Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
1.
Comput Math Methods Med ; 2022: 9422902, 2022.
Article in English | MEDLINE | ID: covidwho-1950460

ABSTRACT

Objective: Molecular targeted drug therapy and chemotherapy are the main treatments for advanced non-small-cell lung cancer, and the combination of both has advantages in prolonging patients' progression-free survival and overall survival. This study investigated the effects of bevacizumab combined with chemotherapy under nursing intervention on CT, cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and gastrin-releasing peptide precursor (ProGRP) and prognosis of lung cancer patients. Methods: 102 patients with non-small-cell lung cancer admitted to our hospital from January 2018 to May 2019 were divided into observation group and control group, with 51 cases each. The control group was treated with basic chemotherapy, and the observation group was treated with bevacizumab in combination with the control group, and both groups used nursing interventions. The clinical effects, CYFRA21-1 and ProGRP levels, baseline data, CT parameters, 24-month cumulative survival, and the effects of CYFRA21-1 and ProGRP on long-term survival and lung function were compared. Results: The disease control rate of the observation group was 94.12%, which was significantly higher than that of the control group (76.47%); after 7 d, 30 d, 60 d, and 90 d of treatment, the levels of CYFRA21-1 and ProGRP were statistically downregulated. The difference in lymph node metastasis, lesion diameter, plain Eff-Z, venous stage, and arterial stage normalized iodine concentrations (NIC) was statistically significant; the survival rate at 24 months in the observation group was 74.51% (38/51); the cumulative survival rate at 24 months in the control group was 52.94% (27/51), and the difference was statistically significant (X 2 = 4.980, P = 0.026). The cumulative survival rate at 24 months was significantly lower in patients with high expression of CYFRA21-1 and ProGRP compared with those with low expression of CYFRA21-1 and ProGRP. After treatment, in the observation group, the forceful spirometry (FVC), forceful expiratory volume in one second (FEV1), and FEV1/FVC levels were significantly different from those before treatment and were significantly different from those in the control group. Conclusion: Bevacizumab in combination with standard chemotherapy regimens with nursing interventions could benefit patients with advanced non-small-cell lung cancer and had a good prospect of application.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antigens, Neoplasm , Bevacizumab/therapeutic use , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/drug therapy , Humans , Keratin-19 , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Peptide Fragments , Prognosis , Protein Precursors , Recombinant Proteins , Tomography, X-Ray Computed
2.
Sci Rep ; 12(1): 9583, 2022 06 10.
Article in English | MEDLINE | ID: covidwho-1921701

ABSTRACT

TACSTD2 encodes a transmembrane glycoprotein Trop2 commonly overexpressed in carcinomas. While the Trop2 protein was discovered already in 1981 and first antibody-drug conjugate targeting Trop2 were recently approved for cancer therapy, the physiological role of Trop2 is still not fully understood. In this article, we show that TACSTD2/Trop2 expression is evolutionarily conserved in lungs of various vertebrates. By analysis of publicly available transcriptomic data we demonstrate that TACSTD2 level consistently increases in lungs infected with miscellaneous, but mainly viral pathogens. Single cell and subpopulation based transcriptomic data revealed that the major source of TACSTD2 transcript are lung epithelial cells and their progenitors and that TACSTD2 is induced directly in lung epithelial cells following infection. Increase in TACSTD2 expression may represent a mechanism to maintain/restore epithelial barrier function and contribute to regeneration process in infected/damaged lungs.


Subject(s)
Antigens, Neoplasm , Cell Adhesion Molecules , Animals , Antigens, Neoplasm/metabolism , Cell Adhesion Molecules/metabolism , Epithelial Cells/metabolism , Lung/metabolism , Up-Regulation
3.
Cancer Med ; 11(13): 2711-2726, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1919249

ABSTRACT

Recent evidence suggested that the mRNA vaccine has been effective for many tumors, but its progress in gliomas was slow. In this study, we screened potential tumor antigens and suitable populations for mRNA vaccine to develop mRNA vaccine for glioma. We integrated the normalized RNA sequencing expression data and somatic mutation data from TCGA-GBM, TCGA-LGG, and CGGA datasets. Putative antigens in glioma were identified by selecting highly mutated genes with intimate correlation with clinical survival and immune infiltration. An unsupervised partition around medoids algorithm was utilized to stably cluster the patients into five different immune subtypes. Among them, IS1/2 was cold tumor with low tumor mutation burden (TMB), immunogenic cell death (ICDs), and immune checkpoints (ICPs), and IS4/5 was hot tumor with high TMB, ICDs, and ICPs. Monocle3 package was used to evaluate the immune status similarity and evolution in glioma, which identified cluster IS2A/2B within IS2 subtype to be more suitable vaccination receivers. Weighted gene co-expression network analysis identified five hub immune genes as the biomarkers of patients' immune status in glioma. In conclusion, NAT1, FRRS1, GTF2H2C, BRCA2, GRAP, NR5A2, ABCB4, ZNF90, ERCC6L, and ZNF813 are potential antigens suitable for glioma mRNA vaccine. IS1/2A/2B are suitable for mRNA vaccination.


Subject(s)
Brain Neoplasms , Glioma , Antigens, Neoplasm/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Brain Neoplasms/pathology , Glioma/pathology , Humans , Prognosis , RNA, Messenger/genetics , Vaccines, Synthetic , mRNA Vaccines
4.
Genes (Basel) ; 13(4)2022 03 29.
Article in English | MEDLINE | ID: covidwho-1834773

ABSTRACT

Inherited retinal degenerations (IRDs) account for over one third of the underlying causes of blindness in the paediatric population. Patients with IRDs often experience long delays prior to reaching a definitive diagnosis. Children attending a tertiary care paediatric ophthalmology department with phenotypic (i.e., clinical and/or electrophysiologic) evidence suggestive of IRD were contacted for genetic testing during the SARS-CoV-2-19 pandemic using a "telegenetics" approach. Genetic testing approach was panel-based next generation sequencing (351 genes) via a commercial laboratory (Blueprint Genetics, Helsinki, Finland). Of 70 patient samples from 57 pedigrees undergoing genetic testing, a causative genetic variant(s) was detected for 60 patients (85.7%) from 47 (82.5%) pedigrees. Of the 60 genetically resolved IRD patients, 5% (n = 3) are eligible for approved therapies (RPE65) and 38.3% (n = 23) are eligible for clinical trial-based gene therapies including CEP290 (n = 2), CNGA3 (n = 3), CNGB3 (n = 6), RPGR (n = 5) and RS1 (n = 7). The early introduction of genetic testing in the diagnostic/care pathway for children with IRDs is critical for genetic counselling of these families prior to upcoming gene therapy trials. Herein, we describe the pathway used, the clinical and genetic findings, and the therapeutic implications of the first systematic coordinated round of genetic testing of a paediatric IRD cohort in Ireland.


Subject(s)
COVID-19 , Retinal Degeneration , Antigens, Neoplasm , Cell Cycle Proteins/genetics , Child , Cytoskeletal Proteins/genetics , Electrophysiology , Eye Proteins/genetics , Genetic Testing , Humans , Retinal Degeneration/diagnosis , Retinal Degeneration/genetics , Retinal Degeneration/therapy , SARS-CoV-2
5.
Aging (Albany NY) ; 14(4): 1597-1610, 2022 02 16.
Article in English | MEDLINE | ID: covidwho-1689674

ABSTRACT

BACKGROUND: COVID-19 survivors report residual lung abnormalities after discharge from the hospital. The aim of this study was to identify biomarkers in serum and induced sputum samples from patients after hospitalization for COVID-19. METHODS: Patients admitted to hospitals in Spain with laboratory-confirmed COVID-19 were recruited for this study. SARS-CoV-2-infected patients were divided into groups with mild/moderate and severe disease according to the severity of their symptoms during hospitalization. Levels of 92 biomarkers were measured in serum and induced sputum samples. RESULTS: A total of 108 patients (46.2% severe cases) were included in this study. The median number of days after the onset of symptoms was 104. A significant difference was observed in diffusing capacity for carbon monoxide (DLCO), an indicator of lung function, whereby DLCO <80% was significantly lower in severe cases (p <0.001). Differences in inflammatory biomarkers were observed between patients with mild/moderate and severe disease. For some biomarkers, correlations in serum and induced sputum levels were detected. Independent predictors of severe disease were DLCO <80% and the serum CDCP1 value. CONCLUSIONS: Higher levels of CDCP1 remain after hospital discharge and are associated with the severity of COVID-19. The possible prognostic implications warrant further investigation.


Subject(s)
Antigens, Neoplasm/blood , COVID-19/blood , Cell Adhesion Molecules/blood , Antigens, Neoplasm/analysis , Biomarkers/blood , Cell Adhesion Molecules/analysis , Female , Humans , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Sputum/chemistry
6.
MAbs ; 13(1): 1978130, 2021.
Article in English | MEDLINE | ID: covidwho-1442969

ABSTRACT

Recent years have seen unparalleled development of microfluidic applications for antibody discovery in both academic and pharmaceutical research. Microfluidics can support native chain-paired library generation as well as direct screening of antibody secreting cells obtained by rodent immunization or from the human peripheral blood. While broad diversities of neutralizing antibodies against infectious diseases such as HIV, Ebola, or COVID-19 have been identified from convalescent individuals, microfluidics can expedite therapeutic antibody discovery for cancer or immunological disease indications. In this study, a commercially available microfluidic device, Cyto-Mine, was used for the rapid identification of natively paired antibodies from rodents or human donors screened for specific binding to recombinant antigens, for direct screening with cells expressing the target of interest, and, to our knowledge for the first time, for direct broad functional IgG antibody screening in droplets. The process time from cell preparation to confirmed recombinant antibodies was four weeks. Application of this or similar microfluidic devices and methodologies can accelerate and enhance pharmaceutical antibody hit discovery.


Subject(s)
Antibodies, Neutralizing/isolation & purification , Immunoglobulin G/isolation & purification , Microfluidics/methods , Animals , Antibodies, Bacterial/immunology , Antibodies, Bacterial/isolation & purification , Antibodies, Monoclonal/isolation & purification , Antibodies, Viral/isolation & purification , Antibody Specificity , Antigens/immunology , Antigens, Neoplasm/immunology , Blood Preservation , COVID-19/immunology , Fluorescence Resonance Energy Transfer , Humans , Hybridomas/immunology , Immunomagnetic Separation , Lab-On-A-Chip Devices , Mice , Microfluidics/instrumentation , Muromonab-CD3/immunology , Plasma Cells , Recombinant Proteins/immunology , SARS-CoV-2/immunology , Tetanus Toxoid/immunology , Vaccination
7.
Eur J Immunol ; 51(12): 3194-3201, 2021 12.
Article in English | MEDLINE | ID: covidwho-1437042

ABSTRACT

Accelerate lung repair in SARS-CoV-2 pneumonia is essential for pandemic handling. Innate lymphoid cells (ILCs) are likely players, given their role in mucosal protection and tissue homeostasis. We studied ILC subpopulations at two time points in a cohort of patients admitted in the hospital due to SARS-CoV-2 infection. COVID-19 patients with moderate/severe respiratory failure featured profound depletion of circulating ILCs at hospital admission, in agreement with overall lymphocyte depletion. However, ILCs recovered in direct correlation with lung function improvement as measured by oxygenation index and in negative association with inflammatory and lung/endothelial damage markers like RAGE. While both ILC1 and ILC2 expanded, ILC2 showed the most striking phenotype changes, with CCR10 upregulation in strong correlation with these parameters. Overall, CCR10+ ILC2 emerge as relevant contributors to SARS-CoV-2 pneumonia recovery.


Subject(s)
Biomarkers/metabolism , COVID-19/immunology , Lung/pathology , Lymphocytes/immunology , Pneumonia, Viral/immunology , Receptors, CCR10/metabolism , SARS-CoV-2/physiology , Adult , Aged , Antigens, Neoplasm/metabolism , Cell Proliferation , Cytokines/metabolism , Female , Humans , Immunity, Innate , Male , Middle Aged , Mitogen-Activated Protein Kinases/metabolism , Recovery of Function , Th2 Cells/immunology , Up-Regulation
9.
J Nucl Med ; 61(12): 1717-1719, 2020 12.
Article in English | MEDLINE | ID: covidwho-1369627

ABSTRACT

The true impact and long-term damage to organs such as the lungs after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain to be determined. Noninvasive molecularly targeted imaging may play a critical role in aiding visualization and understanding of the systemic damage. We have identified αvß6 as a molecular target; an epithelium-specific cell surface receptor that is low or undetectable in healthy adult epithelium but upregulated in select injured tissues, including fibrotic lung. Herein we report the first human PET/CT images using the integrin αvß6-binding peptide (18F-αvß6-BP) in a patient 2 mo after the acute phase of infection. Minimal uptake of 18F-αvß6-BP was noted in normal lung parenchyma, with uptake being elevated in areas corresponding to opacities on CT. This case suggests that 18F-αvß6-BP PET/CT is a promising noninvasive approach to identify the presence and potentially monitor the persistence and progression of lung damage.


Subject(s)
Antigens, Neoplasm/metabolism , COVID-19/diagnostic imaging , COVID-19/metabolism , Integrins/metabolism , Lung/diagnostic imaging , Positron Emission Tomography Computed Tomography , Aged , Humans , Male
10.
J Immunol ; 206(12): 2819-2827, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1261380

ABSTRACT

The etiology and pathology of Kawasaki disease (KD) remain elusive. Cub domain-containing protein 1 (CDCP1), a cell-surface protein that confers poor prognosis of patients with certain solid tumors, was recently identified as one of the most significantly upregulated genes in SARS-CoV-2-infected children who developed systemic vasculitis, a hallmark of KD. However, a potential role of CDCP1 in KD has not previously been explored. In this study, we found that CDCP1 knockout (KO) mice exhibited attenuated coronary and aortic vasculitis and decreased serum Candida albicans water-soluble fraction (CAWS)-specific IgM/IgG2a and IL-6 concentrations compared with wild-type mice in an established model of KD induced by CAWS administration. CDCP1 expression was not detectable in cardiomyocytes, cardio fibroblasts, or coronary endothelium, but constitutive expression of CDCP1 was observed on dendritic cells (DCs) and was upregulated by CAWS stimulation. CAWS-induced IL-6 production was significantly reduced in CDCP1 KO DCs, in association with impaired Syk-MAPK signaling pathway activation. These novel findings suggest that CDCP1 might regulate KD development by modulating IL-6 production from DCs via the Syk-MAPK signaling pathway.


Subject(s)
Antigens, Neoplasm/immunology , Cell Adhesion Molecules/immunology , Dendritic Cells/immunology , Disease Models, Animal , Mucocutaneous Lymph Node Syndrome/immunology , Animals , Cell Adhesion Molecules/deficiency , Cells, Cultured , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout
11.
Nat Commun ; 12(1): 3406, 2021 06 07.
Article in English | MEDLINE | ID: covidwho-1260941

ABSTRACT

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.


Subject(s)
COVID-19/prevention & control , Critical Care/statistics & numerical data , Proteomics/methods , RNA, Viral/genetics , SARS-CoV-2/genetics , Adult , Animals , Antibodies, Neutralizing/immunology , Antigens, Neoplasm/metabolism , Biomarkers, Tumor/metabolism , C-Reactive Protein/metabolism , COVID-19/metabolism , COVID-19/virology , Female , HEK293 Cells , Humans , Kaplan-Meier Estimate , Male , Middle Aged , RNA, Viral/blood , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Serum Amyloid P-Component/metabolism , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Viral Load/immunology
13.
J Clin Invest ; 131(9)2021 05 03.
Article in English | MEDLINE | ID: covidwho-1223642

ABSTRACT

Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. Using microdissection and next-generation RNA-Seq, we identified 5 genes, including Mapk8ip2, Cdkn1a, Itgb6, Rgs4, and Ccl2, that were most upregulated in proliferating BECs after acute injury. Immunohistochemical analyses confirmed robust upregulation of integrin αvß6 (ITGß6) expression in this BEC injury model, after bile duct ligation, and in patients with chronic cholangiopathies. Deletion of the Itgb6 gene attenuated BEC proliferation after acute bile duct injury. Macrophage depletion or Ccr2 deficiency impaired ITGß6 expression and BEC proliferation. In vitro experiments revealed that bile acid-activated monocytes promoted BEC proliferation through ITGß6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGß6, which work together to promote BEC proliferation and therefore represent potential therapeutic targets for cholangiopathies.


Subject(s)
Antigens, Neoplasm/biosynthesis , Bile Acids and Salts/metabolism , Biliary Tract/metabolism , Cell Proliferation , Epithelial Cells/metabolism , Integrins/biosynthesis , Macrophage Activation , Macrophages/metabolism , Up-Regulation , Animals , Antigens, Neoplasm/genetics , Bile Acids and Salts/genetics , Female , Humans , Integrins/genetics , Male , Mice , Mice, Transgenic , RNA-Seq
14.
Biomarkers ; 26(2): 114-118, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1165038

ABSTRACT

INTRODUCTION: Coronavirus disease-2019 (COVID-19) with lung involvement frequently causes morbidity and mortality. Advanced age appears to be the most important risk factor. The receptor for advanced glycation end-product (RAGE) pathway is considered to play important roles in the physiological aging and pathogenesis of lung diseases. This study aimed to investigate the possible relationship between COVID-19 and RAGE pathway. MATERIALS AND METHODS: This study included 23 asymptomatic patients and 35 patients with lung involvement who were diagnosed with COVID-19 as well as 22 healthy volunteers. Lung involvement was determined using computed tomography. Serum soluble-RAGE (sRAGE) levels were determined using enzyme-linked immunosorbent assay. RESULTS: The sRAGE levels were significantly higher in the asymptomatic group than in the control group. Age, fibrinogen, C-reactive protein, and ferritin levels were higher and the sRAGE level was lower in the patients with lung involvement than in the asymptomatic patients. CONCLUSIONS: In this study, patients with high sRAGE levels were younger and had asymptomatic COVID-19. Patients with low sRAGE levels were elderly patients with lung involvement, which indicates that the RAGE pathway plays an important role in the aggravation of COVID-19.


Subject(s)
Antigens, Neoplasm/metabolism , COVID-19/physiopathology , Mitogen-Activated Protein Kinases/metabolism , Signal Transduction , Adult , Aged , Aging , COVID-19/complications , Case-Control Studies , Cross-Sectional Studies , Female , Humans , Lung/diagnostic imaging , Male , Middle Aged , Pneumonia/diagnostic imaging , Pneumonia/etiology , Tomography, X-Ray Computed
15.
Mol Cancer ; 20(1): 52, 2021 03 15.
Article in English | MEDLINE | ID: covidwho-1136226

ABSTRACT

In vitro-transcribed messenger RNA-based therapeutics represent a relatively novel and highly efficient class of drugs. Several recently published studies emphasize the potential efficacy of mRNA vaccines in treating different types of malignant and infectious diseases where conventional vaccine strategies and platforms fail to elicit protective immune responses. mRNA vaccines have lately raised high interest as potent vaccines against SARS-CoV2. Direct application of mRNA or its electroporation into dendritic cells was shown to induce polyclonal CD4+ and CD8+ mediated antigen-specific T cell responses as well as the production of protective antibodies with the ability to eliminate transformed or infected cells. More importantly, the vaccine composition may include two or more mRNAs coding for different proteins or long peptides. This enables the induction of polyclonal immune responses against a broad variety of epitopes within the encoded antigens that are presented on various MHC complexes, thus avoiding the restriction to a certain HLA molecule or possible immune escape due to antigen-loss. The development and design of mRNA therapies was recently boosted by several critical innovations including the development of technologies for the production and delivery of high quality and stable mRNA. Several technical obstacles such as stability, delivery and immunogenicity were addressed in the past and gradually solved in the recent years.This review will summarize the most recent technological developments and application of mRNA vaccines in clinical trials and discusses the results, challenges and future directions with a special focus on the induced innate and adaptive immune responses.


Subject(s)
Cancer Vaccines/genetics , Cancer Vaccines/immunology , Neoplasms/etiology , Neoplasms/therapy , RNA, Messenger/genetics , RNA, Messenger/immunology , Animals , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Cancer Vaccines/administration & dosage , Drug Delivery Systems , Gene Expression Regulation, Neoplastic , Gene Transfer Techniques , Humans , Immunity , Immunotherapy , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Neoplasms/pathology , RNA Stability , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
16.
Crit Care ; 25(1): 74, 2021 02 19.
Article in English | MEDLINE | ID: covidwho-1090628

ABSTRACT

BACKGROUND: Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. METHODS: This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. RESULTS: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). CONCLUSIONS: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.


Subject(s)
Biomarkers/analysis , Lung Injury/diagnosis , Respiration, Artificial/adverse effects , Aged , Antigens, Neoplasm/analysis , Antigens, Neoplasm/blood , Area Under Curve , COVID-19/blood , COVID-19/prevention & control , Cohort Studies , E-Selectin/analysis , E-Selectin/blood , Female , Humans , Intensive Care Units/organization & administration , Intensive Care Units/statistics & numerical data , Intercellular Adhesion Molecule-1/analysis , Intercellular Adhesion Molecule-1/blood , Lung Injury/blood , Lung Injury/physiopathology , Male , Middle Aged , Mitogen-Activated Protein Kinases/analysis , Mitogen-Activated Protein Kinases/blood , P-Selectin/analysis , P-Selectin/blood , Prospective Studies , ROC Curve , Respiration, Artificial/standards , Respiration, Artificial/statistics & numerical data , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/physiopathology , Versicans/analysis , Versicans/blood , Vesicular Transport Proteins/analysis , Vesicular Transport Proteins/blood
17.
Nutrients ; 13(2)2021 Feb 03.
Article in English | MEDLINE | ID: covidwho-1067767

ABSTRACT

African Americans have higher incidence of, and mortality from, many health-related problems than European Americans. They also have a 15 to 20-fold higher prevalence of severe vitamin D deficiency. Here we summarize evidence that: (i) this health disparity is partly due to insufficient vitamin D production, caused by melanin in the skin blocking the UVB solar radiation necessary for its synthesis; (ii) the vitamin D insufficiency is exacerbated at high latitudes because of the combination of dark skin color with lower UVB radiation levels; and (iii) the health of individuals with dark skin can be markedly improved by correcting deficiency and achieving an optimal vitamin D status, as could be obtained by supplementation and/or fortification. Moderate-to-strong evidence exists that high 25-hydroxyvitamin D levels and/or vitamin D supplementation reduces risk for many adverse health outcomes including all-cause mortality rate, adverse pregnancy and birth outcomes, cancer, diabetes mellitus, Alzheimer's disease and dementia, multiple sclerosis, acute respiratory tract infections, COVID-19, asthma exacerbations, rickets, and osteomalacia. We suggest that people with low vitamin D status, which would include most people with dark skin living at high latitudes, along with their health care provider, consider taking vitamin D3 supplements to raise serum 25-hydroxyvitamin D levels to 30 ng/mL (75 nmol/L) or possibly higher.


Subject(s)
COVID-19/etiology , COVID-19/prevention & control , Cholecalciferol/administration & dosage , Dietary Supplements , Health Status Disparities , Vitamin D Deficiency/ethnology , Vitamin D Deficiency/epidemiology , African Americans , Alzheimer Disease/etiology , Alzheimer Disease/prevention & control , Antigens, Neoplasm , Dementia/etiology , Dementia/prevention & control , Diabetes Mellitus/etiology , Diabetes Mellitus/prevention & control , Female , Humans , Male , Prevalence , Status Asthmaticus/etiology , Status Asthmaticus/prevention & control , Vitamin D/analogs & derivatives , Vitamin D/blood , Vitamin D Deficiency/complications
18.
Proteins ; 89(4): 416-426, 2021 04.
Article in English | MEDLINE | ID: covidwho-947002

ABSTRACT

To greatly expand the druggable genome, fast and accurate predictions of cryptic sites for small molecules binding in target proteins are in high demand. In this study, we have developed a fast and simple conformational sampling scheme guided by normal modes solved from the coarse-grained elastic models followed by atomistic backbone refinement and side-chain repacking. Despite the observations of complex and diverse conformational changes associated with ligand binding, we found that simply sampling along each of the lowest 30 modes is near optimal for adequately restructuring cryptic sites so they can be detected by existing pocket finding programs like fpocket and concavity. We further trained machine-learning protocols to optimize the combination of the sampling-enhanced pocket scores with other dynamic and conservation scores, which only slightly improved the performance. As assessed based on a training set of 84 known cryptic sites and a test set of 14 proteins, our method achieved high accuracy of prediction (with area under the receiver operating characteristic curve >0.8) comparable to the CryptoSite server. Compared with CryptoSite and other methods based on extensive molecular dynamics simulation, our method is much faster (1-2 hours for an average-size protein) and simpler (using only pocket scores), so it is suitable for high-throughput processing of large datasets of protein structures at the genome scale.


Subject(s)
Binding Sites , Computational Biology/methods , Ligands , Machine Learning , Algorithms , Antigens, CD/chemistry , Antigens, Neoplasm/chemistry , Area Under Curve , Coronavirus 3C Proteases/chemistry , Coronavirus Papain-Like Proteases/chemistry , Elasticity , Hepacivirus , Humans , Interleukin-2/chemistry , Karyopherins/chemistry , Models, Statistical , Molecular Dynamics Simulation , Protein Conformation , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , ROC Curve , Receptors, Cytoplasmic and Nuclear/chemistry , Regression Analysis , Reproducibility of Results , SARS-CoV-2
19.
FASEB J ; 34(11): 14103-14119, 2020 11.
Article in English | MEDLINE | ID: covidwho-787296

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has provoked major stresses on the health-care systems of several countries, and caused the death of more than a quarter of a million people globally, mainly in the elderly population with preexisting pathologies. Previous studies with coronavirus (SARS-CoV) point to gender differences in infection and disease progression with increased susceptibility in male patients, indicating that estrogens may be associated with physiological protection against the coronavirus. Therefore, the objectives of this work are threefold. First, we aim to summarize the SARS-CoV-2 infection pathway and the roles both the virus and patient play in COVID-19 (Coronavirus disease 2019) progression, clinical symptomatology, and mortality. Second, we detail the effect estrogen has on viral infection and host infection response, including its role in both the regulation of key viral receptor expression and the mediation of inflammatory activity. Finally, we describe how ERs (estrogen receptors) and RAGE (receptor for advanced glycation end-products) play a critical role in metabolic pathways, which we envisage could maintain a close interplay with SARS-CoV and COVID-19 mortality rates, despite a current lack of research directly determining how. Taken together, we present the current state of the field regarding SARS-CoV-2 research and illuminate where research is needed to better define the role both estrogen and metabolic comorbidities have in the COVID-19 disease state, which can be key in screening potential therapeutic options as the search for effective treatments continue.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Age Factors , Angiotensin-Converting Enzyme 2 , Animals , Antigens, Neoplasm/metabolism , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Disease Susceptibility , Estrogens/metabolism , Female , Humans , Lung/pathology , Male , Mitogen-Activated Protein Kinases/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Receptors, Estrogen/metabolism , SARS-CoV-2 , Sex Factors , Signal Transduction
SELECTION OF CITATIONS
SEARCH DETAIL