Variability in dentofacial phenotypes in four families with WNT10A mutations

This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schöpf–Schulz–Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology.     

Application of an activity‐based receptor bioassay to investigate the in vitro activity of selected indole‐ and indazole‐3‐carboxamide‐based synthetic cannabinoids at CB1 and CB2 receptors

Synthetic cannabinoids (SCs) are the most chemically diverse group of new psychoactive substances. This group has been associated with several intoxications, many with fatal outcomes. Although advancements have been achieved in pharmacology, metabolism, and detection of these compounds in recent years, these aspects are still unresolved for many SCs. The aim of this study was to investigate the in vitro potency of 14 indole‐ and indazole‐based SCs by applying a stable CB1 or CB2 receptor activation assay and correlating the activity with their structure. The half‐maximal effective concentration (EC₅₀) of 5‐chloropentyl, 5‐bromopentyl, and 5‐iodopentyl JWH‐122 analogs varied from 74.1 to 283.7 nM for CB1 and 7.05 to 23.4 nM for CB2, where the addition of a chlorine atom enhanced the potency at CB1 compared with the bromo and iodo analogs. AM‐2201 was the most active at CB1 within this naphthoylindole family, with an EC₅₀ of 23.5 nM but with the lowest efficacy (E_max 98.8%). Within the indole‐3‐carboxamide derivatives, 5F‐MDMB‐PICA was the most active compound, with a CB1/CB2 EC₅₀ of 3.26/0.87 nM and an E_max around three times higher than JWH‐018. ADB‐FUBINACA was the most potent tested SC overall, with a CB1/CB2 EC₅₀ of 0.69/0.59 nM, and an E_max around 3‐fold higher than that for JWH‐018 at CB1. The data obtained in this study confirm how small differences in the structure of SCs might lead to large differences in their activity, especially at CB1, which may be correlated with differences in their toxic effects in humans.     

Reversible switching between superhydrophobic states on a hierarchically structured surface

Nature offers exciting examples for functional wetting properties based on superhydrophobicity, such as the self-cleaning surfaces on plant leaves and trapped air on immersed insect surfaces allowing underwater breathing. They inspire biomimetic approaches in science and technology. Superhydrophobicity relies on the Cassie wetting state where air is trapped within the surface topography. Pressure can trigger an irreversible transition from the Cassie state to the Wenzel state with no trapped air--this transition is usually detrimental for nonwetting functionality and is to be avoided. Here we present a new type of reversible, localized and instantaneous transition between two Cassie wetting states, enabled by two-level (dual-scale) topography of a superhydrophobic surface, that allows writing, erasing, rewriting and storing of optically displayed information in plastrons related to different length scales.     

Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma

An international, Phase II trial was conducted to assess two doses of ofatumumab, a human CD20 monoclonal antibody, combined with cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), prednisone (100 mg days 3–7) and vincristine (1·4 mg/m²) (O‐CHOP), as frontline treatment for follicular lymphoma (FL). 59 patients with previously untreated FL were randomized to ofatumumab 500 mg (n = 29) or 1000 mg (n = 30) day 1, with CHOP on day 3 every 3 weeks for six cycles. Median duration of FL was 0·1 years for both dose groups; 34% and 38% of patients had high‐risk Follicular Lymphoma International Prognostic Index (FLIPI) scores in the 500‐ and 1000‐mg dose groups, respectively. Overall response rate was 90% for the 500‐mg group and 100% for the 1000‐mg group. 62% of patients achieved complete response (CR)/unconfirmed CR (CRu). 76% of patients with FLIPI score 3–5 attained CR/CRu. Longer follow‐up time is needed for analysis of survival end points. The most common Common Terminology Criteria grade 3–4 investigator‐reported adverse events were leucopenia (29%) and neutropenia (22%). No deaths have been reported. O‐CHOP was safe and efficacious in patients with previously untreated FL, including high‐risk FLIPI groups. This trial was registered at www.clinicaltrials.gov (NCT00494780).