motorized spiral enteroscope.
Monocentric retrospective analysis of 115 patients who underwent enteroscopy using PSF-1 motorized spiral enteroscope between January 2020 and December 2022.
A total of 115 patients underwent PSF-1 enteroscopy. 44 (38%) were antegrade procedures and 24 (21%) were retrograde procedures in patients with normal gastrointestinal anatomy with conventional enteroscopy indications. The remaining 47 (41%) patients underwent PSF-1 procedures for secondary less conventional indications: n=25 (22%) enteroscopy-assisted ERCP, n=8 (7%) endoscopy of the excluded stomach after Roux-en-Y gastric bypass, n=7 (6%) retrograde enteroscopy after previous incomplete conventional colonoscopy and n=7 (6%) antegrade panenteroscopy of the entire small bowel. In this group of secondary indications, technical success rate was significantly lower (72.5%) as compared to technical success rates in the conventional groups (98-100%, p<0.001 Chi-square). Minor adverse events occurred in 17/115 patients (15%), all treated conservatively (AGREE I and II).
This study demonstrates the capabilities of PSF-1 motorized spiral enteroscope for secondary indications. PSF-1 is useful to complete colonoscopy in case of long redundant colon, to reach the excluded stomach after Roux-en-Y gastric bypass, to perform unidirectional pan-enteroscopy and to perform ERCP in patients with surgically altered anatomy. However, technical success rates are lower as compared to conventional antegrade and retrograde enteroscopy procedures, with only minor adverse events.
Background and Aims Endoscopic management of post-Whipple pancreatic adverse events (AEs) with enteroscopy-assisted endoscopic retrograde pancreatography (e-ERP) is associated with high failure ...rates. EUS-guided pancreatic duct drainage (EUS-PDD) has shown promising results; however, no comparative data have been done for these 2 modalities. The goal of this study is to compare EUS-PDD with e-ERP in terms of technical success (PDD through dilation/stent), clinical success (improvement/resolution of pancreatic-type symptoms), and AE rates in patients with post-Whipple anatomy. Methods This is an international multicenter comparative retrospective study at 7 tertiary centers (2 United States, 2 European, 2 Asian, and 1 South American). All consecutive patients who underwent EUS-PDD or e-ERP between January 2010 and August 2015 were included. Results In total, 66 patients (mean age, 57 years; 48% women) and 75 procedures were identified with 40 in EUS-PDD and 35 in e-ERP. Technical success was achieved in 92.5% of procedures in the EUS-PDD group compared with 20% of procedures in the e-ERP group (OR, 49.3; P < .001). Clinical success (per patient) was attained in 87.5% of procedures in the EUS-PDD group compared with 23.1% in the e-ERP group (OR, 23.3; P < .001). AEs occurred more commonly in the EUS-PDD group (35% vs 2.9%, P < .001). However, all AEs were rated as mild or moderate. Procedure time and length of stay were not significantly different between the 2 groups. Conclusions EUS-PDD is superior to e-ERP in post-Whipple anatomy in terms of efficacy with acceptable safety. As such, EUS-PDD should be considered as a potential first-line treatment in post-pancreaticoduodenectomy anatomy when necessary expertise is available.
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