RESUMO
Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status. We find that acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, thereby inhibiting the activity of lysosome-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation. Our findings thus reveal a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.
Assuntos
Hipóxia Celular , Relógios Circadianos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Aminoácidos Dicarboxílicos/farmacologia , Animais , Proteínas CLOCK/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Células Cultivadas , Relógios Circadianos/efeitos dos fármacos , Meios de Cultura/química , Fatores de Iniciação em Eucariotos , Concentração de Íons de Hidrogênio , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/citologia , Linfócitos T/metabolismo , Transcriptoma/efeitos dos fármacos , Proteína 2 do Complexo Esclerose Tuberosa/deficiência , Proteína 2 do Complexo Esclerose Tuberosa/genéticaRESUMO
Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.
Assuntos
Imunoterapia , Neoplasias , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Tirosina Fosfatase não Receptora Tipo 2 , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico , Imunoterapia/métodos , Interferons/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 2/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
The asymmetric partitioning of fate-determining proteins has been shown to contribute to the generation of CD8(+) effector and memory T cell precursors. Here we demonstrate the asymmetric partitioning of mTORC1 activity after the activation of naive CD8(+) T cells. This results in the generation of two daughter T cells, one of which shows increased mTORC1 activity, increased glycolytic activity and increased expression of effector molecules. The other daughter T cell has relatively low mTORC1 activity and increased lipid metabolism, expresses increased amounts of anti-apoptotic molecules and subsequently displays enhanced long-term survival. Mechanistically, we demonstrate a link between T cell antigen receptor (TCR)-induced asymmetric expression of amino acid transporters and RagC-mediated translocation of mTOR to the lysosomes. Overall, our data provide important insight into how mTORC1-mediated metabolic reprogramming affects the fate decisions of T cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Divisão Celular/imunologia , Lisossomos/metabolismo , Complexos Multiproteicos/metabolismo , Células Precursoras de Linfócitos T/imunologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Feminino , Glicólise , Memória Imunológica , Metabolismo dos Lipídeos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transporte Proteico , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified. METHODS: We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K. Biobank, the Multi-Ethnic Study of Atherosclerosis, and the Organ Procurement and Transplantation Network. Using these data, we compared the race-based 2012 Global Lung Function Initiative (GLI-2012) equations with race-neutral equations introduced in 2022 (GLI-Global). Evaluated outcomes included national projections of clinical, occupational, and financial reclassifications; individual lung-allocation scores for transplantation priority; and concordance statistics (C statistics) for clinical prediction tasks. RESULTS: Among the 249 million persons in the United States between 6 and 79 years of age who are able to produce high-quality spirometric results, the use of GLI-Global equations may reclassify ventilatory impairment for 12.5 million persons, medical impairment ratings for 8.16 million, occupational eligibility for 2.28 million, grading of chronic obstructive pulmonary disease for 2.05 million, and military disability compensation for 413,000. These potential changes differed according to race; for example, classifications of nonobstructive ventilatory impairment may change dramatically, increasing 141% (95% confidence interval [CI], 113 to 169) among Black persons and decreasing 69% (95% CI, 63 to 74) among White persons. Annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among White veterans. GLI-2012 and GLI-Global equations had similar discriminative accuracy with regard to respiratory symptoms, health care utilization, new-onset disease, death from any cause, death related to respiratory disease, and death among persons on a transplant waiting list, with differences in C statistics ranging from -0.008 to 0.011. CONCLUSIONS: The use of race-based and race-neutral equations generated similarly accurate predictions of respiratory outcomes but assigned different disease classifications, occupational eligibility, and disability compensation for millions of persons, with effects diverging according to race. (Funded by the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences.).
Assuntos
Testes de Função Respiratória , Insuficiência Respiratória , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Pneumopatias/diagnóstico , Pneumopatias/economia , Pneumopatias/etnologia , Pneumopatias/terapia , Transplante de Pulmão/estatística & dados numéricos , Inquéritos Nutricionais/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/economia , Doença Pulmonar Obstrutiva Crônica/etnologia , Doença Pulmonar Obstrutiva Crônica/terapia , Grupos Raciais , Testes de Função Respiratória/classificação , Testes de Função Respiratória/economia , Testes de Função Respiratória/normas , Espirometria , Estados Unidos/epidemiologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/economia , Insuficiência Respiratória/etnologia , Insuficiência Respiratória/terapia , Negro ou Afro-Americano/estatística & dados numéricos , Brancos/estatística & dados numéricos , Avaliação da Deficiência , Ajuda a Veteranos de Guerra com Deficiência/classificação , Ajuda a Veteranos de Guerra com Deficiência/economia , Ajuda a Veteranos de Guerra com Deficiência/estatística & dados numéricos , Pessoas com Deficiência/classificação , Pessoas com Deficiência/estatística & dados numéricos , Doenças Profissionais/diagnóstico , Doenças Profissionais/economia , Doenças Profissionais/etnologia , Financiamento Governamental/economia , Financiamento Governamental/estatística & dados numéricosRESUMO
Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence almost all metrics associated with their pharmacokinetic and pharmacodynamic profile1-4. Drug candidates increasingly contain trifluoromethyl (CF3) and difluoromethyl (CF2H) groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect and plant life5,6. New fluoroalkylation reactions have undoubtedly stimulated this shift; however, methods that directly convert C-H bonds into C-CF2X groups (where X is F or H) in complex drug-like molecules are rare7-13. Pyridines are the most common aromatic heterocycles in pharmaceuticals14, but only one approach-via fluoroalkyl radicals-is viable for achieving pyridyl C-H fluoroalkylation in the elaborate structures encountered during drug development15-17. Here we develop a set of bench-stable fluoroalkylphosphines that directly convert the C-H bonds in pyridine building blocks, drug-like fragments and pharmaceuticals into fluoroalkyl derivatives. No preinstalled functional groups or directing groups are required. The reaction tolerates a variety of sterically and electronically distinct pyridines, and is exclusively selective for the 4-position in most cases. The reaction proceeds through initial formation of phosphonium salts followed by sp2-sp3 coupling of phosphorus ligands-an underdeveloped manifold for forming C-C bonds.
Assuntos
Carbono/química , Flúor/química , Hidrogênio/química , Fósforo/química , Piridinas/química , Alquilação , Animais , Humanos , Ligantes , Preparações Farmacêuticas/química , Farmacocinética , Fosfinas/químicaRESUMO
Peptide- and protein-based therapeutics are becoming a promising treatment regimen for myriad diseases. Toxicity of proteins is the primary hurdle for protein-based therapies. Thus, there is an urgent need for accurate in silico methods for determining toxic proteins to filter the pool of potential candidates. At the same time, it is imperative to precisely identify non-toxic proteins to expand the possibilities for protein-based biologics. To address this challenge, we proposed an ensemble framework, called VISH-Pred, comprising models built by fine-tuning ESM2 transformer models on a large, experimentally validated, curated dataset of protein and peptide toxicities. The primary steps in the VISH-Pred framework are to efficiently estimate protein toxicities taking just the protein sequence as input, employing an under sampling technique to handle the humongous class-imbalance in the data and learning representations from fine-tuned ESM2 protein language models which are then fed to machine learning techniques such as Lightgbm and XGBoost. The VISH-Pred framework is able to correctly identify both peptides/proteins with potential toxicity and non-toxic proteins, achieving a Matthews correlation coefficient of 0.737, 0.716 and 0.322 and F1-score of 0.759, 0.696 and 0.713 on three non-redundant blind tests, respectively, outperforming other methods by over $10\%$ on these quality metrics. Moreover, VISH-Pred achieved the best accuracy and area under receiver operating curve scores on these independent test sets, highlighting the robustness and generalization capability of the framework. By making VISH-Pred available as an easy-to-use web server, we expect it to serve as a valuable asset for future endeavors aimed at discerning the toxicity of peptides and enabling efficient protein-based therapeutics.
Assuntos
Proteínas , Proteínas/metabolismo , Proteínas/química , Aprendizado de Máquina , Bases de Dados de Proteínas , Biologia Computacional/métodos , Humanos , Peptídeos/toxicidade , Peptídeos/química , Simulação por Computador , Algoritmos , SoftwareRESUMO
SGK1 is an AGC kinase that regulates the expression of membrane sodium channels in renal tubular cells in a manner dependent on the metabolic checkpoint kinase complex mTORC2. We hypothesized that SGK1 might represent an additional mTORC2-dependent regulator of the differentiation and function of T cells. Here we found that after activation by mTORC2, SGK1 promoted T helper type 2 (TH2) differentiation by negatively regulating degradation of the transcription factor JunB mediated by the E3 ligase Nedd4-2. Simultaneously, SGK1 repressed the production of interferon-γ (IFN-γ) by controlling expression of the long isoform of the transcription factor TCF-1. Consistent with those findings, mice with selective deletion of SGK1 in T cells were resistant to experimentally induced asthma, generated substantial IFN-γ in response to viral infection and more readily rejected tumors.
Assuntos
Asma/imunologia , Proteínas Imediatamente Precoces/metabolismo , Melanoma Experimental/imunologia , Complexos Multiproteicos/imunologia , Infecções por Poxviridae/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Serina-Treonina Quinases TOR/imunologia , Células Th1/imunologia , Células Th2/imunologia , Vaccinia virus/imunologia , Imunidade Adaptativa/genética , Animais , Diferenciação Celular/genética , Células Cultivadas , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Regulação da Expressão Gênica/genética , Fator 1-alfa Nuclear de Hepatócito , Proteínas Imediatamente Precoces/genética , Interferon gama/genética , Interferon gama/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ubiquitina-Proteína Ligases Nedd4 , Proteínas Serina-Treonina Quinases/genética , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Carga Tumoral/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The KidGen Collaborative's Policy Implementation Workshop 2023 celebrated the 10th anniversary of Australia's first kidney genetics clinic in Brisbane. This event marked the establishment of a national network now comprising 19 kidney genetics clinics across Australia, all dedicated to providing equitable access to genomic testing for families affected by genetic kidney diseases. The workshop reflected on past progress and outlined future objectives for kidney genetics in Australia, recognising the collaborative efforts of clinical teams, researchers, and patients. Key insights from the workshop are documented in the proceedings.
Assuntos
Nefropatias , Humanos , Austrália , Nefropatias/genética , Testes Genéticos/tendênciasRESUMO
Evaluating the relationship between the human gut microbiome and disease requires computing reliable statistical associations. Here, using millions of different association modeling strategies, we evaluated the consistency-or robustness-of microbiome-based disease indicators for 6 prevalent and well-studied phenotypes (across 15 public cohorts and 2,343 individuals). We were able to discriminate between analytically robust versus nonrobust results. In many cases, different models yielded contradictory associations for the same taxon-disease pairing, some showing positive correlations and others negative. When querying a subset of 581 microbe-disease associations that have been previously reported in the literature, 1 out of 3 taxa demonstrated substantial inconsistency in association sign. Notably, >90% of published findings for type 1 diabetes (T1D) and type 2 diabetes (T2D) were particularly nonrobust in this regard. We additionally quantified how potential confounders-sequencing depth, glucose levels, cholesterol, and body mass index, for example-influenced associations, analyzing how these variables affect the ostensible correlation between Faecalibacterium prausnitzii abundance and a healthy gut. Overall, we propose our approach as a method to maximize confidence when prioritizing findings that emerge from microbiome association studies.
Assuntos
Bactérias/genética , Pesquisa Biomédica/métodos , Microbioma Gastrointestinal/genética , Metagenoma/genética , Metagenômica/métodos , Algoritmos , Bactérias/classificação , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/microbiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/microbiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Fezes/microbiologia , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/microbiologia , Modelos Teóricos , RNA Ribossômico 16S/genéticaRESUMO
Vaccines against coronavirus disease 2019 (COVID-19) have been discovered within a very small duration of time as compared to the traditional way for the development of vaccines, which raised the question about the safety and efficacy of the approved vaccines. The purpose of this study is to look at the effectiveness and safety of vaccine platforms against the incidence of COVID-19. The literature search was performed on PubMed/Medline, Cochrane, and clinical trials.gov databases for studies published between 1 January 2020 and 19 February 2022. Preferred Reporting Items for Systemic Review and Meta-Analysis Statement guidelines were followed. Among 284 articles received by keywords, a total of 11 studies were eligible according to the inclusion and exclusion criteria (studies in special populations, e.g., pregnant women, paediatric patients, editorials, case reports, review articles, preclinical and in vitro studies) of the study. A total of 247,186 participants were considered for randomisation at baseline, among them, 129,572 (52.42%) were provided with vaccine (Intervention group) and 117,614 (47.58%) with the placebo (Control group). A pooled fold change estimation of 0.19 (95% CI: 0.12-0.31, p < 0.0001) showed significant protection against the incidence of COVID-19 in the vaccines received group versus the placebo group. mRNA based, inactivated vaccines and non-replicating viral vector-based vaccines showed significantly protection against the incidence of COVID-19 compared to placebo with pooled fold change estimation was 0.08 (95% CI: 0.06-0.10), 0.20 (95% CI: 0.14-0.29) and 0.36 (95% CI: 0.28-0.46), respectively. Injection site discomfort and fatigue were the most common side effect observed in mRNA, non-replicating viral vector, inactivated, and protein subunit-based vaccines. All the approved vaccines were found safe and efficacious but mRNA-based vaccines were found to be more efficacious against SARS-CoV-2 than other platforms.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Vacinas de Produtos Inativados/efeitos adversosRESUMO
Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. In this study, we report the identification of a previously unappreciated regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate that liver kinase B1 (LKB1)-mediated activation of salt-inducible kinases epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed that salt-inducible kinase-mediated phosphorylation-dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels, which correlated with total and cytokine loci-specific reductions in the activating transcription mark histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine genes upon restimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a previously unrecognized target for enhancing effector T cell functionality.
Assuntos
Citocinas , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases , Animais , Camundongos , Diferenciação Celular , Citocinas/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, metabolism, protein synthesis and autophagy1. Its hyperactivation contributes to disease in numerous organs, including the heart1,2, although broad inhibition of mTORC1 risks interference with its homeostatic roles. Tuberin (TSC2) is a GTPase-activating protein and prominent intrinsic regulator of mTORC1 that acts through modulation of RHEB (Ras homologue enriched in brain). TSC2 constitutively inhibits mTORC1; however, this activity is modified by phosphorylation from multiple signalling kinases that in turn inhibits (AMPK and GSK-3ß) or stimulates (AKT, ERK and RSK-1) mTORC1 activity3-9. Each kinase requires engagement of multiple serines, impeding analysis of their role in vivo. Here we show that phosphorylation or gain- or loss-of-function mutations at either of two adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans) can bidirectionally control mTORC1 activity stimulated by growth factors or haemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remains unchanged. In the heart, or in isolated cardiomyocytes or fibroblasts, protein kinase G1 (PKG1) phosphorylates these TSC2 sites. PKG1 is a primary effector of nitric oxide and natriuretic peptide signalling, and protects against heart disease10-13. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knock-in mice that express a phosphorylation-silencing mutation in TSC2 (TSC2(S1365A)) develop worse heart disease and have higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that cannot be rescued by PKG1 stimulation. However, cardiac disease is reduced and survival of heterozygote Tsc2S1365A knock-in mice subjected to the same stress is improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (TSC2(S1365E)). Resting mTORC1 activity is not altered in either knock-in model. Therefore, TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. The serine residues identified here provide a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity.
Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Cardiopatias/prevenção & controle , Cardiopatias/fisiopatologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/química , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Animais , Autofagia , Células Cultivadas , Progressão da Doença , Ativação Enzimática , Everolimo/farmacologia , Feminino , Técnicas de Introdução de Genes , Células HEK293 , Cardiopatias/genética , Cardiopatias/patologia , Humanos , Hipertrofia/tratamento farmacológico , Hipertrofia/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos , Mutação , Miócitos Cardíacos/patologia , Fosforilação , Fosfosserina/metabolismo , Pressão , Ratos , Ratos Wistar , Serina/genética , Serina/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genéticaRESUMO
BACKGROUND: Routine sexually transmitted infection and human immunodeficiency virus (STI/HIV) testing and HIV pre-exposure prophylaxis (PrEP) use are recommended for men who have sex with men (MSM) at increased risk of HIV. METHODS: Using Healthverity, a large administrative dataset in the United States, we assessed STI/HIV testing, chlamydia and gonorrhea positivity by specimen type, and HIV PrEP use among MSM and men who have sex with men and women (MSMW) at their first visits (index date) for those at increased risk of HIV and STIs from 2019 through 2022. RESULTS: Among 81,716 MSM and MSMW aged 15-64 years at their index date visit, STI testing rates were 57.9% for chlamydia, 58.1% for gonorrhea, and 52.2% for syphilis testing, respectively; 55.5%, 30.9%, and 18.1% had HIV testing, HIV PrEP use, and PrEP initiation, respectively, among the patients who did not have HIV. Of patients with chlamydia and gonorrhea testing, 48% were tested from the genital site only and 25% from three anatomic sites (rectal, pharyngeal, and urogenital). Chlamydia and gonorrhea positivity was 9.8% for chlamydia rectal infection, 7.3% for gonorrhea rectal infection, and 5.3% for gonorrhea pharyngeal infection. CONCLUSION: Our results present current medical services provided during initial clinic visits for MSM and MSMW in private outpatient settings. Our study suggests that the assessment of STI/HIV testing is periodically needed due to the high prevalence of infection, and efforts to promote HIV PrEP for MSM and MSMW in private settings are urgently needed.
RESUMO
Methods to synthesize diverse collections of substituted piperidines are valuable due to the prevalence of this heterocycle in pharmaceutical compounds. Here, we present a general strategy to access N-(hetero)arylpiperidines using a pyridine ring-opening and ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from a wide variety of substituted pyridines and (heteroaryl)anilines; hydrogenation reactions and nucleophilic additions then access the N-(hetero)arylpiperidine derivatives. We successfully applied high-throughput experimentation (HTE) using pharmaceutically relevant pyridines and (heteroaryl)anilines as inputs and developed a one-pot process using anilines as nucleophiles in the pyridinium salt-forming processes. This strategy is viable for generating piperidine libraries and applications such as the convergent coupling of complex fragments.
RESUMO
Clinical validity assessments of gene-disease associations underpin analysis and reporting in diagnostic genomics, and yet wide variability exists in practice, particularly in use of these assessments for virtual gene panel design and maintenance. Harmonization efforts are hampered by the lack of agreed terminology, agreed gene curation standards, and platforms that can be used to identify and resolve discrepancies at scale. We undertook a systematic comparison of the content of 80 virtual gene panels used in two healthcare systems by multiple diagnostic providers in the United Kingdom and Australia. The process was enabled by a shared curation platform, PanelApp, and resulted in the identification and review of 2,144 discordant gene ratings, demonstrating the utility of sharing structured gene-disease validity assessments and collaborative discordance resolution in establishing national and international consensus.
Assuntos
Consenso , Curadoria de Dados/normas , Doenças Genéticas Inatas/genética , Genômica/normas , Anotação de Sequência Molecular/normas , Austrália , Biomarcadores/metabolismo , Curadoria de Dados/métodos , Atenção à Saúde , Expressão Gênica , Ontologia Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Genômica/métodos , Humanos , Aplicativos Móveis/provisão & distribuição , Terminologia como Assunto , Reino UnidoRESUMO
BACKGROUND: In 2020, the Lancet Commission identified 12 risk factors as priorities for prevention of dementia, and other studies identified APOE e4/e4 genotype and family history of Alzheimer's disease strongly associated with dementia outcomes; however, it is unclear how robust these relationships are across dementia subtypes and analytic scenarios. Specification curve analysis (SCA) is a new tool to probe how plausible analytical scenarios influence outcomes. METHODS: We evaluated the heterogeneity of odds ratios for 12 risk factors reported from the Lancet 2020 report and two additional strong associated non-modifiable factors (APOE e4/e4 genotype and family history of Alzheimer's disease) with dementia outcomes across 450,707 UK Biobank participants using SCA with 5357 specifications across dementia subtypes (outcomes) and analytic models (e.g., standard demographic covariates such as age or sex and/or 14 correlated risk factors). RESULTS: SCA revealed variable dementia risks by subtype and age, with associations for TBI and APOE e4/e4 robust to model specification; in contrast, diabetes showed fluctuating links with dementia subtypes. We found that unattributed dementia participants had similar risk factor profiles to participants with defined subtypes. CONCLUSIONS: We observed heterogeneity in the risk of dementia, and estimates of risk were influenced by the inclusion of a combination of other modifiable risk factors; non-modifiable demographic factors had a minimal role in analytic heterogeneity. Future studies should report multiple plausible analytic scenarios to test the robustness of their association. Considering these combinations of risk factors could be advantageous for the clinical development and evaluation of novel screening models for different types of dementia.
Assuntos
Bancos de Espécimes Biológicos , Demência , Humanos , Demência/epidemiologia , Fatores de Risco , Reino Unido/epidemiologia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Biobanco do Reino UnidoRESUMO
PURPOSE: To develop and evaluate a scalable national program to build confidence, competence and capability in the use of rapid genomic testing in the acute pediatric setting. METHODS: We used theory-informed approaches to design a modular, adaptive program of blended learning aimed at diverse professional groups involved in acute pediatric care. The program comprised four online learning modules and an online workshop and was centered on case-based learning. We evaluated the program using the Kirkpatrick four-level model of training evaluation and report our findings using the RISE2 guidelines for genomics education and evaluation. RESULTS: Two hundred and two participants engaged with at least one component of the program. Participants self-reported increased confidence in using rGT, (p<0.001) and quiz responses objectively demonstrated increased competence (e.g., correct responses to a question on pre-test counseling increased from 30% to 64%; p<0.001). Additionally, their capability in applying genomic principles to simulated clinical cases increased (p<0.001), as did their desire to take on more responsibility for performing rGT. The clinical interpretation of more complex test results (such as negative results or variants of uncertain significance) appeared to be more challenging, indicating a need for targeted education in this area. CONCLUSION: The program format was effective in delivering multidisciplinary and wide-scale genomics education in the acute care context. The modular approach we have developed now lends itself to application in other medical specialties or areas of healthcare.
RESUMO
BACKGROUND: The association between illicit opioid use and prescription opioid misuse and sexually transmitted infections (STIs) has not been examined recently. Our study aimed to explore differences in STI/HIV care, and delivery of recommended testing and diagnoses among patients with and without opioid use disorder (OUD). METHODS: Using 2019 MarketScan commercial claims data, we identified 15- to 44-year-old male and female patients, to assess the percentages of STI/HIV diagnoses (using International Classification of Diseases, Tenth Revision, Clinical Modification ) and screening (using Current Procedure Terminology codes) among patients with or without OUD diagnoses codes. We further assessed STI/HIV testing and diagnoses by demographic factors. RESULTS: We identified 24,724 patients with OUD codes among 7.31 million patients. Both STI/HIV testing and diagnoses were significantly ( P < 0.05) higher among patients with OUD codes versus without: testing percentages were 16.81% versus 12.93% for chlamydia, 22.31% versus 16.62% for gonorrhea, 15.26% versus 7.61% for syphilis, and 18.18% versus 7.60% for HIV; diagnoses were 0.80% versus 0.35% for chlamydia, 0.30% versus 0.11% for gonorrhea, 0.23% versus 0.07% for syphilis, and 0.74% versus 0.33% for HIV. Similarly, among 0.53 million 15- to 24-year-old females who received services suggestive of sexual activity, chlamydia testing was significantly ( P < 0.05) higher among patients with OUD codes versus without (59.78% vs. 55.66%). CONCLUSIONS: Patients with OUD codes have higher percentages of STI/HIV testing and diagnoses codes compared with those without OUD codes. Clinicians may want to consider a comprehensive multidisciplinary (OUD and STI prevention) approach in patient care and provide recommended STI/HIV screening among patients with OUD if not performed.
Assuntos
Infecções por HIV , Teste de HIV , Transtornos Relacionados ao Uso de Opioides , Infecções Sexualmente Transmissíveis , Humanos , Masculino , Feminino , Adulto , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/complicações , Infecções Sexualmente Transmissíveis/diagnóstico , Adulto Jovem , Infecções por HIV/diagnóstico , Infecções por HIV/complicações , Adolescente , Teste de HIV/estatística & dados numéricos , Programas de Rastreamento , Estados Unidos/epidemiologia , Gonorreia/diagnósticoRESUMO
BACKGROUND: In the United States, most chlamydia cases are reported from non-sexually transmitted disease clinics, and there is limited information focusing on the reasons for chlamydia testing in private settings. These analyses describe clinical visits to primary care providers where chlamydia testing was performed to help discern between screening and diagnostic testing for chlamydia. METHODS: Using the largest primary care clinical registry in the United States, the PRIME registry, chlamydia tests were identified using Current Procedural Terminology procedure codes and categorized as diagnostic testing for sexually transmitted infection (STI)-related symptoms, screening for chlamydia, or "other," based on Classification of Diseases, Tenth Revision Evaluation and Management codes selected for visits. RESULTS: Of 120,013 clinical visits with chlamydia testing between January 1, 2019, and December 31, 2022, 70.4% were women; 20.6% were with STI-related symptoms, 59.9% were for screening, and 19.5% for "other" reasons. Of those 120,013 clinical visits with chlamydia testing, the logit model showed that patients were significantly more likely to have STI-related symptoms if they were female than male, non-Hispanic Black than non-Hispanic White, aged 15 to 24 years than aged ≥45 years, and resided in the South than in the Northeast. CONCLUSION: It is important to know what proportion of chlamydial infections is identified through screening programs and to have this information stratified by demographics. The inclusion of laboratory results could further facilitate a better understanding of the impact of chlamydia screening programs on the identification and treatment of chlamydia in private office settings in the United States.
Assuntos
Infecções por Chlamydia , Programas de Rastreamento , Atenção Primária à Saúde , Humanos , Feminino , Estados Unidos , Masculino , Infecções por Chlamydia/diagnóstico , Adulto , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Sistema de RegistrosRESUMO
Hypothesis generation in observational, biomedical data science often starts with computing an association or identifying the statistical relationship between a dependent and an independent variable. However, the outcome of this process depends fundamentally on modeling strategy, with differing strategies generating what can be called "vibration of effects" (VoE). VoE is defined by variation in associations that often lead to contradictory results. Here, we present a computational tool capable of modeling VoE in biomedical data by fitting millions of different models and comparing their output. We execute a VoE analysis on a series of widely reported associations (e.g., carrot intake associated with eyesight) with an extended additional focus on lifestyle exposures (e.g., physical activity) and components of the Framingham Risk Score for cardiovascular health (e.g., blood pressure). We leveraged our tool for potential confounder identification, investigating what adjusting variables are responsible for conflicting models. We propose modeling VoE as a critical step in navigating discovery in observational data, discerning robust associations, and cataloging adjusting variables that impact model output.