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1.
J Pathol ; 255(2): 190-201, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34184758

RESUMEN

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Trampas Extracelulares/inmunología , Interleucina-8/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Microambiente Tumoral/inmunología , Humanos
2.
Eur Heart J Suppl ; 23(Suppl B): B46-B48, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-34248430

RESUMEN

Hypertension awareness and control is poor in low- and middle-income countries. Thus, implementing strategies to increase hypertension detection is needed. Colombia participated as one of the 92 countries involved in the third campaign of the May Measurement Month in 2019. Blood pressure (BP) was measured in 48 324 volunteers from 13 departments in Colombia. In total, 27.9% individuals were identified with hypertension. Of those with hypertension, 63.7% were aware of their condition, 60.0% were on antihypertensive medication, and 38.4% had controlled BP. These results showed low levels of awareness, treatment, and control of hypertension in this sample of subjects volunteered to participate, suggest the urgent necessity of implementing programmes to improve the diagnosis and management of hypertension in Colombia.

3.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802143

RESUMEN

(1) Background: Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a dose reduction and/or the interruption of chemotherapy treatment, limiting its effectiveness. Potential pathophysiological mechanisms involved in the pathogenesis of CIPN include chronic oxidative stress and subsequent increase in free radicals and proinflammatory cytokines. Approaches for the treatment of CIPN are highly limited in their number and efficacy, although several antioxidant-based therapies have been tried. On the other hand, ozone therapy can induce an adaptive antioxidant and anti-inflammatory response, which could be potentially useful in the management of CIPN. (2) Methods: The aims of this works are: (a) to summarize the potential mechanisms that could induce CIPN by the most relevant drugs (platinum, taxanes, vinca alkaloids, and bortezomib), with particular focus on the role of oxidative stress; (b) to summarize the current situation of prophylactic and treatment approaches; (c) to describe the action mechanisms of ozone therapy to modify oxidative stress and inflammation with its potential repercussions for CIPN; (d) to describe related experimental and clinical reports with ozone therapy in chemo-induced neurologic symptoms and CIPN; and (e) to show the main details about an ongoing focused clinical trial. (3) Results: A wide background relating to the mechanisms of action and a small number of experimental and clinical reports suggest that ozone therapy could be useful to prevent or improve CIPN. (4) Conclusions: Currently, there are no clinically relevant approaches for the prevention and treatment of stablished CIPN. The potential role of ozone therapy in this syndrome merits further research. Randomized controlled trials are ongoing.


Asunto(s)
Antineoplásicos/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Ozono/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto
4.
Eur Heart J Suppl ; 21(Suppl D): D40-D43, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31043874

RESUMEN

Despite the availability of efficient methods to evaluate blood pressure (BP) and of safe and efficient medication to treat and control hypertension, the levels of awareness, treatment and control are very low globally, particularly in low- and middle-income countries. To highlight the importance of improving these rates, the International Society of Hypertension (ISH) endorsed by the World Hypertension League have implemented the May Measurement Month initiative. We present here the results obtained in Colombia. The Fundación Oftalmológica de Santander (FOSCAL) led the implementation of this strategy in Colombia and 11 departments participated. The data collection followed the guidelines of the ISH. The information collected was compiled for the report generation and the submission to the Technical Secretariat of the ISH. Data cleaning was performed locally by FOSCAL. Data were collated and analysed centrally. A total of 22 258 participants (58.8% female) were included in the analysis. Mean age was 40.9 ± 17.7 years. Age and sex-standardized BP excluding participants receiving BP medications was 118/74.3 mmHg, and in those on treatment 125/78 mmHg. High BP was present in 5036 (22.8%) individuals, 1637 of 18 644 (8.8%) who were not receiving anti-hypertensive medications were hypertensive, and 961 of 3359 (28.6%) receiving treatment were not controlled. These results highlight the need to develop innovative promotion strategies at individual and population levels to increase the awareness of the importance of BP, and the consequences of not having well-controlled hypertension. This initiative is an effective and easy to implement strategy that should be maintained in the coming years.

5.
J Org Chem ; 81(7): 2713-29, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-26924820

RESUMEN

A broadly applicable catalyst system consisting of water-soluble Pd--imidate complexes has been enployed for the Suzuki-Miyaura cross-coupling of four different nucleosides in water under mild conditions. The efficient nature of the catalyst system also allowed its application in developing a microwave-assisted protocol with the purpose of expediting the catalytic reaction. Preliminary mechanistic studies, assisted by catalyst poison tests and stoichiometric tests performed using an electrospray ionization spectrometer, revealed the possible presence of a homotopic catalyst system.

6.
Med Sci Sports Exerc ; 56(7): 1291-1296, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38648672

RESUMEN

PURPOSE: This study aimed to investigate longitudinal associations between physical activity levels and obesity in adults in Colombia, where participation in large amounts of light-intensity physical activity is a necessity for many people. METHODS: Participation in moderate- and vigorous-intensity physical activity was assessed from 2005 to 2009, and obesity was assessed from 2011 to 2019 in men and women from the Prospective Urban Rural Epidemiology (PURE) study. Total physical activity level was categorized as low (<600 MET·min·wk -1 ), medium (600-3000 MET·min·wk -1 ), or high (>3000 MET·min·wk -1 ; 600 MET·min·wk -1 is equivalent to 150 min of moderate activity or 75 min of vigorous activity per week). Obesity was defined as body mass index ≥30 kg·m -2 . Analyses were adjusted for age, sex, smoking, socioeconomic status, diet, alcohol, sedentary time, and sleep. RESULTS: The main analysis included 3086 men and women aged 51 ± 9 yr at baseline (mean ± SD). Compared with the low physical activity group, the odds ratio (95% confidence interval) for obesity was 0.67 (0.53-0.85) in the medium physical activity group and 0.78 (0.62-0.98) in the high physical activity group after adjustment for potential confounders. Smoking is probably a major confounder, and it is noteworthy that similar associations were observed in participants who reported never smoking. CONCLUSIONS: The PURE study is the only prospective cohort study in Colombia. The present analysis is important because it suggests that even the busy people of Colombia could substantially reduce their risk of obesity by participating in moderate- and vigorous-intensity physical activity.


Asunto(s)
Ejercicio Físico , Obesidad , Humanos , Colombia/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Obesidad/epidemiología , Estudios Prospectivos , Adulto , Factores de Riesgo , Índice de Masa Corporal , Conducta Sedentaria , Población Rural/estadística & datos numéricos , Estudios Longitudinales
7.
Clin Cancer Res ; 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38630754

RESUMEN

PURPOSE: Cancer patients frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NETs), we have investigated the mechanisms, consequences and the occurrence of such phenomena in patients undergoing radiotherapy. EXPERIMENTAL DESIGN: NETosis was analyzed in cultures of neutrophils isolated from healthy donors, cancer patients and cancer-bearing mice under confocal microscopy. Cocultures of radiation-induced NETs, immune effector lymphocytes and tumor cells were used to study the effects of irradiation-induced NETs on immune cytotoxicity. Radiation-induced NETs were intravenously injected to mice assessing their effects on metastasis. Circulating NETs in irradiated cancer patients were measured by ELISA methods detecting MPO-DNA complexes and citrullinated H3. RESULTS: Very low γ-radiation doses (0.5-1 Gy) given to neutrophils elicit NET formation in a manner dependent on oxidative stress, NADPH oxidase activity and autocrine interleukin-8. Radiation-induced NETs interfere with NK- and T-cell cytotoxicity. As a consequence, pre-injection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs were readily detected in two prospective series of patients following the first fraction of their radiotherapy courses. CONCLUSIONS: NETosis is induced by low-dose ionizing irradiation in a neutrophil-intrinsic fashion and radiation-induced NETs are able to interfere with immune-mediated cytotoxicity. Radiation-induced NETs foster metastasis in mouse models and can be detected in the circulation of patients undergoing conventional radiotherapy treatments.

8.
J Cardiovasc Pharmacol ; 61(2): 160-5, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23222311

RESUMEN

Atherosclerosis is a major cause of death in the Western World. It is known that Lipofundin 20% induces atherosclerotic lesions, whereas ozone at low doses has been satisfactorily used in the prevention of oxidative stress-associated pathologies, such as coronary artery diseases. The aim of the present work was to evaluate the effects of ozone therapy on Lipofundin-induced atherosclerotic lesions in New Zealand White rabbits. Ozone (1 mg), mixed with oxygen as passive carrier, was administered by rectal insufflation during 15 sessions in 5 weeks. Then, the animals were intravenously treated with 2 mL/kg of Lipofundin, daily during 8 days. Animals were euthanized and eosin and hematoxylin staining was used for aortic histopathological analysis. The biomarkers of oxidative stress and lipid profile in serum were determined by spectrophotometric techniques. The results demonstrated that ozone induced inhibitory effects on aortic lesions formation. On the other hand, a reduction of biomolecular damage and an increase of antioxidant systems were observed at the end of the experiment. The serum lipids profiles were not modified after only 1 cycle of ozone treatment. Our results reinforced the hypotheses that antioxidant effects induced by ozone in the context of atherosclerosis demonstrate the antiatherogenic properties of the gas in the experimental conditions of this study.


Asunto(s)
Antioxidantes/farmacología , Aterosclerosis/prevención & control , Estrés Oxidativo/efectos de los fármacos , Ozono/farmacología , Animales , Antioxidantes/administración & dosificación , Antioxidantes/metabolismo , Aorta/efectos de los fármacos , Aorta/patología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Lípidos/sangre , Masculino , Oxígeno/administración & dosificación , Ozono/administración & dosificación , Fosfolípidos/toxicidad , Conejos , Sorbitol/toxicidad , Espectrofotometría
9.
Bioengineering (Basel) ; 10(10)2023 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-37892900

RESUMEN

An aneurysm is a vascular malformation that can be classified according to its location (cerebral, aortic) or shape (saccular, fusiform, and mycotic). Recently, the study of blood flow interaction with aneurysms has gained attention from physicians and engineers. Shear stresses, oscillatory shear index (OSI), gradient oscillatory number (GON), and residence time have been used as variables to describe the hemodynamics as well as the origin and evolution of aneurysms. However, the causes and hemodynamic conditions that promote their growth are still under debate. The present work presents numerical simulations of three types of aneurysms: two aortic and one cerebral. Simulation results showed that the blood rheology is not relevant for aortic aneurysms. However, for the cerebral aneurysm case, blood rheology could play a relevant role in the hemodynamics. The evaluated turbulence models showed equivalent results in both cases. Lastly, a simulation considering the fluid-structure interaction (FSI) showed that this phenomenon is the dominant factor for aneurysm simulation.

10.
EMBO Mol Med ; 15(11): e17804, 2023 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-37782273

RESUMEN

NK-cell reactivity against cancer is conceivably suppressed in the tumor microenvironment by the interaction of the inhibitory receptor NKG2A with the non-classical MHC-I molecules HLA-E in humans or Qa-1b in mice. We found that intratumoral delivery of NK cells attains significant therapeutic effects only if co-injected with anti-NKG2A and anti-Qa-1b blocking monoclonal antibodies against solid mouse tumor models. Such therapeutic activity was contingent on endogenous CD8 T cells and type-1 conventional dendritic cells (cDC1). Moreover, the anti-tumor effects were enhanced upon combination with systemic anti-PD-1 mAb treatment and achieved partial abscopal efficacy against distant non-injected tumors. In xenografted mice bearing HLA-E-expressing human cancer cells, intratumoral co-injection of activated allogeneic human NK cells and clinical-grade anti-NKG2A mAb (monalizumab) synergistically achieved therapeutic effects. In conclusion, these studies provide evidence for the clinical potential of intratumoral NK cell-based immunotherapies that exert their anti-tumor efficacy as a result of eliciting endogenous T-cell responses.


Asunto(s)
Anticuerpos Monoclonales , Neoplasias , Ratones , Humanos , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Histocompatibilidad Clase I , Células Asesinas Naturales , Linfocitos T CD8-positivos , Microambiente Tumoral
11.
Mol Ther Nucleic Acids ; 33: 668-682, 2023 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-37650116

RESUMEN

Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor ß (TGF-ß) and CD137 (4-1BB). Several neutralizing TGF-ß agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-ß and CD137 binding by the constructions, we used bispecific tandem scFv antibodies (taFvs) derived from the specific 1D11 and 1D8 monoclonal antibodies (mAbs), respectively. Transfection of mRNAs encoding the chimeric constructs achieved functional expression of the proteins able to act on their targets. Upon mRNA intratumoral injections in the transplantable mouse cancer models CT26, MC38, and B16OVA, potent therapeutic effects were observed following repeated injections into the tumors. Efficacy was dependent on the number of CD8+ T cells able to recognize tumor antigens that infiltrated the malignant tissue. Although the abscopal effects on concomitant uninjected lesions were modest, such distant effects on untreated lesions were markedly increased when combined with systemic PD-1 blockade.

12.
Cell Rep Med ; 4(4): 101009, 2023 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-37040772

RESUMEN

Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular carcinoma (HCC) patients, but improvements in efficacy are needed to improve response rates. We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co-expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms. We show that treatment of the mice with a combination of anti-CTLA-4 + anti-PD1 mAbs results in partial clearance of the tumor with an improvement in survival. However, the addition of either recombinant IL-2 or an anti-CD137 mAb markedly improves both outcomes in these mice. Combining tumor-specific adoptive T cell therapy to the aCTLA-4/aPD1/rIL2 or aCTLA-4/aPD1/aCD137 regimens enhances efficacy in a synergistic manner. As shown by multiplex tissue immunofluorescence and intravital microscopy, combined immunotherapy treatments enhance T cell infiltration and the intratumoral performance of T lymphocytes.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/genética , Anticuerpos Monoclonales , Terapia Combinada , Inmunoterapia/métodos
13.
Cancer Immunol Res ; 11(2): 184-198, 2023 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-36478221

RESUMEN

IL12-based local gene therapy of cancer constitutes an active area of clinical research using plasmids, mRNAs, and viral vectors. To improve antitumor effects, we have experimentally tested the combination of mRNA constructs encoding IL12 and IL18. Moreover, we have used a form of IL18 [decoy-resistant IL18 (DR-18)] which has preserved bioactivity but does not bind to the IL18 binding protein decoy receptor. Both cytokines dramatically synergize to induce IFNγ release from mouse splenocytes, and, if systemically cotransferred to the liver, they mediate lethal toxicity. However, if given intratumorally to B16OVA tumor-bearing mice, the combination attains efficacy against the directly treated tumor and moderate tumor-delaying activity on distant noninjected lesions. Cotreatment was conducive to the presence of more activated CD8+ T cells in the treated and noninjected tumors. In keeping with these findings, the efficacy of treatment was contingent on the integrity of CD8+ T cells and cDC1 dendritic cells in the treated mice. Furthermore, efficacy of IL12 plus DR-18 local mRNA coinjection against distant concomitant tumors could be enhanced upon combination with anti-PD-1 mAb systemic treatment, thus defining a feasible synergistic immunotherapy strategy.


Asunto(s)
Interleucina-18 , Neoplasias , Animales , Ratones , Neoplasias/genética , Neoplasias/terapia , Linfocitos T CD8-positivos , Inmunoterapia , Interleucina-12/metabolismo
14.
Front Physiol ; 13: 935269, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36111149

RESUMEN

Background: Pain secondary to chemotherapy-induced peripheral neuropathy (CIPN) can limit the administration of chemotherapy, cancer-treatment outcomes, and the quality of life of patients. Oxidative stress and inflammation are some of the key mechanisms involved in CIPN. Successful treatments for CIPN are limited. This report shows our preliminary experience using ozone treatment as a modulator of oxidative stress in chronic pain secondary to CIPN. Methods: Ozone treatment, by rectal insufflation, was administered in seven patients suffering from pain secondary to grade II or III CIPN. Pain was assessed by the visual analog scale (VAS). Results: All patients, except one, showed clinically relevant pain improvement. Median pain score according to the VAS was 7 (range: 5-8) before ozone treatment, 4 (range: 2-6) at the end of ozone treatment (p = 0.004), 5.5 (range: 1.8-6.3) 3 months after the end of ozone treatment (p = 0.008), and 6 (range: 2.6-6.6) 6 months after the end of ozone treatment (p = 0.008). The toxicity grade, according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0), improved in half of the patients. Conclusion: This report shows that most patients obtained clinically relevant and long-lasting improvement in chronic pain secondary to CIPN after treatment with ozone. These observed effects merit further research and support our ongoing randomized clinical trial (NCT04299893).

15.
Nat Metab ; 4(12): 1847-1857, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36344766

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).


Asunto(s)
COVID-19 , Fenofibrato , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , SARS-CoV-2 , Fenofibrato/uso terapéutico , Metabolismo de los Lípidos , PPAR alfa
16.
Res Sq ; 2022 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-35982675

RESUMEN

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.

17.
Nat Commun ; 12(1): 7296, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34911975

RESUMEN

CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell cycle and DNA damage repair gene expression programs. Here we report that the superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which may provide costimulation either in cis or in trans.


Asunto(s)
Complejo CD3/inmunología , Linfocitos T CD8-positivos/inmunología , Complejo Receptor-CD3 del Antígeno de Linfocito T/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Animales , Complejo CD3/genética , Proliferación Celular , Citocinas/genética , Citocinas/inmunología , Humanos , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Complejo Receptor-CD3 del Antígeno de Linfocito T/genética , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética
18.
Antioxidants (Basel) ; 9(5)2020 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-32384798

RESUMEN

(1) Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China at the end of 2019 has caused a large global outbreak. Systemic ozone therapy (OT) could be potentially useful in the clinical management of several complications secondary to SARS-CoV-2. The rationale and mechanism of action has already been proven clinically in other viral infections and has been shown in research studies to be highly effective at decreasing organ damage mediated by inflammation and oxidative stress. This review summarizes the OT studies that illustrate the possible cytoprotective mechanism of action of ozone and its physiological by-products in target organs affected by SARS-CoV-2. (2) Methods: This review encompasses a total of 74 peer-reviewed original articles. It is mainly focused on ozone as a modulator of the NF-κ B/Nrf2 pathways and IL-6/IL-1ß expression. (3) Results: In experimental models and the few existent clinical studies, homeostasis of the free radical and antioxidant balance by OT was associated with a modulation of NF-κ B/Nrf2 balance and IL-6 and IL-1ß expression. These molecular mechanisms support the cytoprotective effects of OT against tissue damage present in many inflammatory diseases, including viral infections. (4) Conclusions: The potential cytoprotective role of OT in the management of organ damage induced by COVID-19 merits further research. Controlled clinical trials are needed.

19.
Glob Heart ; 15(1): 35, 2020 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-32489808

RESUMEN

Background: Chronic non-communicable diseases are prevalent conditions in developing countries, such as Colombia. Several socioeconomic and educational factors have been associated with these pathologies. However, there is little country-specific information regarding the self-reported prevalence of chronic diseases and their association with the aforementioned factors in Colombia. Objectives: To evaluate the current situation of chronic non-transmissible diseases in Colombia by self-report and to analyze its potential relationship with sociodemographic, economic and educational factors. Methods: This is a cross-sectional baseline sub-analysis from the prospective, standardized collaborative PURE study in Colombia. Participants were recruited between 2005 to 2009, in 11 departments of the country, and included 7,485 subjects of 35 to 70 years old. Questionnaires of self-reported chronic non-communicable diseases, and demographic, socioeconomic and educational variables were applied. Results: Hypertension was the most prevalent chronic condition reported with a prevalence of 22.2% (21.2%-23.1%, 95% CI), followed by diabetes with a prevalence of 5.7% (5.1%-6.2%, 95% CI), asthma 2.7% (2.2%-3.0%, 95% CI), coronary heart disease 2.4% (2.0%-2.7%, 95% CI), stroke and heart failure 1.5% (1.2%-1.8%, 95% CI) each, chronic obstructive pulmonary disease 1.2% (0.6%-1.5%, 95% CI), and cancer 1.2% (1.0%-1.5%, 95% CI). Among the study sample, 23.3% (22.4%-24.3%, 95% CI) reported having one chronic NCDs, and 6.4% (5.9%-7.0%, 95% CI) reported having multiple chronic NCDs. The prevalence of multiple NCDs increased significantly with age, was more common in those from households with higher income, whereas it was significantly lower in persons with high education.The central and central-east regions of the country are those with the higher prevalence of self-reported NCDs. Conclusion: The results of the current study indicate the presence of socioeconomic and educational inequalities in the distribution of chronic NCDs in the Colombian population.


Asunto(s)
Enfermedades no Transmisibles/epidemiología , Autoinforme , Adulto , Anciano , Enfermedad Crónica , Colombia/epidemiología , Estudios Transversales , Escolaridad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades no Transmisibles/economía , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Factores Socioeconómicos
20.
Int J Cardiol ; 284: 111-117, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-30463681

RESUMEN

BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular diseases (CVD). Worldwide, a third of ischemic heart disease is due to abnormal cholesterol levels and it is the most common cause of cardiovascular deaths in Colombia. In Colombia, no representative, large-scale study has assessed the prevalence of dyslipidemia. The aim of the present analysis was to identify the magnitude of the problem in Colombia, a middle-income-country with large regional, geographic, and socio-economical differences. MATERIAL AND METHODS: The sample comprised 6628 individuals aged 35 to 70 years (mean age 50.7 years, 64.1% women) residing in the four Colombian regions. RESULTS: The overall prevalence of dyslipidemia was 87.7% and was substantially higher among participants older than 50 years, male, rural residents, and those with a lower level of education (66.8%), and with a lower income (66.4%). High non HDL-c was the most common abnormality (75.3%). The values of total cholesterol and non-HDL-cholesterol were higher in areas with the lowest health needs index than in the areas with intermediate and highest health need index, the isolated HDL-c value was much lower. CONCLUSION: Colombia has a high prevalence of abnormalities of the lipid profile. The causes of the high rates of dyslipidemia were not well define in this study, but were more common in rural and poorer regions and among those with lower socio-economical status. Strategies to tackle the adverse lipid profile to reduce CVD are needed in Colombia, particularly in rural areas and among the areas with the higher health need index.


Asunto(s)
Dislipidemias/epidemiología , Lípidos/sangre , Medición de Riesgo/métodos , Población Rural , Población Urbana , Adulto , Distribución por Edad , Anciano , Colombia/epidemiología , Dislipidemias/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Factores de Riesgo
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