Atopic dermatitis (AD) is a chronic, heterogenous, inflammatory skin disorder associated with a high skin‐related health burden, typically starting in childhood and often persisting into adulthood. ...AD is characterized by a wide range of clinical phenotypes, reflecting multiple underlying pathophysiological mechanisms and interactions between genetics, immune system dysregulation and environmental factors. In this review, we describe the diverse cellular and molecular mechanisms involved in AD, including the critical role of T‐cell‐driven inflammation, primarily via T helper (Th) 2‐ and Th17‐derived cytokines, many of which are mediated by the Janus kinase (JAK) signaling pathway. These local inflammatory processes interact with sensory neuronal pathways, contributing to the clinical manifestations of AD, including itch, pain and sleep disturbance. The recent elucidation of the molecular pathways involved in AD has allowed treatment strategies to evolve from broad‐acting systemic immunosuppressive therapies to more targeted agents, including JAK inhibitors and cytokine‐specific biologic agents. Evidence from the clinical development of these targeted therapies has reinforced and expanded our understanding of the pathophysiological mechanisms underlying AD and holds promise for individualized treatment strategies tailored to specific AD subtypes.
Surface compositions across Pluto and Charon Grundy, W. M.; Binzel, R. P.; Buratti, B. J. ...
Science (American Association for the Advancement of Science),
03/2016, Letnik:
351, Številka:
6279
Journal Article
Recenzirano
Odprti dostop
The Kuiper Belt hosts a swarm of distant, icy objects ranging in size from small, primordial planetesimals to much larger, highly evolved objects, representing a whole new class of previously ...unexplored cryogenic worlds. Pluto, the largest among them, along with its system of five satellites, has been revealed by NASAs New Horizons spacecraft flight through the system in July 2015, nearly a decade after its launch.
A class of rotaxane is created, not by encapsulating a conventional linear thread, but rather by wrapping a large cucurbit10uril macrocycle about a three-dimensional, cylindrical, nanosized, ...self-assembled supramolecular helicate as the axle. The resulting pseudo-rotaxane is readily converted into a proper interlocked rotaxane by adding branch points to the helicate strands that form the surface of the cylinder (like branches and roots on a tree trunk). The supramolecular cylinder that forms the axle is itself a member of a unique and remarkable class of helicate metallo-drugs that bind Y-shaped DNA junction structures and induce cell death. While pseudo-rotaxanation does not modify the DNA-binding properties, proper, mechanically-interlocked rotaxanation transforms the DNA-binding and biological activity of the cylinder. The ability of the cylinder to de-thread from the rotaxane (and thus to bind DNA junction structures) is controlled by the extent of branching: fully-branched cylinders are locked inside the cucurbit10uril macrocycle, while cylinders with incomplete branch points can de-thread from the rotaxane in response to competitor guests. The number of branch points can thus afford kinetic control over the drug de-threading and release.
Squamous cell cancers of the anal canal (ASCC) are increasing in frequency and lack effective therapies for advanced disease. Although an association with human papillomavirus (HPV) has been ...established, little is known about the molecular characterization of ASCC. A comprehensive genomic analysis of ASCC was undertaken to identify novel genomic alterations (GAs) that will inform therapeutic choices for patients with advanced disease.
Hybrid-capture-based next-generation sequencing of exons from 236 cancer-related genes and intronic regions from 19 genes commonly rearranged in cancer was performed on 70 patients with ASCC. HPV status was assessed by aligning tumor sequencing reads to HPV viral genomes. GAs were identified using an established algorithm and correlated with HPV status.
Sixty-one samples (87%) were HPV-positive. A mean of 3.5 GAs per sample was identified. Recurrent alterations in phosphoinositol-3-kinase pathway (PI3K/AKT/mTOR) genes including amplifications and homozygous deletions were present in 63% of cases. Clinically relevant GAs in genes involved in DNA repair, chromatin remodeling, or receptor tyrosine kinase signaling were observed in 30% of cases. Loss-of-function mutations in TP53 and CDKN2A were significantly enhanced in HPV-negative cases (P < 0.0001).
This is the first comprehensive genomic analysis of ASCC, and the results suggest new therapeutic approaches. Differing genomic profiles between HPV-associated and HPV-negative ASCC warrants further investigation and may require novel therapeutic and preventive strategies.
Spintronic computing promises superior energy efficiency and nonvolatility compared to conventional field-effect transistor logic. But, it has proven difficult to realize spintronic circuits with a ...versatile, scalable device design that is adaptable to emerging material physics. Here we present prototypes of a logic device that encode information in the position of a magnetic domain wall in a ferromagnetic wire. We show that a single three-terminal device can perform inverter and buffer operations. We demonstrate one device can drive two subsequent gates and logic propagation in a circuit of three inverters. This prototype demonstration shows that magnetic domain wall logic devices have the necessary characteristics for future computing, including nonlinearity, gain, cascadability, and room temperature operation.
Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. ...Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse.
Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes.
Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035).
The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.
•The extent and composition of the pathological response after neoadjuvant DT in BRAFV600E/K melanoma correlates with RFS.•Patients achieving pCR had longer RFS compared with patients who did not.•Hyalinized fibrosis correlated with longer RFS, while necrosis and proliferative fibrosis correlated with shorter RFS.•Absence of pCR or presence of immature fibrosis independently predicted shorter RFS.•Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS.
To avoid negative impacts on food production, novel non-food biofuel feedstocks need to be identified and utilised. One option is to utilise marine biomass, notably fast-growing, large marine ...‘plants’ such as the macroalgal kelps. This paper reports on the changing composition of
Laminaria digitata throughout it growth cycle as determined by new technologies. The potential of
Laminaria sp. as a feedstock for biofuel production and future biorefining possibilities was assessed through proximate and ultimate analysis, initial pyrolysis rates using thermo-gravimetric analysis (TGA), metals content and pyrolysis gas chromatography–mass spectrometry.
Samples harvested in March contained the lowest proportion of carbohydrate and the highest ash and alkali metal content, whereas samples harvested in July contained the highest proportions of carbohydrate, lowest alkali metals and ash content. July was therefore considered the most suitable month for harvesting kelp biomass for thermochemical conversion to biofuels.
No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors ...associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge.
The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing.
2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 25·5% of 1965) and 1 year (232 28·9% of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 95% CI 0·46–0·99), obesity (0·50 0·34–0·74) and invasive mechanical ventilation (0·42 0·23–0·76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 IQR 0·74–1·00), at 5 months (0·74 0·64–0·88) to 1 year (0·75 0·62–0·88), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters.
The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.
UK Research and Innovation and National Institute for Health Research.
Ghrelin exerts various metabolic activities, including regulation of glucose levels in humans. To verify whether the glucose response to ghrelin reflects a modulation of an insulin-independent ...hepatic phenomenon, we studied glucose output by primary porcine hepatocytes in suspension culture, after incubation with acylated ghrelin (AG), unacylated ghrelin (UAG), and hexarelin (HEX). AG induced glucose output dose dependently after 20 min of incubation (P < 0.001), whereas HEX, a GH secretagogue receptor type 1a (GHS-R1a) agonist, had no effect. UAG inhibited glucose release also dose dependently and after 20 min (P < 0.001). Moreover, UAG completely reversed AG-induced glucose output (P < 0.01). Using real-time PCR, GHS-R1a gene expression was undetectable in all the hepatocyte preparations studied. The lack of efficacy of HEX, the efficacy of UAG, and the absence of GHS-R1a expression indicate the involvement of a yet uncharacterized ghrelin receptor type.
In conclusion, glucose output by primary hepatocytes is time- and dose-dependently stimulated by AG and inhibited by UAG. Moreover, UAG counteracts the stimulatory effect of AG on glucose release. These actions might be mediated by a different receptor than GHS-R1a, and apparently, we must consider AG and UAG as separate hormones that can modify each other’s actions on glucose handling, at least in the liver.
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