RESUMEN
Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Anticuerpos Monoclonales Humanizados/uso terapéutico , Método Doble Ciego , Humanos , InflamaciónRESUMEN
OBJECTIVES: Defining the mechanism of infection with human herpesvirus-8 (HHV-8) or Kaposi's sarcoma associated herpesvirus (KSHV) is an important clinical issue. HHV-8 has been linked to Kaposi's sarcoma (KS) development in HIV-1-infected individuals, and KS develops in 40% of those infected with both viruses. A series of epidemiological data suggest that sexual transmission is one of the routes of transmission for HHV-8. In our studies, we sought to assess the cellular reservoirs of HHV-8 DNA in the semen of HIV-1-infected men and the potential role of HHV-8 infected spermatozoa in horizontal transmission. DESIGN AND METHODS: A nested polymerase chain reaction (PCR), in situ PCR (ISPCR) and a sodium iodide (NaI) DNA isolation technique that extracts both nuclear and episomal DNA were utilized to amplify specific genes in vitro and within intact cells to evaluate the types of seminal cells infected with HHV-8 in HIV-1-infected and uninfected men. RESULTS: HHV-8 was present in the spermatozoa and mononuclear cells of the semen in 64 of 73 (88%) HIV-1 infected individuals. Both the sperms as well as the mononuclear cells of the semen specimens of HIV-1 infected men were found to be infected with HHV-8. Multiplex ISPCR revealed that a significantly higher percentage of semen cells were infected with HHV-8 than HIV-1 (p>0.001). Rare (less than one in a 100,000) sperm cells were co-infected with both viruses. A co-culture of HHV-8 infected sperm with uninfected 293 or Sup-T1 cell lines resulted in an abortive infection of these cells with HHV-8. DNA isolation by NaI yielded 73% of the positive sperm, whereas the standard phenol/chloroform method resulted in significantly lower positives (45%) from the same specimens. CONCLUSIONS: Design and methods: Our data strongly suggest a potential sexual/horizontal route of transmission of HHV-8, via the HHV-8 infected sperm and other semen cells, where a large percentage of HIV-1 infected men's sperm and other semen cells are infected with HHV-8. Co-culture studies have further supported the observations that HHV-8 in the sperm cells is infectious and capable of transmission of the virus to uninfected cells.
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ADN Viral/análisis , ADN Viral/genética , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/aislamiento & purificación , Etiquetado in Situ Primed/métodos , Espermatozoides/virología , Síndrome de Inmunodeficiencia Adquirida/virología , Técnicas de Cocultivo , Electroforesis en Gel de Agar , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Masculino , Espermatozoides/citología , Fracciones Subcelulares/virología , Factores de TiempoRESUMEN
In the United States, prostate cancer is the most commonly diagnosed male cancer and the second leading cause of all male cancer deaths. Furthermore, incidence rates are higher in African Americans than in any other racial group. Our laboratory is attempting to decipher the environmental and molecular mechanisms involved in the development of prostate cancer in African Americans. Because Africa is a mineral-rich continent, and the zinc levels in the water and diet are high, it is hypothesized that Africans may have genetically downregulated their zinc absorption capacity; otherwise, they would absorb abnormally high levels of zinc, resulting in various serious neurodegenerative and biochemical disorders. It is therefore possible that people of African origin may have a lower capacity to absorb zinc when compared with other racial groups because of their inherent downregulation of zinc transporters. Extensive research has shown that low serum levels of zinc are associated with the increased incidence of prostate cancer. We have evaluated 58 prostate cancer tissues in 2 major racial groups (30 from whites and 28 from African Americans) for their ability to express 2 major human zinc transporters, hZIP1 and hZIP2. In all 30 prostate cancer specimens obtained from white people, the degree of expression of these 2 zinc receptors was high when compared with age-matched and Gleason score-matched specimens obtained from African American patients. We also found a significant downregulation of these 2 zinc transporters in normal prostate tissues from African American men when compared with age-matched white men. The loss of the unique ability to retain normal intracellular levels of zinc may be an important factor in the development and progression of prostate cancer. Our observation that the uptake of zinc may be different in racial groups is intriguing and relevant. Once these data are confirmed in larger groups, this finding could have significant application as a preventive maneuver for at least for some people. Because dietary zinc supplements are relatively nontoxic, any efficacy trial would be low-risk.
Asunto(s)
Negro o Afroamericano/estadística & datos numéricos , Proteínas Portadoras/genética , Regulación hacia Abajo , Neoplasias de la Próstata/etnología , Secuencia de Bases , Cartilla de ADN , Humanos , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Población Blanca/estadística & datos numéricosRESUMEN
Blau syndrome is an autosomal dominant syndrome characterized by arthritis, uveitis, skin rash, granuloma, and camptodactyly. It has overlapping symptoms with sarcoidosis and rheumatoid arthritis. Our study was directed toward determining the role of cytokines in granuloma formation in Blau syndrome. Antigenic stimulation usually follows two pathways: Th-1, which activates macrophages and cytotoxic T-lymphocytes and produces interleukin (IL)-2, IL-3, interferon gamma, and tumor necrosis factor alpha, and Th-2, which activates the humoral immune system and produces IL-4, IL-5, and IL-10. The development of cytokine profiles may shed some light on our understanding of this illness. Therefore, we studied the relative roles of two opposing lymphocytes, Th-1 and Th-2, by analyzing their relative expression in the skin lesions of patients with Blau syndrome, using the in situ reverse transcription-polymerase chain reaction technique. Our data revealed a significant upregulation of IL-2, an event that appears to play an important role in the formation of granuloma and in the pathogenesis of Blau syndrome. Expression of IL-10, however, was downregulated, and this may have an inhibitory role in the development of the disease. Further studies would be necessary to confirm the presence of other cytokines and to establish the regulatory roles of Th-1 and Th-2 lymphocytes in the pathogenesis of Blau syndrome.