Sex hormones and the total testosterone:estradiol ratio as predictors of severe acute respiratory syndrome coronavirus 2 infection in hospitalized men.

BACKGROUND: The predictive ability of the early determination of sex steroids and the total testosterone:estradiol ratio for the risk of severe coronavirus disease 2019 or the potential existence of a biological gradient in this relationship has not been evaluated. OBJECTIVES: To assess the relationship of sex steroid levels and the total testosterone:estradiol ratio with the risk of severe acute respiratory syndrome coronavirus 2 infection in men, defined as the need for intensive care unit admission or death, and the predictive ability of each biomarker. MATERIALS AND METHODS: This was a prospective observational study. We included all consecutive adult men with severe acute respiratory syndrome coronavirus 2 infections in a single center admitted to a general hospital ward or to the intensive care unit. Sex steroids were evaluated at the centralized laboratory of our hospital. RESULTS: We recruited 98 patients, 54 (55.1%) of whom developed severe coronavirus disease in 2019. Compared to patients with nonsevere coronavirus disease 2019, patients with severe coronavirus disease 2019 had significantly lower serum levels of total testosterone (111 ± 89 vs. 191 ± 143 ng/dL; p < 0.001), dehydroepiandrosterone (1.69 ± 1.26 vs. 2.96 ± 2.64 ng/mL; p < 0.001), and dehydroepiandrosterone sulfate (91.72 ± 76.20 vs. 134.28 ± 98.261 µg/dL; p = 0.009), significantly higher levels of estradiol (64.61 ± 59.35 vs. 33.78 ± 13.78 pg/mL; p = 0.001), and significantly lower total testosterone:estradiol ratio (0.28 ± 0.31 vs. 0.70 ± 0.75; p < 0.001). The lower the serum level of androgen and the lower the total testosterone:estradiol ratio values, the higher the likelihood of developing severe coronavirus disease 2019, with the linear trend in the adjusted analyses being statistically significant for all parameters except for androstenedione (p = 0.064). In the receiver operating characteristic analysis, better predictive performance was shown by the total testosterone:estradiol ratio, with an area under the curve of 0.77 (95% confidence interval 0.68-0.87; p < 0.001). DISCUSSION AND CONCLUSION: Our results suggest that men with severe acute respiratory syndrome coronavirus 2 infection, decreased androgen levels and increased estradiol levels have a higher likelihood of developing an unfavorable outcome. The total testosterone:estradiol ratio showed the best predictive ability.

EMBL's European Bioinformatics Institute (EMBL-EBI) in 2023.

The European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI) is one of the world's leading sources of public biomolecular data. Based at the Wellcome Genome Campus in Hinxton, UK, EMBL-EBI is one of six sites of the European Molecular Biology Laboratory (EMBL), Europe's only intergovernmental life sciences organisation. This overview summarises the latest developments in the services provided by EMBL-EBI data resources to scientific communities globally. These developments aim to ensure EMBL-EBI resources meet the current and future needs of these scientific communities, accelerating the impact of open biological data for all.

Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity.

Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.

Network expansion of genetic associations defines a pleiotropy map of human cell biology.

Interacting proteins tend to have similar functions, influencing the same organismal traits. Interaction networks can be used to expand the list of candidate trait-associated genes from genome-wide association studies. Here, we performed network-based expansion of trait-associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share an underlying genetic and biological process. We identified 73 pleiotropic gene modules linked to multiple traits, enriched in genes involved in processes such as protein ubiquitination and RNA processing. In contrast to gene deletion studies, pleiotropy as defined here captures specifically multicellular-related processes. We show examples of modules linked to human diseases enriched in genes with known pathogenic variants that can be used to map targets of approved drugs for repurposing. Finally, we illustrate the use of network expansion scores to study genes at inflammatory bowel disease genome-wide association study loci, and implicate inflammatory bowel disease-relevant genes with strong functional and genetic support.

Incidental Diagnosis of Metastatic Breast Cancer in a Man With 99m Tc-PSMA SPECT/CT.

ABSTRACT: Breast cancer in men is a rare and unsuspected malignancy. A 48-year-old man begins with disabling low back pain. The CT scan reported a compression fracture in L2 and diffuse skeletal lesions suggestive of metastatic disease. The serum prostate-specific antigen was 6.2 ng/mL. He was referred for SPECT/CT with 99m Tc-EDDA/HYNIC-inhibitor prostate-specific membrane antigen due to clinical suspicion of prostate cancer. SPECT/CT with 99m Tc-EDDA/HYNIC-inhibitor prostate-specific membrane antigen showed a primary lesion in the left breast and multiple bone lesions. Biopsy confirmed infiltrating ductal carcinoma with positive hormone receptors and indeterminate HER2 (human epidermal growth factor receptor 2).

The next-generation Open Targets Platform: reimagined, redesigned, rebuilt.

The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene-disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases.

Diagnosis of Traumatic Bronchobiliary Fistula With Late 99m Tc-Mebrofenin SPECT/CT.

ABSTRACT: Bronchobiliary fistula (BBF) represents a rare disorder; it consists of abnormal interconnection between the biliary tract and bronchial trees. A 22-year-old woman with persistent chest pain, jaundice, and biliptysis was referred for hepatobiliary scintigraphy under clinical suspicion of a BBF. Patient medical history was consistent with biliary tree reconstruction secondary to an iatrogenic injury during cholecystectomy 4 years ago. Previous complementary studies (CT and MR cholangiopancreatography) were equivocal for diagnosis. Planar dynamic images of hepatobiliary scintigraphy in the first hour were inconclusive. A 24-hour SPECT/CT was performed and confirmed the BBF in a minimally invasive way.

Factores asociados a casos de malaria y plantas medicinales empleadas para su tratamiento en habitantes de Corozal, Colombia / Factors associated with cases of malaria and medicinal plants used for its treatment in inhabitants of Corozal, Colombia

Introducción: La malaria es una de las enfermedades infecciosas más importantes y para tratarla además de medicamentos, la población emplea plantas medicinales. El objetivo fue establecer los factores asociados a malaria y las plantas empleadas para su tratamiento en habitantes de Corozal. Método: Se aplicó una encuesta con preguntas sociodemográficas, de la vivienda, de conocimiento y de actitudes y las plantas medicinales empleadas para tratarla. Resultados: El 48% emplean plantas medicinales solas o con medicamentos, siendo el Gliricidia sepium (matarratón) y el Acmella oppositifolia (yuyo) las plantas más empleadas. En el 48% de las casas ha habido malaria. Por regresión logística se estableció que la malaria se asoció con conocer cómo se adquiere, consultar al médico tradicional y tener más de 15 años en Corozal. Conclusiones: Las plantas que la población de este estudio reportan no muestran evidencia científica como antimalaricos. Es importante una mayor presencia de las autoridades de salud y su trabajo conjunto con el médico tradicional para lograr estrategias más efectivas(AU)

Introduction: Malaria is one of the most important infectious disease and to treat it in addition to medicines the population uses medicinal plants. The objective was to establish the factors associated with malaria and the plants used for its treatment in inhabitants of Corozal. Method: A survey was applied with sociodemographic questions about housing, knowledge and attitudes, in addition to the medicinal plants used to treat it. Results: 48% use medicinal plants alone or with medicines, Gliricidia sepium (rat poisson) and Acmella oppositifolia (Opposite-leaf Spotflower) are the most used. In 48% of the homes there has been malaria. By logistic regression it was established that malaria was associated with knowing how it is acquired, consulting the traditional doctor and living in Corozal for more than 15 years. Conclusions: The plants that the population of this study report usimg do not show scientific evidence antimalarials. A greater presence of health authorities and their joint work with the traditional doctor for more effective strategies is important(AU)

Signo de "doble corteza" visualizado en corregistro 18F-FDG PET/RM en un paciente con heterotopia subcortical en banda / "Double Cortex" Sign Visualized in 18F-FDG PET / MRI Coregistration in a Patient with Band Subcortical Heterotopia

Resumen La heterotopia subcortical en banda (HSB) se refiere a la presencia de bandas lisas bilaterales de sustancia gris cerebral ubicadas en la sustancia blanca subcortical. La presentación clínica es variable, con cuadros que incluyen discapacidad intelectual, crisis epilépticas y trastornos de conducta muy variados, lo que hace complejo su diagnóstico. Presentamos el caso de un varón de 20 años con largo historial de epilepsia refractaria a tratamiento, remitido a nuestra unidad para un estudio de tomografía por emisión de positrones/tomografía computada (PET/CT) con 18F-fluorodesoxiglucos (18F-FDG) para la búsqueda del foco epileptógeno. Adicionalmente, se realizó un corregistro de PET con un estudio de resonancia magnética (RM) de otra institución, observando el signo de doble corteza cerebral por RM y PET/CT, visualizando característicamente un patrón hipermetabólico en las zonas de heterotopia subcortical en banda.

Abstract Subcortical band heterotopia (HSB) refers to the presence of smooth bilateral bands of gray matter located in the subcortical white matter. Clinical presentation is widely variable, the presentation includes intellectual disability, epileptic seizures and varied conduct disorders, making a complex diagnosis. We present a case of a 20-year-old male with a long history of treatment-refractory epilepsy referred to our center for a 18F-FDG (18F-fluorodeoxyglucose) PET/CT (Positron Emission Tomography/Computed Tomography), to search for the epileptogenic focus. Additionally, a registration was carried out with another magnetic resonance imaging study (MRI), where the sign of double cerebral cortex was documented by MRI and PET/CT, visualized as a hypermetabolic pattern in subcortical band heterotopia.

A Comparison of 18F-PSMA-1007 and 64Cu-PSMA in 2 Patients With Metastatic Prostate Cancer.

ABSTRACT: 18F-prostate-specific membrane antigen (PSMA) 1007 is one of the most promising radiotracers for PET imaging in prostate cancer, minimal urinary clearance, and higher spatial resolution, which are the most outstanding features. PSMA can also be labeled with 64Cu, offering a longer half-life and different resolution imaging. We present images of metastatic prostate cancer in two patients, where 64Cu-PSMA PET/CT was performed one day after 18F-PSMA-1007 PET/CT. In the two patients, both radiotracers provided high image quality and a similar range of detection for metastatic lesions.

Semiautomatic assessment of whole-body tumor burden with 18F-PSMA-1007 in biochemical recurrent prostate cancer.

OBJECTIVE: The aim of the study was to evaluate the 18F-PSMA-1007 PET/computed tomography (CT) semiautomatic volumetric parameters to assess the whole-body tumor burden and its correlation with prostate-specific antigen (PSA) and Gleason score in patients with biochemically recurrent prostate cancer (PCa). MATERIALS AND METHODS: A total of 110 patients referred for 18F-PSMA-1007 PET/CT due to biochemical recurrence were retrospectively analyzed. Whole-body total lesion prostate-specific membrane antigen (wbTl-PSMA) and whole-body PSMA-derived tumor volume (wbPSMA-TV) metrics on 18F-PSMA-1007 were obtained semiautomatically in dedicated software. A Spearman test was performed to explore the correlation of volumetric imaging parameters with PSA levels and Gleason score. To analyze the association between volumetric measures and PSA subgroups, we used a Kruskal-Wallis test and a Dunn's test to identify each group causing an observed difference. RESULTS: A total of 492 metastatic lesions were analyzed, and a significant correlation was found between wbTL-PSMA (R = 0.63, P < 0.0001) and wbPSMA-TV (R = 0.49, P < 0.0001) with serum PSA. A statistically significant difference with wbTL-PSMA was found in patients with a PSA less than or equal 0.5 ng/ml and PSA in the range of 0.51-1.0 ng/ml. CONCLUSION: 18F-PSMA-1007 PSMA volumetric parameters can provide a quantitative imaging biomarker for whole-body tumor burden.

High-throughput functional characterization of protein phosphorylation sites in yeast.

Phosphorylation is a critical post-translational modification involved in the regulation of almost all cellular processes. However, fewer than 5% of thousands of recently discovered phosphosites have been functionally annotated. In this study, we devised a chemical genetic approach to study the functional relevance of phosphosites in Saccharomyces cerevisiae. We generated 474 yeast strains with mutations in specific phosphosites that were screened for fitness in 102 conditions, along with a gene deletion library. Of these phosphosites, 42% exhibited growth phenotypes, suggesting that these are more likely functional. We inferred their function based on the similarity of their growth profiles with that of gene deletions and validated a subset by thermal proteome profiling and lipidomics. A high fraction exhibited phenotypes not seen in the corresponding gene deletion, suggestive of a gain-of-function effect. For phosphosites conserved in humans, the severity of the yeast phenotypes is indicative of their human functional relevance. This high-throughput approach allows for functionally characterizing individual phosphosites at scale.

An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci.

Genome-wide association studies (GWASs) have identified many variants associated with complex traits, but identifying the causal gene(s) is a major challenge. In the present study, we present an open resource that provides systematic fine mapping and gene prioritization across 133,441 published human GWAS loci. We integrate genetics (GWAS Catalog and UK Biobank) with transcriptomic, proteomic and epigenomic data, including systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues. We identify 729 loci fine mapped to a single-coding causal variant and colocalized with a single gene. We trained a machine-learning model using the fine-mapped genetics and functional genomics data and 445 gold-standard curated GWAS loci to distinguish causal genes from neighboring genes, outperforming a naive distance-based model. Our prioritized genes were enriched for known approved drug targets (odds ratio = 8.1, 95% confidence interval = 5.7, 11.5). These results are publicly available through a web portal ( http://genetics.opentargets.org ), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance.

Background: The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. Methods: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. Results: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 × 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Conclusions: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. Funding: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Individuals who become infected with the virus that causes COVID-19 can experience a wide variety of symptoms. These can range from no symptoms or minor symptoms to severe illness and death. Key demographic factors, such as age, gender and race, are known to affect how susceptible an individual is to infection. However, molecular factors, such as unique gene mutations and gene expression levels can also have a major impact on patient responses by affecting the levels of proteins in the body. Proteins that are too abundant or too scarce may mean the difference between dying from or surviving COVID-19. Identifying the molecular factors in a host that affect how viruses can infect individuals, evade immune defences or trigger severe illness, could provide new ways to treat patients with COVID-19. Such factors are likely to remain constant, even when the virus mutates into new strains. Hence, insights would likely apply across all virus strains, including current strains, such as alpha and delta, and any new strains that may emerge in the future. Using such a 'natural experiment' approach, Karim et al. compared the genetic profiles of over 30,000 COVID-19 patients and a million healthy individuals. Nine proteins were found to have an impact on COVID-19 infection and disease severity. Four proteins were ranked as top priorities for potential treatment targets. One protein, called CD209 (also known as DC-SIGN), is involved in how the virus enters the host cells, and had one of the strongest associations with COVID-19. Two proteins, called IL-6R and FAS, were involved in the immune response and could be responsible for the immune over-activation often seen in severe COVID-19. Finally, one protein, called OAS1, formed part of the body's innate antiviral defence system and appeared to reduce susceptibility to COVID-19. Knowing more about the proteins that influence the severity of COVID-19 opens up new ways to predict, protect and treat patients who may have severe or fatal reactions to infection. Indeed, one of the identified proteins (IL-6R) had already been targeted in recent clinical trials with some encouraging results. Considering CD209 as a potential receptor for the virus could provide another avenue for therapeutics, similar to previously successful approaches to block the virus' known interaction with a receptor protein. Ultimately, this research could supply an entirely new set of treatment options to help combat the COVID-19 pandemic.

The PROTACtable genome.

Proteolysis-targeting chimeras (PROTACs) are an emerging drug modality that may offer new opportunities to circumvent some of the limitations associated with traditional small-molecule therapeutics. By analogy with the concept of the 'druggable genome', the question arises as to which potential drug targets might PROTAC-mediated protein degradation be most applicable. Here, we present a systematic approach to the assessment of the PROTAC tractability (PROTACtability) of protein targets using a series of criteria based on data and information from a diverse range of relevant publicly available resources. Our approach could support decision-making on whether or not a particular target may be amenable to modulation using a PROTAC. Using our approach, we identified 1,067 proteins of the human proteome that have not yet been described in the literature as PROTAC targets that offer potential opportunities for future PROTAC-based efforts.

Copy number aberrations drive kinase rewiring, leading to genetic vulnerabilities in cancer.

Somatic DNA copy number variations (CNVs) are prevalent in cancer and can drive cancer progression, albeit with often uncharacterized roles in altering cell signaling states. Here, we integrate genomic and proteomic data for 5,598 tumor samples to identify CNVs leading to aberrant signal transduction. The resulting associations recapitulate known kinase-substrate relationships, and further network analysis prioritizes likely causal genes. Of the 303 significant associations we identify from the pan-tumor analysis, 43% are replicated in cancer cell lines, including 44 robust gene-phosphosite associations identified across multiple tumor types. Several predicted regulators of hippo signaling are experimentally validated. Using RNAi, CRISPR, and drug screening data, we find evidence of kinase addiction in cancer cell lines, identifying inhibitors for targeting of kinase-dependent cell lines. We propose copy number status of genes as a useful predictor of differential impact of kinase inhibition, a strategy that may be of use in the future for anticancer therapies.

Open Targets Platform: supporting systematic drug-target identification and prioritisation.

The Open Targets Platform (https://www.targetvalidation.org/) provides users with a queryable knowledgebase and user interface to aid systematic target identification and prioritisation for drug discovery based upon underlying evidence. It is publicly available and the underlying code is open source. Since our last update two years ago, we have had 10 releases to maintain and continuously improve evidence for target-disease relationships from 20 different data sources. In addition, we have integrated new evidence from key datasets, including prioritised targets identified from genome-wide CRISPR knockout screens in 300 cancer models (Project Score), and GWAS/UK BioBank statistical genetic analysis evidence from the Open Targets Genetics Portal. We have evolved our evidence scoring framework to improve target identification. To aid the prioritisation of targets and inform on the potential impact of modulating a given target, we have added evaluation of post-marketing adverse drug reactions and new curated information on target tractability and safety. We have also developed the user interface and backend technologies to improve performance and usability. In this article, we describe the latest enhancements to the Platform, to address the fundamental challenge that developing effective and safe drugs is difficult and expensive.