Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and ...show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
Display omitted
•Functional SMO mutations are detected in the majority of SMO inhibitor-resistant BCCs•Resistance occurs by suppressing drug responsiveness and SMO autoinhibition•SMO mutants explain both intrinsic and acquired tumor resistance•Inhibition of aPKC-ι/λ or GLI2 bypasses SMO variants to suppress Hedgehog signaling
Atwood et al. identify key SMO mutations that confer resistance to SMO inhibitors in basal cell carcinomas (BCC) and show that these mutants respond to aPKC-ι/λ or GLI2 inhibitors, providing potential approaches for treating BCCs resistant to SMO inhibitors.
The dehydrogenation of formic acid permits the production of hydrogen virtually free of carbon monoxide, which is a key requisite for its use in fuel cells. Moreover, HCOOH is a suitable hydrogen ...carrier, better in several crucial characteristics than other liquid organic hydrogen carriers, namely, low toxicity, high hydrogen content and recyclability (via CO2 hydrogenation). The most successfully employed catalysts are those based on Ir, Ru, Rh, and Fe metal centers. The catalytic cycles through which homogeneous metal complexes operate show a wide mechanistic diversity. The nature of catalytic cycle depends mainly on the nuclearity of the active species, the type of CO2 formation step (β‐hydride elimination, hydride ion, or outer‐sphere mechanism), and whether the rate‐limiting step relates to CO2 or H2 formation. Different outer‐sphere interactions have been proposed in the literature in order to explain the success of homogeneous catalyst, which seems to be common ground for most of the catalysts so far reported.
The dehydrogenation of FA permits its use as a promising hydrogen carrier. The most successful homogeneous catalysts are those based on Ir, Ru, Rh, and Fe metal centers, with outer‐sphere interactions playing a key role in the success of the process.
Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally ...advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.
In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma.
In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval CI, 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted.
Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).
The aim of this paper is to study the effects of the spread of the COVID-19 virus in different regions and its impact on the economy and regional tourist flows. To this end, the researchers have been ...guided by a set of propositions which they have tried to demonstrate with the results obtained. This research shows that the impact of the pandemic is still being evaluated. The analysis of the relationship between the tourism sector and the pandemic outbreak in Spain provides an instructive case study to assist tourism in its recovery process. The paper delves into the impacts on the main Spanish touristic regions during the pandemic and providing implications for tourism recovery. In Spain, the tourism sector is of major economic importance, becoming one of the most vulnerable countries when crisis affects this industry. The negative image of the country due to the high infection rates has had a negative impact on travel and tourism. The Balearic Islands have been the most affected region with an 87% decrease in tourist visitors. The trips made by Spanish residents inside the Spanish territory shows the first increase found in the series analyzed. Domestic tourism not only represents an opportunity for all regions in this critical situation, but the types of accommodation also play a key role.
Summary
Background
Because of its rarity, the exact incidence of and mortality from epidermal necrolysis (Stevens–Johnson syndrome/toxic epidermal necrolysis) is difficult to establish and closely ...depends on the size and type of the data source.
Objectives
To estimate the incidence of and mortality due to epidermal necrolysis in France over a 14‐year period.
Methods
Data from four national databases were analysed. A capture–recapture analysis was performed.
Results
A total of 2635 incident cases of epidermal necrolysis were recorded in at least one of the four databases during the study period males: 47·9%; median age: 52 (interquartile range 25–72) years. On capture–recapture analysis, the estimated total number of cases was 5686, for an overall estimated annual incidence of 6·5 (95% confidence interval 4·1–8·9) cases per million inhabitants. The estimated annual incidence rates were 4·1 (0·3–7·9) cases per million inhabitants < 20 years of age, 3·9 (1·5–6·3) cases per million inhabitants aged 20–64 years and 13·7 (5·4–22·0) cases per million inhabitants ≥ 65 years of age. The estimated overall annual mortality rate from epidermal necrolysis was 0·9 (0·1–1·8) case per million inhabitants. It was 0·6 (0·1–1·5) case per million inhabitants aged 20–64 years and 2·8 (0·9–6·6) cases per million inhabitants ≥ 65 years of age (deaths in people < 20 years old were too rare to provide an accurate estimate).
Conclusions
The annual incidence of epidermal necrolysis is higher than the one to five cases per million inhabitants usually reported. Such estimations could be helpful in establishing appropriate healthcare plans for people with epidermal necrolysis, in particular the need for specialized care units.
What's already known about this topic?
Few data are available regarding incidence of and mortality from epidermal necrolysis in the general population.
Experts in epidermal necrolysis have recently proposed an annual incidence of one to five cases per million individuals.
The overall mortality rate is usually reported to be between 10% and 20%.
What does this study add?
Using a four‐source capture–recapture method and data from a 14‐year period (2003–16), the annual incidence of and mortality from epidermal necrolysis were estimated to be 6·5 (95% confidence interval 4·1–8·9) and 0·9 (0·1–1·8) cases per million French inhabitants, respectively.
Such estimations could be helpful in establishing appropriate healthcare plans, in particular the need for specialized care units.
Linked Comment: Walsh and Creamer. Br J Dermatol 2020; 182:528–529.
AIMS: Assess the diversity of the culturable endophytic bacterial population associated with transgenic and nontransgenic soybean grown in field trial sites in Brazil and characterize them ...phenotypically and genotypically focusing on characteristics related to plant growth promotion. METHODS AND RESULTS: Endophytic bacteria were isolated from roots, stems and leaves of soybean cultivars (nontransgenic (C) and glyphosate‐resistant (GR) transgenic soybean), including the isogenic BRS133 and BRS245RR. Significant differences were observed in bacterial densities in relation to genotype and tissue from which the isolates were obtained. The highest number of bacteria was observed in roots and in GR soybean. Based on characteristics related to plant growth promotion, 54 strains were identified by partial 16S rRNA sequence analysis, with most of the isolates belonging to the species Enterobacter ludwigii and Variovorax paradoxus. Among the isolates, 44·4% were able to either produce indoleacetic acid (IAA) or solubilize phosphates, and 9·2% (all from GR soybean) presented both plant growth‐promoting activities. CONCLUSIONS: The results from this study indicate that the abundance of endophytic bacterial communities of soybean differs between cultivars and in general it was higher in the transgenic cultivars than in nontransgenic cultivars. BRS 245 RR exhibited no significant difference in abundance compared to nontransgenic BRS133. This suggests that the impact of the management used in the GR soybean fields was comparable with the impacts of some enviromental factors. However, the bacterial endophytes associated to GR and nontransgenic soybean were different. The soybean‐associated bacteria showing characteristics related to plant growth promotion were identified as belonging to the species Pantoea agglomerans and Variovorax paradoxus. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study demonstrated differences concerning compostion of culturable endophytic bacterial population in nontransgenic and transgenic soybean.
Several problems are emerging in the context of communication networks and most of them must be solved in reduced computing time since they affect to critical tasks. In this research, the monitor ...placement problem is tackled. This problem tries to cover the communications of an entire network by locating a monitor in specific nodes of the network, in such a way that every link remains surveyed. In case that a solution cannot be generated in the allowed computing time, a penalty will be assumed for each link uncovered. The problem is addressed by considering the variable neighborhood search framework, proposing a novel constructive method, an intelligent local search to optimize the improvement phase, and an intensified shake to guide the search to more promising solutions. The proposed algorithm is compared with a hybrid search evolutionary algorithm over a set of instances derived from real‐life networks to prove its performance.
PDF
