Novel resorcin[4]arenes as potassium-selective ion-channel and transporter mimics

A series of novel resorcin[4]arenes with extended it systems have been synthesised and developed as potassium-selective transporters. Resorcin[4]arenes that feature crown ether moieties function as efficient carriers of K+ across bulk liquid membranes showing enhanced selectivity over the other alkali metal ions relative to a model system (benzo[15]crown-5). Incorporation of functionalities suitable for pore formation, in addition to an extra annulus of aromatic residues, gives molecules which have remarkable ion-channel-mimicking behaviour in a biological lipid bilayer with outstanding K+/Na+ selectivity

ß-Cyclodextrin Host-Guest Complexes Probed under Thermodynamic Equilibrium: Thermodynamics and AFM Force Spectroscopy

The rupture forces of individual host-guest complexes between ß-cyclodextrin (ß-CD) heptathioether monolayers on Au(111) and several surface-confined guests were measured in aqueous medium by single molecule force spectroscopy using an atomic force microscope. Anilyl, toluidyl, tert-butylphenyl, and adamantylthiols (0.2-1%) were immobilized in mixed monolayers with 2-mercaptoethanol on gold-coated AFM tips. For all guests and for all surface coverages, the force-displacement curves measured between the functionalized tips and monolayers of ß-CD exhibited single, as well as multiple, pull-off events. The histograms of the pull-off forces showed several maxima at equidistant forces, with force quanta characteristic for each guest of 39 ± 15, 45 ± 15, 89 ± 15, and 102 ± 15 pN, respectively. These force quanta were independent of the loading rate, indicating that, because of the fast complexation/decomplexation kinetics, the rupture forces were probed under thermodynamic equilibrium

Impact of a diverting ileostomy in total mesorectal excision with primary anastomosis for rectal cancer

Background: The role of diverting ileostomy in total mesorectal excision (TME) for rectal cancer with primary anastomosis is debated. The aim of this study is to gain insight in the clinical consequences of a diverting ileostomy, with respect to stoma rate at one year and stoma-related morbidity. Methods: Patients undergoing TME with primary anastomosis for rectal cancer between 2015 and 2017 in eleven participating hospitals were included. Retrospectively, two groups were compared: patients with or without diverting ileostomy construction during primary surgery. Primary endpoint was stoma rate at one year. Secondary endpoints were severity and rate of anastomotic leakage, overall morbidity rate within thirty days and stoma (reversal) related morbidity. Results: In 353 out of 595 patients (59.3%) a diverting ileostomy was constructed during primary surgery. Stoma rate at one year was 9.9% in the non-ileostomy group and 18.7% in the ileostomy group (p = 0.003). After correction for confounders, multivariate analysis showed that the construction of a diverting ileostomy during primary surgery was an independent risk factor for stoma at one year (OR 2.563 (95%CI 1.424–4.611), p = 0.002). Anastomotic leakage rate was 17.8% in the non-ileostomy group and 17.2% in the ileostomy group (p = 0.913). Overall 30-days morbidity rate was 37.6% in the non-ileostomy group and 56.1% in the ileostomy group (p < 0.001). Stoma reversal related morbidity rate was 17.9%. Conclusions: The stoma rate at one year was higher in patients with ileostomy construction during primary surgery. The incidence and severity of anastomotic leakage were not reduced by construction of an ileostomy. The morbidity related to the presence and reversal of a diverting ileostomy was substantial

Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.

Despite the presence of mutations in APC or beta-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when beta-catenin localization is analysed, indicating a more complex regulation of Wnt signalling. We explored this heterogeneity with a Wnt reporter construct and observed that high Wnt activity functionally designates the colon cancer stem cell (CSC) population. In adenocarcinomas, high activity of the Wnt pathway is observed preferentially in tumour cells located close to stromal myofibroblasts, indicating that Wnt activity and cancer stemness may be regulated by extrinsic cues. In agreement with this notion, myofibroblast-secreted factors, specifically hepatocyte growth factor, activate beta-catenin-dependent transcription and subsequently CSC clonogenicity. More significantly, myofibroblast-secreted factors also restore the CSC phenotype in more differentiated tumour cells both in vitro and in vivo. We therefore propose that stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity

Can we Save the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR‐TREC)? Protocol for the international, multicentre, rolling phase II/III partially randomised patient preference trial evaluating long course concurrent chemoradiotherapy versus short course radiotherapy organ preservation approaches

International audienceAim: Organ-saving treatment for early-stage rectal cancer can reduce patient-reported side effects compared to standard total mesorectal excision (TME) and preserve quality of life. An optimal strategy for achieving organ preservation and longer-term oncological outcomes are unknown; thus there is a need for high quality trials.Method: Can we Save the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR-TREC) is an international three-arm multicentre, partially randomized controlled trial incorporating an external pilot. In phase III, patients with cT1-3b N0 tumours, ≤40 mm in diameter, who prefer organ preservation are randomized 1:1 between mesorectal long-course chemoradiation versus mesorectal short-course radiotherapy, with selective transanal microsurgery. Patients preferring radical surgery receive TME. STAR-TREC aims to recruit 380 patients to organ preservation and 120 to TME surgery. The primary outcome is the rate of organ preservation at 30 months. Secondary clinician-reported outcomes include acute treatment-related toxicity, rate of non-operative management, non-regrowth pelvic tumour control at 36 months, non-regrowth disease-free survival at 36 months and overall survival at 60 months, and patient-reported toxicity, health-related quality of life at baseline, 12 and 24 months. Exploratory biomarker research uses circulating tumour DNA to predict response and relapse.Discussion: STAR-TREC will prospectively evaluate contrasting therapeutic strategies and implement new measures including a smaller mesorectal target volume, two-step response assessment and non-operative management for complete response. The trial will yield important information to guide routine management of patients with early-stage rectal cancer