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1.
Oxid Med Cell Longev ; 2021: 6646923, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33628371

RESUMEN

Inflammatory lung disease results in a high global burden of death and disability. There are no effective treatments for the most severe forms of many inflammatory lung diseases, such as chronic obstructive pulmonary disease, emphysema, corticosteroid-resistant asthma, and coronavirus disease 2019; hence, new treatment options are required. Here, we review the role of oxidative imbalance in the development of difficult-to-treat inflammatory lung diseases. The inflammation-induced overproduction of reactive oxygen species (ROS) means that endogenous antioxidants may not be sufficient to prevent oxidative damage, resulting in an oxidative imbalance in the lung. In turn, intracellular signaling events trigger the production of proinflammatory mediators that perpetuate and aggravate the inflammatory response and may lead to tissue damage. The production of high levels of ROS in inflammatory lung diseases can induce the phosphorylation of mitogen-activated protein kinases, the inactivation of phosphoinositide 3-kinase (PI3K) signaling and histone deacetylase 2, a decrease in glucocorticoid binding to its receptor, and thus resistance to glucocorticoid treatment. Hence, antioxidant treatment might be a therapeutic option for inflammatory lung diseases. Preclinical studies have shown that antioxidants (alone or combined with anti-inflammatory drugs) are effective in the treatment of inflammatory lung diseases, although the clinical evidence of efficacy is weaker. Despite the high level of evidence for the efficacy of antioxidants in the treatment of inflammatory lung diseases, the discovery and clinical investigation of safer, more efficacious compounds are now a priority.


Asunto(s)
Antioxidantes/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/metabolismo , Animales , Humanos , Inflamación/inmunología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Enfermedades Pulmonares/inmunología , Oxidación-Reducción/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Especies Reactivas de Oxígeno/metabolismo
2.
J Nanobiotechnology ; 19(1): 59, 2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33632278

RESUMEN

Virus-like particles (VLPs) are virus-derived structures made up of one or more different molecules with the ability to self-assemble, mimicking the form and size of a virus particle but lacking the genetic material so they are not capable of infecting the host cell. Expression and self-assembly of the viral structural proteins can take place in various living or cell-free expression systems after which the viral structures can be assembled and reconstructed. VLPs are gaining in popularity in the field of preventive medicine and to date, a wide range of VLP-based candidate vaccines have been developed for immunization against various infectious agents, the latest of which is the vaccine against SARS-CoV-2, the efficacy of which is being evaluated. VLPs are highly immunogenic and are able to elicit both the antibody- and cell-mediated immune responses by pathways different from those elicited by conventional inactivated viral vaccines. However, there are still many challenges to this surface display system that need to be addressed in the future. VLPs that are classified as subunit vaccines are subdivided into enveloped and non- enveloped subtypes both of which are discussed in this review article. VLPs have also recently received attention for their successful applications in targeted drug delivery and for use in gene therapy. The development of more effective and targeted forms of VLP by modification of the surface of the particles in such a way that they can be introduced into specific cells or tissues or increase their half-life in the host is likely to expand their use in the future. Recent advances in the production and fabrication of VLPs including the exploration of different types of expression systems for their development, as well as their applications as vaccines in the prevention of infectious diseases and cancers resulting from their interaction with, and mechanism of activation of, the humoral and cellular immune systems are discussed in this review.


Asunto(s)
/uso terapéutico , Anticuerpos Neutralizantes/inmunología , /inmunología , Humanos , Inmunidad/fisiología , /patogenicidad , Vacunación/métodos , Vacunas de Partículas Similares a Virus/biosíntesis , Vacunas de Partículas Similares a Virus/inmunología , Vacunas de Partículas Similares a Virus/uso terapéutico
3.
Int J Med Sci ; 18(5): 1137-1142, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33526973

RESUMEN

Background: It's reported SARS-CoV-2 could transmit via gastrointestinal tract, with or without pulmonary symptoms. However, as far as we know, there is no effective marker to predict the virus discharge in stool and initial gastrointestinal involvement of COVID-19 patients. Aims: We aimed to investigate the likely biomarker predicting virus discharge in stool and initial gastrointestinal involvement of COVID-19, which may assist the clinicians in better preventing COVID-19 spread. Methods: The patients complained of gastrointestinal symptoms, including vomiting, diarrhea, with or without respiratory symptoms, attending the Sixth People's Hospital of Wenzhou, and the Second Affiliated Hospital of Wenzhou Medical University, were screened by qRT-PCR for SARS-CoV-2. The confirmed COVID-19 patients, without any history of intaking contaminated food or water, were all enrolled to investigate the association between circulating lymphocyte count and virus discharge, initial gastrointestinal involvement. Results: Seventy-six COVID-19 patients were included in the final analysis (mean age of 44.5 years, male 44.7%), with 24 (31.5%) complained of initial gastrointestinal symptoms. Significantly lower circulating lymphocyte count was found in the patients with positive results of qRT-PCR on stool (p = 0.012). Patients were divided into tertile groups by circulating lymphocyte count: lymphocyte ≤0.88*10^9/l ( n = 25 ), 0.88*10^9/l -1.2*10^9/l ( n = 28 ), and >1.2*10^9/l ( n = 23 ), respectively. When circulating lymphocyte count increased from 1st tertile to the 2nd and 3rd tertiles, the risk of initial gastrointestinal symptoms decreased by nearly 75% (OR = 0.25, 95% CI: 0.07, 0.98, p = 0.047), 83% (OR = 0.17, 95% CI: 0.05, 0.63, p = 0.008), after adjusting for likely confounders. Conclusions: The circulating lymphocyte count is inversely associated with virus discharge in stool, and the risk of initial gastrointestinal involvement in COVID-19 patients.


Asunto(s)
/inmunología , Enfermedades Gastrointestinales/virología , Adulto , Heces/virología , Femenino , Enfermedades Gastrointestinales/inmunología , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
4.
Int J Med Sci ; 18(5): 1143-1152, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33526974

RESUMEN

Highly pathogenic coronaviruses (CoVs) induce acute respiratory distress syndrome, and the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused a pandemic since late 2019. The diversity of clinical manifestations after SARS-CoV-2 infection results in great challenges to diagnose CoV disease 2019 (COVID-19). There is a growing body of published research on this topic; however, effective medications are still undergoing a long process of being assessed. In the search for potential genetic targets for this infection, we applied a holistic bioinformatics approach to study alterations of gene signatures between SARS-CoV-2-infected cells and mock-infected controls. Two different kinds of lung epithelial cells, A549 with angiotensin-converting enzyme 2 (ACE2) overexpression and normal human bronchial epithelial (NHBE) cells, were infected with SARS-CoV-2. We performed bioinformatics analyses of RNA-sequencing in this study. Through a Venn diagram, Database for Annotation, Visualization and Integrated Discovery, Gene Ontology, Ingenuity Pathway Analysis, and Gene Set Enrichment Analysis, the pathways and networks were constructed from commonly upregulated genes in SARS-CoV-2-infected lung epithelial cells. Genes associated with immune-related pathways, responses of host cells after intracellular infection, steroid hormone biosynthesis, receptor signaling, and the complement system were enriched. Dysregulation of the immune system and malfunction of interferon contribute to a failure to kill SARS-CoV-2 and exacerbate respiratory distress in severely ill patients. Current findings from this study provide a comprehensive investigation of SARS-CoV-2 infection using high-throughput technology.


Asunto(s)
/inmunología , Redes Reguladoras de Genes , Células A549 , Simulación por Computador , Interacciones Huésped-Patógeno/inmunología , Humanos , /fisiología
6.
Immunotherapy ; 13(5): 397-407, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557591

RESUMEN

Background: This study assesses the feasibility of producing hyperimmune anti-COVID-19 intravenously administrable immunoglobulin (C-IVIG) from pooled convalescent plasma (PCP) to provide a safe and effective passive immunization treatment option for COVID-19. Materials & methods: PCP was fractionated by modified caprylic acid precipitation followed by ultrafiltration/diafiltration to produce hyperimmune C-IVIG. Results: In C-IVIG, the mean SARS-CoV-2 antibody level was found to be threefold (104 ± 30 cut-off index) that of the PCP (36 ± 8.5 cut-off index) and mean protein concentration was found to be 46 ± 3.7 g/l, comprised of 89.5% immunoglobulins. Conclusion: The current method of producing C-IVIG is feasible as it uses locally available PCP and simpler technology and yields a high titer of SARS-CoV-2 antibody. The safety and efficacy of C-IVIG will be evaluated in a registered clinical trial (NCT04521309).


Asunto(s)
Anticuerpos Antivirales/aislamiento & purificación , Inmunoglobulinas Intravenosas/aislamiento & purificación , /inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , Caprilatos/química , Fraccionamiento Químico , Humanos , Inmunización Pasiva , Inmunoglobulinas Intravenosas/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico
7.
Crit Care ; 25(1): 53, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33557908

RESUMEN

The current pandemic of COVID-19 caused thousands of deaths and healthcare professionals struggle to properly manage infected patients. This review summarizes information about SARS-CoV-2 receptor binding dynamics and intricacies, lung autopsy findings, immune response patterns, evidence-based explanations for the immune response, and COVID-19-associated hypercoagulability.


Asunto(s)
/fisiopatología , Proteínas Portadoras/fisiología , Enfermedades Pulmonares/fisiopatología , Neumonía Viral/fisiopatología , /patogenicidad , /inmunología , Proteínas Portadoras/inmunología , Humanos , Enfermedades Pulmonares/inmunología , Pandemias , Neumonía Viral/inmunología , /inmunología
8.
Crit Care ; 25(1): 51, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33557911

RESUMEN

BACKGROUND: Thrombosis and coagulopathy are highly prevalent in critically ill patients with COVID-19 and increase the risk of death. Immunothrombosis has recently been demonstrated to contribute to the thrombotic events in COVID-19 patients with coagulopathy. As the primary components of immunothrombosis, neutrophil extracellular traps (NETs) could be induced by complement cascade components and other proinflammatory mediators. We aimed to explore the clinical roles of NETs and the regulation of complement on the NET formation in COVID-19. METHODS: We recruited 135 COVID-19 patients and measured plasma levels of C5, C3, cell-free DNA and myeloperoxidase (MPO)-DNA. Besides, the formation of NETs was detected by immunofluorescent staining and the cytotoxicity to vascular endothelial HUVEC cells was evaluated by CCK-8 assay. RESULTS: We found that the plasma levels of complements C3 and MPO-DNA were positively related to coagulation indicator fibrin(-ogen) degradation products (C3: r = 0.300, p = 0.005; MPO-DNA: r = 0.316, p = 0.002) in COVID-19 patients. Besides, C3 was positively related to direct bilirubin (r = 0.303, p = 0.004) and total bilirubin (r = 0.304, p = 0.005), MPO-DNA was positively related to lactate dehydrogenase (r = 0.306, p = 0.003) and creatine kinase (r = 0.308, p = 0.004). By using anti-C3a and anti-C5a antibodies, we revealed that the complement component anaphylatoxins in the plasma of COVID-19 patients strongly induced NET formation. The pathological effect of the anaphylatoxin-NET axis on the damage of vascular endothelial cells could be relieved by recombinant carboxypeptidase B (CPB), a stable homolog of enzyme CPB2 which can degrade anaphylatoxins to inactive products. CONCLUSIONS: Over-activation in anaphylatoxin-NET axis plays a pathological role in COVID-19. Early intervention in anaphylatoxins might help prevent thrombosis and disease progression in COVID-19 patients.


Asunto(s)
Anafilatoxinas/metabolismo , /inmunología , Carboxipeptidasa B/metabolismo , Carboxipeptidasa B/uso terapéutico , Trampas Extracelulares/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Trombosis/prevención & control , Adulto , Anciano , Trampas Extracelulares/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Trombosis/inmunología
9.
J Korean Med Sci ; 36(6): e54, 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33559409

RESUMEN

Coronavirus disease 2019 (COVID-19), which started at the end of 2019 and has spread worldwide, has remained unabated in 2021. Since non-pharmaceutical interventions including social distancing are facing limitations in controlling COVID-19, additional absolute means to change the trend are necessary. To this end, coronavirus-specific antiviral drugs and vaccines are urgently needed, but for now, the priority is to promote herd immunity through extensive nationwide vaccination campaign. In addition to the vaccines based on the conventional technology such inactivated or killed virus or protein subunit vaccines, several vaccines on the new technological platforms, for example, nucleic acids-based vaccines delivered by viral carriers, nanoparticles, or plasmids as a medium were introduced in this pandemic. In addition to achieving sufficient herd immunity with vaccination, the development of antiviral treatments that work specifically against COVID-19 will also be necessary to terminate the epidemic completely.


Asunto(s)
/inmunología , /prevención & control , Adenoviridae/genética , /virología , Variación Genética , Vectores Genéticos/genética , Humanos , Inmunidad Colectiva , ARN Mensajero/genética , ARN Mensajero/inmunología , ARN Mensajero/metabolismo , /aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología
10.
Ann R Coll Surg Engl ; 103(2): e53-e55, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33559560

RESUMEN

Inflammatory myofibroblastic tumours (IMTs) are rare tumours with unpredictable biological behaviour ranging from benign to locally invasive and rarely, distant metastasis. While neurofibromatosis type 1 (NF1) may manifest with gastrointestinal soft tissue tumours, this is the first report in the literature that describes an IMT occurring in a NF1 patient who presented with intestinal obstruction. Our patient presented with intestinal obstruction secondary to an obstructing terminal ileum mesenteric tumour. En bloc bowel resection was performed, with histology revealing an IMT and an adjacent neurofibroma. The resection margins were clear and the patient was free of recurrence at six months.


Asunto(s)
Obstrucción Intestinal/etiología , Mesenterio/patología , Neoplasias de Tejido Muscular/diagnóstico , Neurofibromatosis 1/complicaciones , Neoplasias Peritoneales/diagnóstico , Humanos , Obstrucción Intestinal/cirugía , Masculino , Mesenterio/diagnóstico por imagen , Mesenterio/inmunología , Mesenterio/cirugía , Persona de Mediana Edad , Neoplasias de Tejido Muscular/etiología , Neoplasias de Tejido Muscular/inmunología , Neoplasias de Tejido Muscular/cirugía , Neoplasias Peritoneales/etiología , Neoplasias Peritoneales/inmunología , Neoplasias Peritoneales/cirugía , Tomografía por Rayos X , Resultado del Tratamiento
11.
Immunity ; 54(2): 340-354.e6, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33567252

RESUMEN

Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4+ T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Inmunidad Celular/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Femenino , Humanos , Inmunidad Humoral/inmunología , Masculino , Persona de Mediana Edad , Adulto Joven
12.
Nat Commun ; 12(1): 729, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33526794

RESUMEN

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.


Asunto(s)
/uso terapéutico , Linfocitos/inmunología , Neoplasias/tratamiento farmacológico , Neutrófilos/inmunología , Anciano , Resistencia a Antineoplásicos/inmunología , Femenino , Estudios de Seguimiento , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Tasa de Mutación , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/mortalidad , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Estudios Retrospectivos
13.
Nat Commun ; 12(1): 805, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547295

RESUMEN

Efforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17-IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Disbiosis/inmunología , Enfermedad Injerto contra Huésped/inmunología , Interferón gamma/inmunología , Interleucinas/inmunología , Fagocitos/inmunología , Animales , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/trasplante , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/inmunología , Modelos Animales de Enfermedad , Disbiosis/genética , Disbiosis/microbiología , Disbiosis/patología , Microbioma Gastrointestinal/inmunología , Regulación de la Expresión Génica , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/microbiología , Enfermedad Injerto contra Huésped/patología , Interferón gamma/deficiencia , Interferón gamma/genética , Interleucina-17/deficiencia , Interleucina-17/genética , Interleucina-17/inmunología , Interleucinas/genética , Intestinos/inmunología , Intestinos/microbiología , Intestinos/patología , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Pancreatitis/genética , Proteínas Asociadas a Pancreatitis/inmunología , Fagocitos/citología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Linfocitos T Colaboradores-Inductores , Linfocitos T Reguladores , Irradiación Corporal Total
14.
Nat Commun ; 12(1): 832, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547304

RESUMEN

The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1+TIM-3+ T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3+ cytotoxic CD8 T cells and immunosuppressive regulatory T cells (Treg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes Treg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon ß and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.


Asunto(s)
Adenocarcinoma/terapia , Neoplasias del Colon/terapia , Galectinas/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Animales , Anticuerpos/farmacología , Antineoplásicos Inmunológicos/farmacología , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Neoplasias del Colon/mortalidad , Galectinas/antagonistas & inhibidores , Galectinas/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/agonistas , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Inmunoterapia/métodos , Células Jurkat , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/mortalidad , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos BALB C , Receptor de Muerte Celular Programada 1/genética , Unión Proteica , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/terapia , Análisis de Supervivencia , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología
15.
J Ovarian Res ; 14(1): 28, 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33550983

RESUMEN

Improving early diagnosis along with timely and effective treatment of COVID-19 are urgently needed. However, at present, the mechanisms underlying disease spread and development, defined prognosis, and immune status of patients with COVID-19 remain to be determined. Patients with severe disease state exhibit a hyperinflammatory response associated with cytokine storm syndrome, hypercoagulability, and depressed cell-mediated immunity. These clinical manifestations, sharing similar pathogenesis, have been well-studied in patients with advanced ovarian cancer. The present review suggests treatment approaches for COVID-19 based on strategies used against ovarian cancer, which shares similar immunopathology and associated coagulation disorders.The chronicization of the hyperinflammatory cytokine storm in patients with severe COVID-19 highlights a defective resistance phase that leads to aspecific chronic inflammation, associated with oxidative stress, which impairs specific T-cell response, induces tissue and endothelial damage, and thrombosis associated with systemic effects that lead to severe multi-organ failure and death. These events are similar to those observed in advanced ovarian cancer which share similar pathogenesis mediated primarily by Interleukin-6, which is, as well demonstrated in ovarian cancer, the key cytokine driving the immunopathology, related systemic symptoms, and patient prognosis.Consistent with findings in other disease models with similar immunopathology, such as advanced ovarian cancer, treatment of severe COVID-19 infection should target inflammation, oxidative stress, coagulation disorders, and immunodepression to improve patient outcome. Correctly identifying disease stages, based on available laboratory data, and developing a specific protocol for each phase is essential for effective treatment.


Asunto(s)
/complicaciones , Síndrome de Liberación de Citoquinas/etiología , Interleucina-6/metabolismo , Neoplasias Ováricas/metabolismo , Corticoesteroides/uso terapéutico , Aspirina/uso terapéutico , /metabolismo , /terapia , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/prevención & control , Femenino , Humanos , Inmunización Pasiva , Inflamación/tratamiento farmacológico , Inflamación/virología , Interleucina-6/inmunología , Necrosis , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inmunología , Estrés Oxidativo
16.
N Engl J Med ; 384(6): 541-549, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33567193

RESUMEN

BACKGROUND: A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. METHODS: In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months. RESULTS: A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups. CONCLUSIONS: In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).


Asunto(s)
Anticuerpos contra la Hepatitis C/sangre , Hepatitis C Crónica/prevención & control , Inmunogenicidad Vacunal , Vacunas contra Hepatitis Viral/inmunología , Adenovirus de los Simios/genética , Adolescente , Adulto , Animales , Método Doble Ciego , Femenino , Vectores Genéticos , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/inmunología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pan troglodytes , Abuso de Sustancias por Vía Intravenosa , Linfocitos T/inmunología , Vacunas Sintéticas/inmunología , Vacunas contra Hepatitis Viral/efectos adversos , Adulto Joven
17.
Viruses ; 13(2)2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33525328

RESUMEN

There have been reports of neurological abnormalities associated with the Zika virus (ZIKV), such as congenital Zika syndrome (CZS) in children born to mothers infected during pregnancy. We investigated how the immune response to ZIKV during pregnancy is primed and conduct a thorough evaluation of the inflammatory and cytotoxic profiles as well as the expression of CCR5 and CX3CR1. We compared the reactivity of T cells to ZIKV peptides in convalescent mothers infected during pregnancy. The child's clinical outcome (i.e., born with or without CZS) was taken to be the variable. The cells were stimulated in vitro with ZIKV peptides and evaluated using the ELISPOT and flow cytometry assays. After in vitro stimulation with ZIKV peptides, we observed a tendency toward a higher Interferon gamma (IFN-γ)-producing T cell responses in mothers who had asymptomatic children and a higher CD107a expression in T cells in mothers who had children with CZS. We found a higher frequency of T cells expressing CD107a+ and co-expressing CX3CR1+CCR5+, which is much clearer in the T cells of mothers who had CZS children. We suggest that this differential profile influenced the clinical outcome of babies. These data need to be further investigated, including the evaluation of other ZIKV peptides and markers and functional assays.


Asunto(s)
Receptor 1 de Quimiocinas CX3C/metabolismo , Complicaciones Infecciosas del Embarazo/inmunología , Receptores CCR5/metabolismo , Linfocitos T/inmunología , Infección por el Virus Zika/inmunología , Adulto , Estudios Transversales , Citotoxicidad Inmunológica , Femenino , Humanos , Lactante , Interferón gamma/metabolismo , Glicoproteínas de la Membrana Asociadas a los Lisosomas/metabolismo , Embarazo , Resultado del Embarazo , Linfocitos T/metabolismo , Adulto Joven , Virus Zika/inmunología
18.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-33525632

RESUMEN

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel epidemic strain of Betacoronavirus that is responsible for the current viral pandemic, coronavirus disease 2019 (COVID-19), a global health crisis. Other epidemic Betacoronaviruses include the 2003 SARS-CoV-1 and the 2009 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the genomes of which, particularly that of SARS-CoV-1, are similar to that of the 2019 SARS-CoV-2. In this extensive review, we document the most recent information on Coronavirus proteins, with emphasis on the membrane proteins in the Coronaviridae family. We include information on their structures, functions, and participation in pathogenesis. While the shared proteins among the different coronaviruses may vary in structure and function, they all seem to be multifunctional, a common theme interconnecting these viruses. Many transmembrane proteins encoded within the SARS-CoV-2 genome play important roles in the infection cycle while others have functions yet to be understood. We compare the various structural and nonstructural proteins within the Coronaviridae family to elucidate potential overlaps and parallels in function, focusing primarily on the transmembrane proteins and their influences on host membrane arrangements, secretory pathways, cellular growth inhibition, cell death and immune responses during the viral replication cycle. We also offer bioinformatic analyses of potential viroporin activities of the membrane proteins and their sequence similarities to the Envelope (E) protein. In the last major part of the review, we discuss complement, stimulation of inflammation, and immune evasion/suppression that leads to CoV-derived severe disease and mortality. The overall pathogenesis and disease progression of CoVs is put into perspective by indicating several stages in the resulting infection process in which both host and antiviral therapies could be targeted to block the viral cycle. Lastly, we discuss the development of adaptive immunity against various structural proteins, indicating specific vulnerable regions in the proteins. We discuss current CoV vaccine development approaches with purified proteins, attenuated viruses and DNA vaccines.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/metabolismo , Proteínas de la Matriz Viral/metabolismo , Animales , Betacoronavirus/genética , Betacoronavirus/inmunología , /metabolismo , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Genoma Viral , Interacciones Huésped-Patógeno , Humanos , Evasión Inmune , Mapas de Interacción de Proteínas , /inmunología , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/inmunología , Internalización del Virus , Replicación Viral
19.
Medicine (Baltimore) ; 100(4): e24492, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530269

RESUMEN

INTRODUCTION: Multiple wasp stings is an emergency result from systemic reactions to the toxin with a wide range of manifestations, and we presented 2 patients with distinct clinical and transcriptomic findings. PATIENT CONCERNS: Two patients without systemic disease presented with nearly 90 painful papules after attacked by a swarm of wasps (Vespa basalis). DIAGNOSIS: Patient 1 was a 44-year-old healthy male whose clinical manifestations mainly comprised hemolysis, hepatic injury, rhabdomyolysis, and acute kidney injury. Patient 2 was a 49-year-old healthy female who presented with severe acute respiratory distress syndrome (ARDS) in addition to certain clinical manifestations that were also found in patient 1. We used ribo- nucleic acid sequencing (RNA-Seq) to characterize the inflammatory responses of 2 patients with distinct clinical manifestations after multiple wasp stings. INTERVENTIONS: Both 2 patients received 5 sessions of plasmapheresis, and patient-1 further received mechanical ventilation for 8 days as well as 8 sessions of hemodialysis until day 17. OUTCOMES: Both patients recovered uneventfully after the aforementioned management. We used RNA-Seq to demonstrate a largely regulated neutrophil-predominated immune response in patient 1. In patient 2, we found a profound neutrophilc response on week 1 and a robust neutrophilic as well as pro-inflammatory responses on week 2. Furthermore, we found increased expression of signals that were associated with renal system process on week 2. CONCLUSION: In conclusion, we report 2 patients who manifested with shared and distinct presentations after an attack by the same swarm of wasps. Both patients had hemolysis, rhabdomyolysis, hepatic injury and acute kidney injury, and 1 patient had ARDS. The whole transcriptomic analyses were consistent with the distinct clinical manifestation, and these results suggest the potential of RNA-Sequencing to disentangle complex inflammatory responses in patients with multiple wasp stings. Plasmapheresis and corticosteroid were administered to both patients and case 2 also underwent 8 sessions of hemodialysis.


Asunto(s)
Mordeduras y Picaduras de Insectos/complicaciones , Venenos de Avispas/efectos adversos , Lesión Renal Aguda/etiología , Corticoesteroides/uso terapéutico , Adulto , Animales , Femenino , Humanos , Mordeduras y Picaduras de Insectos/inmunología , Mordeduras y Picaduras de Insectos/terapia , Masculino , Persona de Mediana Edad , Plasmaféresis , Rabdomiólisis/etiología , Resultado del Tratamiento , Venenos de Avispas/inmunología , Avispas
20.
Nat Commun ; 12(1): 776, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33536425

RESUMEN

The rapid expansion of the COVID-19 pandemic has made the development of a SARS-CoV-2 vaccine a global health and economic priority. Taking advantage of versatility and rapid development, three SARS-CoV-2 mRNA vaccine candidates have entered clinical trials with a two-dose immunization regimen. However, the waning antibody response in convalescent patients after SARS-CoV-2 infection and the emergence of human re-infection have raised widespread concerns about a possible short duration of SARS-CoV-2 vaccine protection. Here, we developed a nucleoside-modified mRNA vaccine in lipid-encapsulated form that encoded the SARS-CoV-2 RBD, termed as mRNA-RBD. A single immunization of mRNA-RBD elicited both robust neutralizing antibody and cellular responses, and conferred a near-complete protection against wild SARS-CoV-2 infection in the lungs of hACE2 transgenic mice. Noticeably, the high levels of neutralizing antibodies in BALB/c mice induced by mRNA-RBD vaccination were maintained for at least 6.5 months and conferred a long-term notable protection for hACE2 transgenic mice against SARS-CoV-2 infection in a sera transfer study. These data demonstrated that a single dose of mRNA-RBD provided long-term protection against SARS-CoV-2 challenge.


Asunto(s)
/inmunología , /inmunología , /genética , /inmunología , /genética , Animales , Anticuerpos Neutralizantes/inmunología , /genética , Línea Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Pandemias/prevención & control , ARN Mensajero/genética , ARN Mensajero/inmunología , ARN Viral/genética , ARN Viral/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Proteínas del Envoltorio Viral/inmunología
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