RESUMEN
Monkeypox (mpox) cases in the 2022 outbreak have primarily occurred among adult gay, bisexual, and other men who have sex with men (MSM); however, other populations have also been affected (1). To date, data on mpox in cisgender women and pregnant persons have been limited. Understanding transmission in these populations is critical for mpox prevention. In addition, among pregnant persons, Monkeypox virus can be transmitted to the fetus during pregnancy or to the neonate through close contact during or after birth (2-5). Adverse pregnancy outcomes, including spontaneous abortion and stillbirth, have been reported in previous mpox outbreaks (3). During May 11-November 7, 2022, CDC and U.S. jurisdictional health departments identified mpox in 769 cisgender women aged ≥15 years, representing 2.7% of all reported mpox cases. Among cases with available data, 44% occurred in cisgender women who were non-Hispanic Black or African American (Black), 25% who were non-Hispanic White (White), and 23% who were Hispanic or Latino (Hispanic). Among cisgender women with available data, 73% reported sexual activity or close intimate contact as the likely route of exposure, with mpox lesions most frequently reported on the legs, arms, and genitals. Twenty-three mpox cases were reported in persons who were pregnant or recently pregnant§; all identified as cisgender women based on the mpox case report form.¶ Four pregnant persons required hospitalization for mpox. Eleven pregnant persons received tecovirimat, and no adverse reactions were reported. Continued studies on mpox transmission risks in populations less commonly affected during the outbreak, including cisgender women and pregnant persons, are important to assess and understand the impact of mpox on sexual, reproductive, and overall health.
Asunto(s)
Mpox , Femenino , Humanos , Embarazo , Negro o Afroamericano , Etnicidad , Hispánicos o Latinos , Conducta Sexual , Estados Unidos/epidemiología , Blanco , Mpox/epidemiologíaRESUMEN
Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Animales , Línea Celular Tumoral , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , RatonesRESUMEN
We established a catalog of the mouse gut metagenome comprising â¼2.6 million nonredundant genes by sequencing DNA from fecal samples of 184 mice. To secure high microbiome diversity, we used mouse strains of diverse genetic backgrounds, from different providers, kept in different housing laboratories and fed either a low-fat or high-fat diet. Similar to the human gut microbiome, >99% of the cataloged genes are bacterial. We identified 541 metagenomic species and defined a core set of 26 metagenomic species found in 95% of the mice. The mouse gut microbiome is functionally similar to its human counterpart, with 95.2% of its Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous groups in common. However, only 4.0% of the mouse gut microbial genes were shared (95% identity, 90% coverage) with those of the human gut microbiome. This catalog provides a useful reference for future studies.
Asunto(s)
Bacterias/genética , Mapeo Cromosómico/métodos , Bases de Datos Genéticas , Genoma Bacteriano/genética , Intestinos/microbiología , Microbiota/genética , Animales , Proteínas Bacterianas/genética , Catálogos como Asunto , Humanos , Mucosa Intestinal/metabolismo , Especificidad de la EspecieRESUMEN
Chlamydia pneumoniae is responsible for a high prevalence of respiratory infections worldwide and has been implicated in atherosclerosis. Inflammation is regulated by transcription factor (TF) networks. Yet, the core TF network triggered by chlamydiae remains largely unknown. Primary human coronary artery endothelial cells were mock-infected or infected with C. pneumoniae to generate human transcriptome data throughout the chlamydial developmental cycle. Using systems network analysis, the predominant TF network involved receptor, binding and adhesion and immune response complexes. Cells transfected with interfering RNA against activator protein-1 (AP-1) members FOS, FOSB, JUN and JUNB had significantly decreased expression and protein levels of inflammatory mediators interleukin (IL)6, IL8, CD38 and tumour necrosis factor compared with controls. These mediators have been shown to be associated with C. pneumoniae disease. Expression of AP-1 components was regulated by MAPK3K8, a MAPK pathway component. Additionally, knock-down of JUN and FOS showed significantly decreased expression of Toll-like receptor (TLR)3 during infection, implicating JUN and FOS in TLR3 regulation. TLR3 stimulation led to elevated IL8. These findings suggest that C. pneumoniae initiates signalling via TLR3 and MAPK that activate AP-1, a known immune activator in other bacteria not previously shown for chlamydiae, triggering inflammation linked to C. pneumoniae disease.
Asunto(s)
Aterosclerosis/metabolismo , Chlamydophila pneumoniae/metabolismo , Inflamación/metabolismo , Factor de Transcripción AP-1/metabolismo , Aterosclerosis/microbiología , Aterosclerosis/fisiopatología , Chlamydophila pneumoniae/genética , Chlamydophila pneumoniae/patogenicidad , Vasos Coronarios/metabolismo , Vasos Coronarios/microbiología , Vasos Coronarios/patología , Células Endoteliales , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inflamación/genética , Interleucina-8/metabolismo , Neumonía Bacteriana/metabolismo , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/fisiopatología , Receptor Toll-Like 3/metabolismo , Factor de Transcripción AP-1/genéticaRESUMEN
Bacterial entry is a multistep process triggering a complex network, yet the molecular complexity of this network remains largely unsolved. By employing a systems biology approach, we reveal a systemic bacterial-entry network initiated by Chlamydia pneumoniae, a widespread opportunistic pathogen. The network consists of nine functional modules (i.e., groups of proteins) associated with various cellular functions, including receptor systems, cell adhesion, transcription, and endocytosis. The peak levels of gene expression for these modules change rapidly during C. pneumoniae entry, with cell adhesion occurring at 5 min postinfection, receptor and actin activity at 25 min, and endocytosis at 2 h. A total of six membrane proteins (chemokine C-X-C motif receptor 7 [CXCR7], integrin beta 2 [ITGB2], platelet-derived growth factor beta polypeptide [PDGFB], vascular endothelial growth factor [VEGF], vascular cell adhesion molecule 1 [VCAM1], and GTP binding protein overexpressed in skeletal muscle [GEM]) play a key role during C. pneumoniae entry, but none alone is essential to prevent entry. The combination knockdown of three genes (coding for CXCR7, ITGB2, and PDGFB) significantly inhibits C. pneumoniae entry, but the entire network is resistant to the six-gene depletion, indicating a resilient network. Our results reveal a complex network for C. pneumoniae entry involving at least six key proteins.
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Chlamydophila pneumoniae/fisiología , Regulación de la Expresión Génica/fisiología , Interacciones Huésped-Patógeno/fisiología , Transducción de Señal/fisiología , Biología de Sistemas/métodos , Antígenos CD18/genética , Antígenos CD18/metabolismo , Línea Celular Tumoral , Chlamydophila pneumoniae/crecimiento & desarrollo , Regulación de la Expresión Génica/genética , Interacciones Huésped-Patógeno/genética , Humanos , Proteínas de Unión al GTP Monoméricas/genética , Proteínas de Unión al GTP Monoméricas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-sis/genética , Proteínas Proto-Oncogénicas c-sis/metabolismo , Interferencia de ARN , Receptores CXCR/genética , Receptores CXCR/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r) system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity.
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Apetito , Mutación , Receptor trkB/agonistas , Aumento de Peso , Animales , Peso Corporal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Eliminación de Gen , Leptina/sangre , Ligandos , Macaca mulatta , Obesidad/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Proteínas Recombinantes/metabolismo , Transducción de SeñalRESUMEN
Mutations in the tyrosine kinase receptor trkB or in one of its natural ligands, brain-derived neurotrophic factor (BDNF), lead to severe hyperphagia and obesity in rodents and/or humans. Here, we show that peripheral administration of neurotrophin-4 (NT4), the second natural ligand for trkB, suppresses appetite and body weight in a dose-dependent manner in several murine models of obesity. NT4 treatment increased lipolysis, reduced body fat content and leptin, and elicited long-lasting amelioration of hypertriglyceridemia and hyperglycemia. After treatment termination, body weight gradually recovered to control levels in obese mice with functional leptin receptor. A single intrahypothalamic application of minute amounts of NT4 or an agonist trkB antibody also reduced food intake and body weight in mice. Taken together with the genetic evidence, our findings support the concept that trkB signaling, which originates in the hypothalamus, directly modulates appetite, metabolism, and taste preference downstream of the leptin and melanocortin 4 receptor. The trkB agonists mediate anorexic and weight-reducing effects independent of stress induction, visceral discomfort, or pain sensitization and thus emerge as a potential therapeutic for metabolic disorders.
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Factores de Crecimiento Nervioso/farmacología , Obesidad/metabolismo , Receptor trkB/agonistas , Animales , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Leptina/metabolismo , Cloruro de Litio/farmacología , Masculino , Melanocortinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Ratas , Ratas Sprague-Dawley , Receptor trkB/metabolismo , Receptores de Leptina/metabolismo , Gusto/efectos de los fármacos , Triglicéridos/metabolismoRESUMEN
OBJECTIVE: We sought to understand the relationship among components of residency education about hormone therapy (HT), knowledge about HT, and provider attitudes toward HT during a time of rapidly changing practice guidelines. METHODS: We surveyed residents in the University of Pittsburgh Internal Medicine residency programs between February to April 2002 (after the release of the Heart Estrogen/Progestin Replacement Study and prior to the release of preliminary Women's Health Initiative data) regarding demographics, educational (didactic and experiential) exposures to HT and menopause management, knowledge about HT, and attitudes toward HT. RESULTS: Sixty-nine of 92 (75%) eligible residents completed the survey; 38% were women. The race and gender of responders did not differ from nonresponders. Residents had significant didactic exposure to HT and menopause management with 80% reporting more than one didactic exposure. Despite this, HT knowledge was low (mean knowledge score 47 +/- 16%) and only 26% of residents felt prepared to counsel patients about HT. We identified four factors related to provider attitudes toward HT: "persistence" in universally recommending HT, confidence in "HT benefits," concern about "HT cardiac risks," and concern about "HT noncardiac risks." More appropriate attitudes were associated with attending a lecture, having a rotation with a discussion of menopause management (i.e., Women's Health), and a continuity practice including more than 30% women. Pharmaceutical detailing and self-directed study were associated with less appropriate attitudes. Knowledge did not influence attitudes. Strongly held beliefs about the benefits of HT, appropriate or inappropriate, were associated with increasing "persistence." CONCLUSIONS: In an area of rapidly changing information, such as the risks and benefits of HT, knowledge is low. Experiential learning appropriately influences attitudes, while pharmaceutical detailing was associated with inappropriate attitudes toward HT risks.
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Actitud del Personal de Salud , Competencia Clínica/estadística & datos numéricos , Terapia de Reemplazo de Estrógeno/normas , Medicina Interna/educación , Internado y Residencia/normas , Femenino , Hospitales Universitarios , Humanos , Medicina Interna/normas , Modelos Lineales , Masculino , Pennsylvania , Guías de Práctica Clínica como Asunto , Relaciones Profesional-Paciente , Garantía de la Calidad de Atención de Salud , Factores Sexuales , Encuestas y Cuestionarios , Salud de la MujerRESUMEN
BACKGROUND: Knowledge concerning hormone replacement therapy (HRT) is rapidly changing. PURPOSE: We sought to understand the factors that influence how residents assimilate this knowledge. METHODS: We conducted an anonymous survey of residents in an internal medicine residency. Questions included personal demographic information and aspects of training (didactic and experiential) regarding and knowledge about HRT. Data were analyzed using univariable and multivariable linear regression. RESULTS: Sixty-nine of 92 residents (75%) completed the survey. The gender and race of respondents did not differ significantly from the overall group. Knowledge scores were higher among residents in nontraditional (Women's Health, Primary Care, and Internal Medicine-Pediatrics) training tracks (p = .04) and among residents with patient population of < or = 30% postmenopausal women (p = .049). Demographic characteristics and didactic training about HRT did not influence knowledge. CONCLUSIONS: Nontraditional residency track and higher proportion of postmenopausal women in a practice (experiential learning) improve knowledge about HRT. Didactic training has no effect.