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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. LY-CoV1404 potently neutralizes authentic SARS-CoV-2, B.1.1.7, B.1.351, and B.1.617.2. In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The broad and potent neutralization activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants., Competing Interests: Declaration of interests Eli Lilly and Company provided resources for this study. AbCellera Biologics Inc. received funding from the U.S. Department of Defense, Defense Advanced Research Projects Agency (DARPA) Pandemic Prevention Platform, agreement D18AC00002. This research was funded in part by the U.S. Government (the views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the U.S. Government). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357 (https://www.aps.anl.gov/Science/Publications/Acknowledgment-Statement-for-Publications). Use of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline at Sector 31 of the Advanced Photon Source was provided by Eli Lilly and Company, which operates the facility (http://lrlcat.lilly.com/). This work was supported by the Intramural Program at the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center (to B.S.G. and J.R.M.). Operations support of the Galveston National Laboratory was supported by NIAID/NIH grant UC7AI094660. D.F., P.V., A.P., J.H., J.M.S., R.W.S., J.C., I. H., J.J.F., S.H., H.C.P., B.R., B.A.H., R.W.S., J.C., J.M.S., R.E.H., N.K., and B.E.J. are employees and/or stockholders of Eli Lilly and Company. K.W., S.Ž., M.W., E.L., L.K., Y.H., K.J., R.G., M.A.S., D.W.C., D.P., P.X., V.d.P., R.v.d.L., M.R., L.D., C.P., I.L., L.A., P.S., T.L.F., C.L.H., E.F., and B.C.B. are employees and stockholders of AbCellera Biologics Inc. AbCellera Biologics Inc. and the National Institutes of Health have filed patent applications related to the work described herein (US patent application 17/192243 and international patent application PCT/US21/20843, both titled “Anti-Coronavirus Antibodies and Methods of Use”)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at higher risk of severe coronavirus disease 2019 (COVID-19), and therefore vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important. We studied vaccination willingness, speed of vaccination uptake, side effects, and changes in social contact behaviour after vaccination in people with PCD. We used data from COVID-PCD, an international participatory cohort study. A COVID-19 vaccination questionnaire was emailed to participants in May 2021 and 423 participants from 31 countries replied (median age: 30 years, range 1-85 years; 261 (62%) female). Vaccination uptake and willingness were high, with 273 of 287 adults (96%) being vaccinated or willing to be in June 2021; only 4% were hesitant. The most common reason for hesitancy was fear of side effects, reported by 88%. Mild side effects were common, but no participant reported severe side effects. Half of the participants changed their social behaviour after vaccination by seeing friends and family more often. The high vaccination willingness in the study population might reflect the extraordinary effort taken by PCD support groups to inform people about COVID-19 vaccination. Clear and specific information and involvement of representatives is important for high vaccine uptake.

Background: Cancer therapy-related cardiac dysfunction (CTRCD) is a critical problem with an impact on both oncological and cardiovascular prognosis, especially when it prevents patients from receiving cancer treatment. Standard therapy for heart failure (HF) is recommended for CTRCD, but there is no well-established evidence on how sacubitril/valsartan may help cancer patients with cardiotoxicity., Objectives: The aim of this trial was to study the effectiveness of sacubitril-valsartan in patients with CTRCD treated in cardio-oncology units., Methods: We enrolled 635 patients with breast cancer and followed them with echocardiography and NT- proBNP. Patients who developed left ventricular dysfunction and heart failure were treated with angiotensin-converting enzyme inhibitors (ACEI) (enalapril) or angiotensin receptor blockers (ARB) (valsartan), aldosterone antagonists (eplerenone), digitalis and diuretics (furosemide), as needed. When patients remained symptomatic and met the PARADIGM-HF inclusion criteria, sacubitril/valsartan was started instead of enalapril or valsartan. We analyzed clinical, laboratory and echocardiographic variables to determine the beneficial effects of sacubitril/valsartan on left ventricular remodeling (improvement of left ventricular ejection fraction (LVEF), left ventricle internal diameter in diastole), diastolic dysfunction (E/e' ratio), reduction in NT-proBNP levels, New York Heart Association (NHYA) class and improvement in the 6-min walk test. Also, we analyzed serum creatinine and potassium levels to determine treatmentsafety in this population. Median follow-up was 20 months., Results: Twenty-eight patients developed cardiotoxicity and were treated with sacubitril/valsartan. The sacubitril/valsartan dose was 100 mg (sacubitril 49 mg/valsartan 51 mg) in 12 patients (42.85%) and 200 mg (sacubitril 97 mg/valsartan 103 mg) in 16 patients (57.15%). No deaths were reported, and one patient underwent heart transplantation. Baseline median NT-proBNP was 997.5 pg/ml (IQR 663.8 - 2380.8), which decreased to a median of 416.5 pg/ml (IQR 192.0-798.2) on follow-up with p < 0.001. Baseline NYHA functional class was III (78.6%) or IV (21.4%), and it improved to I (57.1%) or II (42.9%) on follow-up. LVEF increased with treatment from 26.7 ± 5.4% to 32.3 ± 5.5% (p < 0.001). There were also significant improvements in left ventricle internal diameter in diastole (LVIDD), diastolic function, 6-min walk test, and mitral valve regurgitation. There were no differences between basal and follow-up levels of serum creatinine or potassium., Conclusion: Sacubitril/valsartan might be a promising treatment option in patients with refractory CTRCD.

Serum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac biomarkers including cardiac troponin and natriuretic peptides can be used to guide initiation of cardioprotective treatments for cancer patients during treatment and to monitor the response to cardioprotective treatments, and they also offer prognostic value. This position statement examines the role of cardiac biomarkers in the management of cancer patients. The Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the Cardio-Oncology Council of the ESC have evaluated the current evidence for the role of cardiovascular biomarkers in cancer patients before, during and after cardiotoxic cancer therapies. The characteristics of the main two biomarkers troponin and natriuretic peptides are discussed, the link to the mechanisms of cardiovascular toxicity, and the evidence for their clinical use in surveillance during and after anthracycline chemotherapy, trastuzumab and HER2-targeted therapies, vascular endothelial growth factor inhibitors, proteasome inhibitors, immune checkpoint inhibitors, cyclophosphamide and radiotherapy. Novel surveillance clinical pathways integrating cardiac biomarkers for cancer patients receiving anthracycline chemotherapy or trastuzumab biomarkers are presented and future direction in cardio-oncology biomarker research is discussed., (© 2020 European Society of Cardiology.)

Background: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored., Methods: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice., Findings: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance., Interpretation: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Exposure to ultraviolet radiation is closely linked to the development of skin cancers in humans. The ultraviolet B (UVB) radiation wavelength (280-320 nm), in particular, causes DNA damage in epidermal keratinocytes, which are linked to the generation of signature premalignant mutations. Interactions between dermal fibroblasts and keratinocytes play a role in epidermal repair and regeneration after UVB-induced damage. To investigate these processes, established two and three-dimensional culture models were utilized to study the impact of fibroblast-keratinocyte crosstalk during the acute UVB response. Using a coculture system it was observed that fibroblasts enhanced keratinocyte survival and the repair of cyclobutane pyrimidine dimers (CPDs) after UVB radiation exposure. These findings were also mirrored in irradiated human skin coculture models employed in this study. Fibroblast coculture was shown to play a role in the expression and activation of members of the apoptotic cascade, including caspase-3 and Bad. Interestingly, the expression and phosphorylation of p53, a key player in the regulation of keratinocyte cell fate postirradiation, was also shown to be influenced by fibroblast-produced factors. This study highlights the importance of synergistic interactions between fibroblasts and keratinocytes in maintaining a functional epidermis while promoting repair and regeneration following UVB radiation-induced damage., (© 2014 The American Society of Photobiology.)

The incidences of skin cancers resulting from chronic ultraviolet radiation (UVR) exposure are on the incline in both Australia and globally. Hence, the cellular and molecular pathways that are associated with UVR-induced photocarcinogenesis need to be urgently elucidated, in order to develop more robust preventative and treatment strategies against skin cancers. In vitro investigations into the effects of UVR (in particular, the highly mutagenic UVB wavelength) have, to date, mainly involved the use of cell culture and animal models. However, these models possess biological disparities to native skin, which, to some extent, have limited their relevance to the in vivo situation. To address this, we characterized a three-dimensional, tissue-engineered human skin equivalent (HSE) model (consisting of primary human keratinocytes cultured on a dermal-derived scaffold) as a representation of a more physiologically relevant platform to study keratinocyte responses to UVB. Significantly, we demonstrate that this model retains several important epidermal properties of native skin. Moreover, UVB irradiation of the HSE constructs was shown to induce key markers of photodamage in the HSE keratinocytes, including the formation of cyclobutane pyrimidine dimers, the activation of apoptotic pathways, the accumulation of p53, and the secretion of inflammatory cytokines. Importantly, we also demonstrate that the UVB-exposed HSE constructs retain the capacity for epidermal repair and regeneration after photodamage. Together, our results demonstrate the potential of this skin equivalent model as a tool to study various aspects of the acute responses of human keratinocytes to UVB radiation damage.

Presently, global rates of skin cancers induced by ultraviolet radiation (UVR) exposure are on the rise. In view of this, current knowledge gaps in the biology of photocarcinogenesis and skin cancer progression urgently need to be addressed. One factor that has limited skin cancer research has been the need for a reproducible and physiologically-relevant model able to represent the complexity of human skin. This review outlines the main currently-used in vitro models of UVR-induced skin damage. This includes the use of conventional two-dimensional cell culture techniques and the major animal models that have been employed in photobiology and photocarcinogenesis research. Additionally, the progression towards the use of cultured skin explants and tissue-engineered skin constructs, and their utility as models of native skin's responses to UVR are described. The inherent advantages and disadvantages of these in vitro systems are also discussed., (© 2012 John Wiley & Sons A/S.)

Due to its small size and versatility, the biarsenical-tetracysteine system is an attractive way to label viral proteins for live cell imaging. This study describes the genetic labeling of the human immunodeficiency virus type 1 (HIV-1) structural proteins (matrix, capsid and nucleocapsid), enzymes (protease, reverse transcriptase, RNAse H and integrase) and envelope glycoprotein 120 with a tetracysteine tag in the context of a full-length virus. We measure the impact of these modifications on the natural virus infection and, most importantly, present the first infectious HIV-1 construct containing a fluorescently-labeled nucleocapsid protein. Furthermore, due to the high background levels normally associated with the labeling of tetracysteine-tagged proteins we have also optimized a metabolic labeling system that produces infectious virus containing the natural envelope glycoproteins and specifically labeled tetracysteine-tagged proteins that can easily be detected after virus infection of T-lymphocytes. This approach can be adapted to other viral systems for the visualization of the interplay between virus and host cell during infection.

In a three-year pilot project in the Philippines, the magnitude of vitamin A deficiency and its clinical manifestation (xerophthalmia) was determined, and three alternate programs for eliminating and preventing it in various ecologic zones were designed and implemented concurrently in separate areas in each ecologic zone. Results were evaluated, and costs and benefits of each program were determined. The results of the fortification program are reported. Monosodium glutamate (MSG) was selected as the ideal carrier was fortified at a level which provided 15,000 I.U. retinol palmitate to the average family each day. Significant increases in serum A, especially for children with more deficient vitamin A status, resulted. The program's economic benefits significantly outweighted the costs, and the MSG fortification program has been expanded to several additional pilot provinces in the Philippines.

An experiment was performed on the maternity wards of three public hospitals in Cebu City, Philippines to determine whether the distribution of free samples of infant formula reduced the likelihood that mothers would breast feed or caused mothers to terminate nursing early. Samples were given or withheld alternately for 2 week intervals to mothers as they left maternity wards. They were followed for 8 months in the first experiment (N = 273) and for 2 months in a replication (N = 284). We found that there were no statistically significant differences between those who received samples and those who did not in initiation or maintenance of breast feeding. Mothers in both groups frequently turned to mixed schedules, but these varied from day to day depending on money to buy other forms of milk, or on the mother's health, or her plan to be away from the baby for one or more feeding periods. After the baby reached an age of 2-3 months, mothers, with few exceptions, used diluted sweetened condensed milk as a supplement and/or substitute for their own milk. It was found that, while mothers recognize the nutritional, economic and health benefits of breast feeding, they may terminate early on the basis of folk beliefs. Receiving formula samples, however, had no measured effect on their breast feeding practices.