A new decorin-like tetrapeptide for optimal organization of collagen fibres

Synopsis Decorin interacts with collagen via its protein core and influences collagen fibrillogenesis, thus regulating excessive bundle-like aggregation of collagen. As skin ages, there is lack of functional decorin, which results in disrupted collagen fibres and in a reduction in the tensile strength of the skin. Therefore, a substitute for decorin would make up for the non-functional decorin that is present as we age. Two tetrapeptide sequences have been identified as the specific binding sites of decorin to collagen fibrils. These sequences were engineered to generate new tetrapeptides with improved affinity that would present a decorin-like activity. A focused library of several candidates was synthesized containing only tetrapeptides that mimicked the binding sequences of decorin. The candidates were screened with an in vitro collagen fibrillogenesis assay and the tetrapeptide with International Nomenclature of Cosmetic Ingredients (INCI) name Tripeptide-10 Citrulline achieved the best results. Like decorin, this synthetic tetrapeptide proved, through in vitro tests, to regulate collagen fibrillogenesis and to influence the diameter of collagen fibres, making them thinner and more uniform. Tripeptide-10 Citrulline is a new cosmetic active to target specifically collagen fibre organization. Skin collagen quality is addressed rather than skin collagen quantity. Tripeptide-10 Citrulline ensures uniformity in fibril diameter and increases skin suppleness because of a better cohesion of collagen fibres. Ré sumé La décorine réagit avec le collagène par sa partie protéinique et influence la fibrillogénèse du collagène, régulant ainsi l'agrégation en paquets excessive de ce dernier. Lorsque la peau vieillit, il se produit une perte en décorine fonctionnelle, ce qui provoque une désorganisation des fibres du collagène et une diminution de la force en traction de la peau. Ainsi, un remplaçant de la décorine compenserait la décorine non fonctionnelle qui apparait lorsque nous vieillissons. Deux séquences tétrapeptidiques ont été identifiées comme étant les sites spécifiques de liaison de la décorine aux fibrilles de collagène. Ces séquences ont été reproduites pour générer de nouveaux tétrapeptides avec une affinité améliorée, ce qui conduit à une activité décorine like. Une librairie de plusieurs candidats a été synthétisée, contenant uniquement les tétrapeptides qui simulent les séquences de liaison de la décorine. Les candidats ont été « screenés » au travers d'un test in vitro de fibrillogénèse du collagène et le tétrapeptide présentant le nom INCI Tripeptide-10 Citruline a conduit aux meilleurs résultats. Comme la décorine, ce tétra-peptide synthétique s'est montré capable, au travers de tests in vitro, de réguler la fibrillogénèse du collagène et d'influencer le diamètre des ses fibres, les rendant plus fines et plus uniformes. Correspondence: A. Puig

Variability of the prevalence of depression in function of sociodemographic and environmental factors: ecological model

Major depression etiopathogenesis is related to a wide variety of genetics, demographic and psychosocial factors, as well as to environmental factors. The objective of this study is to analyze sociodemographic and environmental variables that are related to the prevalence of depression through correlation analysis and to develop a regression model that explains the behavior of this disease from an ecological perspective. This is an ecological, retrospective, cross-sectional study. The target population was 1,148,430 individuals over the age of 16 who were registered in Aragon (Spain) during 2010, with electronic medical records in the community’s primary health care centers. The spatial unit was the Basic Health Area (BHA). The dependent variable was the diagnosis of Depression and the ecological independent variables were: Demographic variables (gender and age), population distribution, typology of the entity, population structure by sex and age, by nationality, by education, by work, by salary, by marital status, structure of the household by number of members, and state of the buildings. The results show moderate and positive correlations with higher rates of depression in areas having a higher femininity index, higher population density, areas with a higher unemployment rate and higher average salary. The results of the linear regression show that aging +75 and rural entities act as protective factors for depression, while urban areas and deficient buildings act as risk factors. In conclusion, the ecological methodology may be a useful tool which, together with the statistical epidemiological analysis, can help in the political decision making process

Reconstructing Viral Genomes from the Environment Using Fosmid Clones: The Case of Haloviruses

Background: Metaviriomes, the viral genomes present in an environment, have been studied by direct sequencing of the viral DNA or by cloning in small insert libraries. The short reads generated by both approaches make it very difficult to assemble and annotate such flexible genomic entities. Many environmental viruses belong to unknown groups or prey on uncultured and little known cellular lineages, and hence might not be present in databases. Methodology and Principal Findings: Here we have used a different approach, the cloning of viral DNA into fosmids before sequencing, to obtain natural contigs that are close to the size of a viral genome. We have studied a relatively low diversity extreme environment: saturated NaCl brines, which simplifies the analysis and interpretation of the data. Forty-two different viral genomes were retrieved, and some of these were almost complete, and could be tentatively identified as head-tail phages (Caudovirales). Conclusions and Significance: We found a cluster of phage genomes that most likely infect Haloquadratum walsbyi, the square archaeon and major component of the community in these hypersaline habitats. The identity of the prey could be confirmed by the presence of CRISPR spacer sequences shared by the virus and one of the available strain genomes. Other viral clusters detected appeared to prey on the Nanohaloarchaea and on the bacterium Salinibacter ruber, covering most of the diversity of microbes found in this type of environment. This approach appears then as a viable alternative to describe metaviriomes in a much more detailed and reliable way than by the more common approaches based on direct sequencing. An example of transfer of a CRISPR cluster including repeats and spacers was accidentally found supporting the dynamic nature and frequent transfer of this peculiar prokaryotic mechanism of cell protection.This work was supported by projects MAGYK (BIO2008-02444), MICROGEN (Programa CONSOLIDERINGENIO 2010 CDS2009-00006), CGL2'09-12651-C02-01 from the Spanish Ministerio de Ciencia e Innovación, DIMEGEN (PROMETEO/2010/089) and ACOMP/2009/155 from the Generalitat Valenciana. FEDER funds supported this project. IG-H was supported by MAGYK from Ministerio de Ciencia e Innovación. A-BM-C was supported by CONSOLIDER-INGENIO 2010

Probabilistic 3D surface reconstruction from sparse MRI information

Surface reconstruction from magnetic resonance (MR) imaging data is indispensable in medical image analysis and clinical research. A reliable and effective reconstruction tool should: be fast in prediction of accurate well localised and high resolution models, evaluate prediction uncertainty, work with as little input data as possible. Current deep learning state of the art (SOTA) 3D reconstruction methods, however, often only produce shapes of limited variability positioned in a canonical position or lack uncertainty evaluation. In this paper, we present a novel probabilistic deep learning approach for concurrent 3D surface reconstruction from sparse 2D MR image data and aleatoric uncertainty prediction. Our method is capable of reconstructing large surface meshes from three quasi-orthogonal MR imaging slices from limited training sets whilst modelling the location of each mesh vertex through a Gaussian distribution. Prior shape information is encoded using a built-in linear principal component analysis (PCA) model. Extensive experiments on cardiac MR data show that our probabilistic approach successfully assesses prediction uncertainty while at the same time qualitatively and quantitatively outperforms SOTA methods in shape prediction. Compared to SOTA, we are capable of properly localising and orientating the prediction via the use of a spatially aware neural network.Comment: MICCAI 202

Oncologist’s knowledge and implementation of guidelines for breakthrough cancer pain in Spain: CONOCE study

[Purpose]: Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP.[Methods]: Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline.[Results]: A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines.[Conclusion]: Despite oncologist’s clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation.This study was funded by Kyowa Kirin Farmacéutica S. L.U. through Fundación ECO

Trajectories of alcohol consumption during life and the risk of developing breast cancer

Background: Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. Objective: To compare the influence of distinctive trajectories of alcohol consumption throughout a woman’s life on development of breast cancer (BC). Methods: 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women’s lifetime. Results: Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (=15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, =15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. Conclusions: The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk. © 2021, The Author(s)

A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study

[Purpose]: To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L.[Materials and methods]: We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L–T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed.[Results]: One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1–43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%).[Conclusion]: The combination of L–T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L–T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.This work was supported by GlaxoSmithKline plc (GSK) through a contract with Medica Scientia Innovation Research (MedSIR), an academic research organization focused on independent clinical research development

Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

The emerging SARS-CoV-2 variants of concern (VOCs) may display enhanced transmissibility, more severity and/or immune evasion; however, the pathogenesis of these new VOCs in experimental SARS-CoV-2 models or the potential infection of other animal species is not completely understood. Here we infected K18-hACE2 transgenic mice with B.1, B.1.351/Beta, B.1.617.2/Delta and BA.1.1/Omicron isolates and demonstrated heterogeneous infectivity and pathogenesis. B.1.351/Beta variant was the most pathogenic, while BA.1.1/Omicron led to lower viral RNA in the absence of major visible clinical signs. In parallel, we infected wildtype (WT) mice and confirmed that, contrary to B.1 and B.1.617.2/Delta, B.1.351/Beta and BA.1.1/Omicron can infect them. Infection in WT mice coursed without major clinical signs and viral RNA was transient and undetectable in the lungs by day 7 post-infection. In silico modeling supported these findings by predicting B.1.351/Beta receptor binding domain (RBD) mutations result in an increased affinity for both human and murine ACE2 receptors, while BA.1/Omicron RBD mutations only show increased affinity for murine ACE2

Double-weak decays of 124Xe and 136Xe in the XENON1T and XENONnT experiments

We present results on the search for two-neutrino double-electron capture (2νECEC) of 124Xe and neutrinoless double-β decay (0νββ) of 136Xe in XENON1T. We consider captures from the K shell up to the N shell in the 2νECEC signal model and measure a total half-life of T2νECEC1/2=(1.1±0.2stat±0.1sys)×1022yr with a 0.87kgyr isotope exposure. The statistical significance of the signal is 7.0σ. We use XENON1T data with 36.16kgyr of 136Xe exposure to search for 0νββ. We find no evidence of a signal and set a lower limit on the half-life of T0νββ1/2>1.2×1024yrat90%CL. This is the best result from a dark matter detector without an enriched target to date. We also report projections on the sensitivity of XENONnT to 0νββ. Assuming a 275kgyr 136Xe exposure, the expected sensitivity is T0νββ1/2>2.1×1025yrat90%CL, corresponding to an effective Majorana mass range of ⟨mββ⟩<(0.19–0.59)eV/c2