Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics

The blood-brain barrier (BBB), while being the gatekeeper of the central nervous system (CNS), is a bottleneck for the treatment of neurological diseases. Unfortunately, most of the biologicals do not reach their brain targets in sufficient quantities. The antibody targeting of receptor-mediated transcytosis (RMT) receptors is an exploited mechanism that increases brain permeability. We previously discovered an anti-human transferrin receptor (TfR) nanobody that could efficiently deliver a therapeutic moiety across the BBB. Despite the high homology between human and cynomolgus TfR, the nanobody was unable to bind the non-human primate receptor. Here we report the discovery of two nanobodies that were able to bind human and cynomolgus TfR, making these nanobodies more clinically relevant. Whereas nanobody BBB00515 bound cynomolgus TfR with 18 times more affinity than it did human TfR, nanobody BBB00533 bound human and cynomolgus TfR with similar affinities. When fused with an anti-beta-site amyloid precursor protein cleaving enzyme (BACE1) antibody (1A11AM), each of the nanobodies was able to increase its brain permeability after peripheral injection. A 40% reduction of brain Aβ1–40 levels could be observed in mice injected with anti-TfR/BACE1 bispecific antibodies when compared to vehicle-injected mice. In summary, we found two nanobodies that could bind both human and cynomolgus TfR with the potential to be used clinically to increase the brain permeability of therapeutic biologicals

ESO Imaging Survey: Optical follow-up of 12 selected XMM-Newton fields

(Abridged) This paper presents the data recently released for the XMM-Newton/WFI survey carried out as part of the ESO Imaging Survey (EIS) project. The aim of this survey is to provide optical imaging follow-up data in BVRI for identification of serendipitously detected X-ray sources in selected XMM-Newton fields. In this paper, fully calibrated individual and stacked images of 12 fields as well as science-grade catalogs for the 8 fields located at high-galactic latitude are presented. The data covers an area of \sim 3 square degrees for each of the four passbands. The median limiting magnitudes (AB system, 2" aperture, 5\sigma detection limit) are 25.20, 24.92, 24.66, and 24.39 mag for B-, V-, R-, and I-band, respectively. These survey products, together with their logs, are available to the community for science exploitation in conjunction with their X-ray counterparts. Preliminary results from the X-ray/optical cross-correlation analysis show that about 61% of the detected X-ray point sources in deep XMM-Newton exposures have at least one optical counterpart within 2" radius down to R \simeq 25 mag, 50% of which are so faint as to require VLT observations thereby meeting one of the top requirements of the survey, namely to produce large samples for spectroscopic follow-up with the VLT, whereas only 15% of the objects have counterparts down to the DSS limiting magnitude.Comment: 24 pages, 10 figures, accepted for publication in Astronomy and Astrophysics. Accompanying data releases available at http://archive.eso.org/archive/public_datasets.html (WFI images), http://www.eso.org/science/eis/surveys/release_65000025_XMM.html (optical catalogs), http://www.aip.de/groups/xray/XMM_EIS/ (X-ray data). Full resolution version available at http://www.astro.uni-bonn.de/~dietrich/publications/3785.ps.g

The Cluster of Galaxies Abell 970

We present a dynamical analysis of the galaxy cluster Abell 970 based on a new set of radial velocities measured at ESO, Pic du Midi and Haute-Provence observatories. Our analysis indicates that this cluster has a substructure and is out of dynamical equilibrium. This conclusion is also supported by differences in the positions of the peaks of the surface density distribution and X-ray emission, as well as by the evidence of a large scale velocity gradient in the cluster. We also found a discrepancy between the masses inferred with the virial theorem and with the X-ray emission, what is expected if the galaxies and the gas inside the cluster are not in hydrostatic equilibrium. Abell 970 has a modest cooling flow, as is expected if it is out of equilibrium as suggested by Allen (1998). We propose that cooling flows may have an intermittent behavior, with phases of massive cooling flows being followed by phases without significant cooling flows after the acretion of a galaxy group massive enough to disrupt the dynamical equilibrium in the center of the clusters. A massive cooling flow will be established again, after a new equilibrium is achieved.Comment: 24 pages, 9 figures, submitted to A&

Enzymkatalysierte späte Modifizierungen: Besser spät als nie

From Wiley via Jisc Publications RouterHistory: received 2020-11-08, rev-recd 2021-01-15, pub-electronic 2021-03-08, pub-print 2021-07-26Article version: VoRPublication status: PublishedFunder: EPSRC; Grant(s): EP/S005226/1Funder: BBSRC; Grant(s): EP/S005226/1Funder: AstraZeneca plc; Id: http://dx.doi.org/10.13039/100004325; Grant(s): EP/S005226/1Funder: European Research Council; Id: http://dx.doi.org/10.13039/100010663; Grant(s): 742987-BIO-H-BORROW-ERC-2016-ADG, 788231-ProgrES-ERC-2017-AD

Enzymatic Late‐Stage Modifications: Better Late Than Never

From Wiley via Jisc Publications RouterHistory: received 2020-11-08, rev-recd 2021-01-15, pub-electronic 2021-03-08, pub-print 2021-07-26Article version: VoRPublication status: PublishedFunder: EPSRC; Grant(s): EP/S005226/1Funder: BBSRC; Grant(s): EP/S005226/1Funder: AstraZeneca plc; Id: http://dx.doi.org/10.13039/100004325; Grant(s): EP/S005226/1Funder: European Research Council; Id: http://dx.doi.org/10.13039/100010663; Grant(s): 742987-BIO-H-BORROW-ERC-2016-ADG, 788231-ProgrES-ERC-2017-ADGAbstract: Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis especially provides excellent opportunities for late‐stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compound libraries. Particularly important and highly topical are enzyme‐catalysed oxyfunctionalisations, halogenations, methylations, reductions, and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymatic late‐stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development

Duration and compliance with antidepressant treatment in immigrant and native-born populations in Spain: a four year follow-up descriptive study

<p>Abstract</p> <p>Background</p> <p>Non-compliance with antidepressant treatment continues to be a complex problem in mental health care. In immigrant populations non-compliance is one of several barriers to adequate management of mental illness; some data suggest greater difficulties in adhering to pharmacological treatment in these groups and an increased risk of therapeutic failure.</p> <p>The aim of this study is to assess differences in the duration and compliance with antidepressant treatment among immigrants and natives in a Spanish health region.</p> <p>Methods</p> <p>Population-based (n=206,603), retrospective cohort study including all subjects prescribed ADT between 2007 and 2009 and recorded in the national pharmacy claims database. Compliance was considered adequate when the duration was longer than 4months and when patients withdrew more than 80% of the packs required.</p> <p>Results</p> <p>5334 subjects (8.5% of them being immigrants) initiated ADT. Half of the immigrants abandoned treatment during the second month (median for natives=3months). Of the immigrants who continued, only 29.5% presented good compliance (compared with 38.8% in natives). The estimated risk of abandoning/ending treatment in the immigrant group compared with the native group, adjusted for age and sex, was 1.28 (95%CI 1.16-1.42).</p> <p>Conclusions</p> <p>In the region under study, immigrants of all origins present higher percentages of early discontinuation of ADT and lower median treatment durations than the native population. Although this is a complex, multifactor situation, the finding of differences between natives and immigrants in the same region suggests the need to investigate the causes in greater depth and to introduce new strategies and interventions in this population group.</p

Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT)

Background: There are very few studies about general quality of life parameters, standards for the description of health status and comparison with general population data on patients with Hereditary hemorrhagic telangiectasia (HHT), a rare disease in which epistaxis is a cardinal symptom. Purpose: To assess the quality of life in a population of Spanish patients with HHT and compare it with the general population. Design and methods: Between January 1st 2005 and December 31st 2013, 187 adult patients diagnosed with HHT who were admitted to the HHT Unit of the Hospital Sierrallana, completed on their first visit, the EuroQol 5D-3L (five dimensions and three levels) quality of life descriptive test and the visual analog scale (VAS). The numerical social index value was also determined and the subjective effect of the nasal epistaxis on their quality of life was estimated classified as mild, moderate or severe. Results: Patients with HHT had greater problems than the general population in the five dimensions of the EuroQol 5D-3L, particularly considering pain/discomfort and anxiety/depression. In the VAS and the social index value, patients with HHT also scored lower than the general population, particularly older patients, males, and patients with HHT2. They also had values similar to those of populations with chronic illnesses. The subjective perception of the severity of epistaxis correlated strongly with the VAS and social index values. Conclusions: The quality of life of patients with HHT, estimated using the EuroQol 5D-3L scale, is affected across all dimensions. The scores are similar to those seen in cases of other chronic diseases. Older patients, males and the carriers of the ACVRL1 mutation generally have worse scores on these scales. The VAS and the social index value are index that correlate well with the severity of the clinical symptoms associated mainly with epistaxis

Emergency hospital services utilization in Lleida (Spain): A cross-sectional study of immigrant and Spanish-born populations

<p>Abstract</p> <p>Background</p> <p>The use of emergency hospital services (EHS) has increased steadily in Spain in the last decade while the number of immigrants has increased dramatically. Studies show that immigrants use EHS differently than native-born individuals, and this work investigates demographics, diagnoses and utilization rates of EHS in Lleida (Spain).</p> <p>Methods</p> <p>Cross-sectional study of all the 96,916 EHS visits by patients 15 to 64 years old, attended during the years 2004 and 2005 in a public teaching hospital. Demographic data, diagnoses of the EHS visits, frequency of hospital admissions, mortality and diagnoses at hospital discharge were obtained. Utilization rates were estimated by group of origin. Poisson regression was used to estimate the rate ratios of being visited in the EHS with respect to the Spanish-born population.</p> <p>Results</p> <p>Immigrants from low-income countries use EHS services more than the Spanish-born population. Differences in utilization patterns are particularly marked for Maghrebi men and women and sub-Saharan women. Immigrant males are at lower risk of being admitted to the hospital, as compared with Spanish-born males. On the other hand, immigrant women are at higher risk of being admitted. After excluding the visits with gynecologic and obstetric diagnoses, women from sub-Saharan Africa and the Maghreb are still at a higher risk of being admitted than their Spanish-born counterparts.</p> <p>Conclusion</p> <p>In Lleida (Spain), immigrants use more EHS than the Spanish born population. Future research should indicate whether the same pattern is found in other areas of Spain and whether EHS use is attributable to health needs, barriers to access to the primary care services or similarities in the way immigrants access health care in their countries of origin.</p

Information Routing Driven by Background Chatter in a Signaling Network

Living systems are capable of processing multiple sources of information simultaneously. This is true even at the cellular level, where not only coexisting signals stimulate the cell, but also the presence of fluctuating conditions is significant. When information is received by a cell signaling network via one specific input, the existence of other stimuli can provide a background activity –or chatter– that may affect signal transmission through the network and, therefore, the response of the cell. Here we study the modulation of information processing by chatter in the signaling network of a human cell, specifically, in a Boolean model of the signal transduction network of a fibroblast. We observe that the level of external chatter shapes the response of the system to information carrying signals in a nontrivial manner, modulates the activity levels of the network outputs, and effectively determines the paths of information flow. Our results show that the interactions and node dynamics, far from being random, confer versatility to the signaling network and allow transitions between different information-processing scenarios

An assessment of existing models for individualized breast cancer risk estimation in a screening program in Spain

Background: The aim of this study was to evaluate the calibration and discriminatory power of three predictive models of breast cancer risk. Methods: We included 13,760 women who were first-time participants in the Sabadell-Cerdanyola Breast Cancer Screening Program, in Catalonia, Spain. Projections of risk were obtained at three and five years for invasive cancer using the Gail, Chen and Barlow models. Incidence and mortality data were obtained from the Catalan registries. The calibration and discrimination of the models were assessed using the Hosmer-Lemeshow C statistic, the area under the receiver operating characteristic curve (AUC) and the Harrell’s C statistic. Results: The Gail and Chen models showed good calibration while the Barlow model overestimated the number of cases: the ratio between estimated and observed values at 5 years ranged from 0.86 to 1.55 for the first two models and from 1.82 to 3.44 for the Barlow model. The 5-year projection for the Chen and Barlow models had the highest discrimination, with an AUC around 0.58. The Harrell’s C statistic showed very similar values in the 5-year projection for each of the models. Although they passed the calibration test, the Gail and Chen models overestimated the number of cases in some breast density categories. Conclusions: These models cannot be used as a measure of individual risk in early detection programs to customize screening strategies. The inclusion of longitudinal measures of breast density or other risk factors in joint models of survival and longitudinal data may be a step towards personalized early detection of BC.This study was funded by grant PS09/01340 and The Spanish Network on Chronic Diseases REDISSEC (RD12/0001/0007) from the Health Research Fund (Fondo de Investigación Sanitaria) of the Spanish Ministry of Health