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1.
Sci Rep ; 12(1): 4163, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1799572

ABSTRACT

SARS-CoV-2 and its variants have persisted in this ongoing COVID-19 pandemic. While the vaccines have greatly reduced the COVID-19 cases, hospitalizations, and death, about half of the world remain unvaccinated due to various reasons. Furthermore, the duration of the immunity gained from COVID-19 vaccination is still unclear. Therefore, there is a need for innovative prophylactic and treatment measures. In response to this need, we previously reported on the successful computer-aided development of potent VHH-based multispecific antibodies that were characterized in vitro. Here, we evaluated in vivo efficacy and safety of the lead trispecific VHH-Fc, ABS-VIR-001. Importantly, our data showed that ABS-VIR-001 treatment prevented SARS-CoV-2 infection and death when provided as an intranasal prophylaxis in a humanized ACE-2 mouse model. In addition, ABS-VIR-001 post-exposure treatment was shown to greatly reduce viral loads by as much as 50-fold. A detailed panel of metabolic and cellular parameters demonstrated that ABS-VIR-001 treatment was overall comparable to the PBS treatment, indicating a favorable safety profile. Notably, our inhibition studies show that ABS-VIR-001 continued to demonstrate unwavering efficacy against SARS-CoV-2 mutants, associated with key variants including Delta and Omicron, owing to its multiple epitope design. Lastly, we rigorously tested and confirmed the excellent thermostability of ABS-VIR-001 when heated to 45 °C for up to 4 weeks. Taken together, our study suggests that ABS-VIR-001 is an efficacious and durable prophylaxis and post-exposure treatment for COVID-19 with promising safety and manufacturability features for global distribution.


Subject(s)
COVID-19/drug therapy , SARS-CoV-2/physiology , Single-Domain Antibodies/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antigen-Antibody Reactions/drug effects , Biomarkers/metabolism , COVID-19/virology , Drug Stability , Humans , Immunocompromised Host , Mice , Mice, Transgenic , SARS-CoV-2/isolation & purification , Single-Domain Antibodies/immunology , Single-Domain Antibodies/pharmacology , Spike Glycoprotein, Coronavirus/immunology , Viral Load
2.
Int J Mol Sci ; 23(7)2022 Mar 28.
Article in English | MEDLINE | ID: covidwho-1785733

ABSTRACT

Patients with head and neck cancer (HNC) and patients with primary Sjögren's syndrome (pSS) may exhibit similar symptoms of dry mouth and dry eyes, as a result of radiotherapy (RT) or a consequence of disease progression. To identify the proteins that may serve as promising disease biomarkers, we analysed saliva and tears from 29 radiated HNC patients and 21 healthy controls, and saliva from 14 pSS patients by mass spectrometry-based proteomics. The study revealed several upregulated, and in some instances overlapping, proteins in the two patient groups. Histone H1.4 and neutrophil collagenase were upregulated in whole saliva of both patient groups, while caspase-14, histone H4, and protein S100-A9 were upregulated in HNC saliva only. In HCN tear fluid, the most highly upregulated protein was mucin-like protein 1. These overexpressed proteins in saliva and tears play central roles in inflammation, host cell injury, activation of reactive oxygen species, and tissue repair. In conclusion, the similarities and differences in overexpressed proteins detected in saliva from HNC and pSS patients may contribute to the overall understanding of the different pathophysiological mechanisms inducing dry mouth. Thus, the recurring proteins identified could possibly serve as future promising biomarkers.


Subject(s)
Head and Neck Neoplasms , Sjogren's Syndrome , Xerostomia , Biomarkers/metabolism , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/radiotherapy , Histones/metabolism , Humans , Neoplasm Recurrence, Local/metabolism , Proteomics , Saliva/metabolism , Sjogren's Syndrome/metabolism , Tears/metabolism , Xerostomia/metabolism
3.
Int J Environ Res Public Health ; 19(6)2022 03 14.
Article in English | MEDLINE | ID: covidwho-1742456

ABSTRACT

Chronic low-grade inflammation that accompanies aging is associated with adverse health outcomes and may exacerbate the severity of infectious disease such as COVID-19. Resistance training (RT) has the potential to improve chronic low-grade inflammation, but the evidence remains inconclusive. This study evaluated the effects of RT on chronic low-grade inflammation in elderly adults. MEDLINE, EMBASE, Cochrane Library, CINAHL, RISS, NDSL, and KoreaMed were searched. We included studies that assessed the effect of RT on C-reactive protein (CRP), interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α in those aged ≥60 years. The effect size was estimated using fixed or random-effects models. Subgroup analysis was performed regarding age, health status, training method, number of exercises, intensity, weekly frequency, and duration. In the 18 randomized controlled trials (539 patients) included, RT was effective in alleviating CRP (effect size = -0.72, 95% confidence interval = -1.06 to -0.38, p < 0.001), IL-10 (-3.34, -6.16 to -0.53, p = 0.02), and TNF-α (-0.56, -1.08 to -0.03, p = 0.04) in elderly adults and tended to reduce IL-6 (-0.59, -1.18 to 0.00, p = 0.05). Subgroup analyses showed CRP reduction regardless of age, training method, number of exercises, intensity, weekly frequency, and duration. RT can be used to ameliorate chronic low-grade inflammation in elderly adults.


Subject(s)
COVID-19 , Resistance Training , Aged , Biomarkers/metabolism , C-Reactive Protein/analysis , Cytokines , Humans , Middle Aged , Randomized Controlled Trials as Topic
4.
Front Immunol ; 13: 838448, 2022.
Article in English | MEDLINE | ID: covidwho-1742220

ABSTRACT

Basophils play a key role in the orientation of immune responses. Though the interaction of SARS-CoV-2 with various immune cells has been relatively well studied, the response of basophils to this pandemic virus is not characterized yet. In this study, we report that SARS-CoV-2 induces cytokine responses and in particular IL-13, in both resting and IL-3 primed basophils. The response was prominent under IL-3 primed condition. However, either SARS-CoV-2 or SARS-CoV-2-infected epithelial cells did not alter the expression of surface markers associated with the activation of basophils, such as CD69, CD13 and/or degranulation marker CD107a. We also validate that human basophils are not permissive to SARS-CoV-2 replication. Though increased expression of immune checkpoint molecule PD-L1 has been reported on the basophils from COVID-19 patients, we observed that SARS-CoV-2 does not induce PD-L1 on the basophils. Our data suggest that basophil cytokine responses to SARS-CoV-2 might help in reducing the inflammation and also to promote antibody responses to the virus.


Subject(s)
Basophils/immunology , COVID-19/immunology , Interleukin-13/metabolism , SARS-CoV-2/physiology , B7-H1 Antigen/metabolism , Biomarkers/metabolism , Cells, Cultured , Humans , Interleukin-3/metabolism , Virus Replication
5.
Front Immunol ; 13: 820350, 2022.
Article in English | MEDLINE | ID: covidwho-1731777

ABSTRACT

Growth differentiation factor 15 (GDF-15) is a transforming growth factor (TGF)-ß superfamily cytokine that plays a central role in metabolism regulation. Produced in response to mitochondrial stress, tissue damage or hypoxia, this cytokine has emerged as one of the strongest predictors of disease severity during inflammatory conditions, cancers and infections. Reports suggest that GDF-15 plays a tissue protective role via sympathetic and metabolic adaptation in the context of mitochondrial damage, although the exact mechanisms involved remain uncertain. In this review, we discuss the emergence of GDF-15 as a distinctive marker of viral infection severity, especially in the context of COVID-19. We will critically review the role of GDF-15 as an inflammation-induced mediator of disease tolerance, through metabolic and immune reprogramming. Finally, we discuss potential mechanisms of GDF-15 elevation during COVID-19 cytokine storm and its limitations. Altogether, this cytokine seems to be involved in disease tolerance to viral infections including SARS-CoV-2, paving the way for novel therapeutic interventions.


Subject(s)
Adaptation, Psychological/physiology , Biomarkers/metabolism , COVID-19/metabolism , Growth Differentiation Factor 15/metabolism , Animals , COVID-19/virology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Cytokines/metabolism , Humans
6.
Biomark Med ; 16(5): 317-330, 2022 04.
Article in English | MEDLINE | ID: covidwho-1703144

ABSTRACT

Aim: To investigate the serum circulating DPP4 activity in patients with COVID-19 disease. Materials & methods: Serum samples from 102 hospitalized COVID-19 patients and 43 post-COVID-19 plasma donors and 39 SARS-CoV-2 naive controls and their medical data were used. Circulating DPP4 activities according to different COVID-19 disease peak severity (WHO) groups at sampling and at peak were assessed. Results: A significant decrease (p < 0.0001) in serum DPP4 activity was found in study groups of higher disease severity. When the circulating DPP4 activity was assessed as a prognostic marker, the logistic regression (p = 0.0023) indicated that the enzyme activity is a predictor of mortality (median 9.5 days before death) with receiver operating characteristic area under the curves of 73.33% (p[area = 0.5] < 0.0001) as single predictor and 83.45% (p[area = 0.5] < 0.0001) in combination with age among hospitalized patients with COVID-19. Conclusion: Decreased circulating DPP4 activity is associated with severe COVID-19 disease and is a strong prognostic biomarker of mortality.


Subject(s)
Biomarkers/blood , COVID-19/blood , Dipeptidyl Peptidase 4/blood , Inpatients/statistics & numerical data , Adult , Aged , Biomarkers/metabolism , C-Reactive Protein/metabolism , COVID-19/diagnosis , COVID-19/therapy , Dipeptidyl Peptidase 4/metabolism , Female , Humans , Interleukin-6/blood , Interleukin-6/metabolism , Logistic Models , Male , Middle Aged , Multivariate Analysis , Prognosis , ROC Curve , Retrospective Studies , SARS-CoV-2/physiology , Severity of Illness Index
7.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1194: 123184, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1701949

ABSTRACT

INTRODUCTION: Ferritin is the major iron-storage glycoprotein found in all tissues. Ferritin glycosylation can be assessed by the differential affinities of ferritin glycoforms for Concanavalin A (ConA), a lectin. The fraction of serum ferritin bound to ConA is called "glycosylated ferritin" (GF). Low GF reflects macrophagic activation and is an essential biomarker used in adult-onset Still's disease (AOSD), macrophage activation syndrome (MAS) and Gaucher disease diagnosis and therapeutic management. To date, no complete assay description and method validation according to the ISO 15189 standard has been published. This study aimed to describe and validate our method used for GF measurement and describe GF values observed in patients. MATERIALS AND METHODS: Ferritin glycoforms were separated based on their affinities for ConA using commercially available TRIS-barbital buffer, Sepharose and ConA/Sepharose 4B gels. Ferritin concentrations were measured on the Siemens Dimension Vista 1500®. We analysed 16,843 GF values obtained between 2000 and 2021 from our database of patients. RESULTS: Optimal separation of ferritin glycoforms was obtained by 15-min incubation of serum with ConA/Sepharose at pH 8. The optimized volume were 0.4 mL for total serum ferritin (TSF) 30-1000 µg/L and 0.5 mL for TSF 1000-2500 µg/L. Serum with higher TSF should be pre-diluted in the TRIS-barbital buffer. Reproducibility of ferritin measurement in the TRIS-barbital buffer matrix was excellent (intra-assay CV < 1%; inter-assay CV < 4%). Reproducibility of GF assay was good (intra-assay CV < 10% for low and high ferritin samples, respectively; and inter-assay CV < 10%). Inter-operator variability was 21.6% for GF < 20%. Ferritin was stable for up to 3 days in the TRIS-barbital buffer. An inter-laboratory exchange program conducted with another French hospital showed good agreement between results. In our database, <20% GF levels were scarce, compatible with the low prevalence of Still's disease, MAS, and Gaucher disease. The 95% confidence interval for GF was [26-58]%, lower than values described in the literature for healthy individuals. CONCLUSION: Thanks to good performances, this technique can become readily available for laboratories servicing patients with AOSD, MAS (including severe COVID-19 patients) and Gaucher disease patients.


Subject(s)
Chemistry Techniques, Analytical/methods , Concanavalin A/metabolism , Ferritins/blood , Macrophage Activation Syndrome/blood , Still's Disease, Adult-Onset/blood , Biomarkers/blood , Biomarkers/metabolism , Ferritins/metabolism , Gaucher Disease/blood , Gaucher Disease/metabolism , Humans , Macrophage Activation Syndrome/metabolism , Protein Binding , Still's Disease, Adult-Onset/metabolism
8.
Nat Cell Biol ; 23(12): 1240-1254, 2021 12.
Article in English | MEDLINE | ID: covidwho-1699219

ABSTRACT

Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer's disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.


Subject(s)
Extracellular Vesicles/metabolism , MicroRNAs/metabolism , Nanoparticles/metabolism , Alzheimer Disease/pathology , Angiotensin-Converting Enzyme 2/metabolism , Biological Transport/physiology , Biomarkers/metabolism , COVID-19/pathology , Cardiovascular Diseases/pathology , Cell Communication/physiology , Cell Line, Tumor , HeLa Cells , Humans , Lactic Acid/metabolism , MicroRNAs/genetics , Nanoparticles/classification , Neoplasms/pathology , Tumor Microenvironment
9.
Brain Behav Immun ; 102: 89-97, 2022 May.
Article in English | MEDLINE | ID: covidwho-1682933

ABSTRACT

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.


Subject(s)
COVID-19 , Pandemics , Biomarkers/metabolism , Brain/metabolism , Communicable Disease Control , Humans , Receptors, GABA/metabolism , SARS-CoV-2
10.
EBioMedicine ; 76: 103856, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1676708

ABSTRACT

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Guanidines/therapeutic use , Administration, Intravenous , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Benzamidines/adverse effects , Benzamidines/pharmacokinetics , Biomarkers/blood , Biomarkers/metabolism , COVID-19/mortality , COVID-19/virology , Drug Administration Schedule , Female , Guanidines/adverse effects , Guanidines/pharmacokinetics , Half-Life , Humans , Immunophenotyping , Kaplan-Meier Estimate , Male , Middle Aged , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Treatment Outcome , Viral Load
11.
Psychoneuroendocrinology ; 138: 105645, 2022 04.
Article in English | MEDLINE | ID: covidwho-1671062

ABSTRACT

BACKGROUND: The COVID-19 pandemic has put chronic pressure on worldwide healthcare systems. While the literature regarding the prevalence of psychological distress and associated risk factors among healthcare workers facing COVID-19 has exploded, biological variables have been mostly overlooked. METHODS: 467 healthcare workers from Quebec, Canada, answered an electronic survey covering various risk factors and mental health outcomes three months after the onset of the COVID-19 pandemic. Of them, 372 (80%) provided a hair sample, providing a history of cortisol secretion for the three months preceding and following the pandemic's start. We used multivariable regression models and a receiver operating characteristic curve to study hair cortisol as a predictor of burnout and psychological health, together with individual, occupational, social, and organizational factors. RESULTS: As expected, hair cortisol levels increased after the start of the pandemic, with a median relative change of 29% (IQR = 3-59%, p < 0.0001). There was a significant association between burnout status and change in cortisol, with participants in the second quarter of change having lower odds of burnout. No association was found between cortisol change and post-traumatic stress disorder, anxiety, and depression symptoms. Adding cortisol to individual-occupational-socio-organizational factors noticeably enhanced our burnout logistic regression model's predictability. CONCLUSION: Change in hair cortisol levels predicted burnout at three months in health personnel at the onset of the COVID-19 pandemic. This non-invasive biological marker of the stress response could be used in further clinical or research initiatives to screen high-risk individuals to prevent and control burnout in health personnel facing an important stressor.


Subject(s)
Burnout, Professional , COVID-19 , Hair , Health Personnel , Hydrocortisone , Biomarkers/metabolism , Burnout, Professional/epidemiology , COVID-19/epidemiology , COVID-19/psychology , Hair/chemistry , Health Personnel/psychology , Humans , Hydrocortisone/metabolism , Pandemics , Quebec/epidemiology
12.
Cell ; 185(5): 881-895.e20, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1649960

ABSTRACT

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.


Subject(s)
COVID-19/complications , COVID-19/diagnosis , Convalescence , Adaptive Immunity/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Autoantibodies/blood , Biomarkers/metabolism , Blood Proteins/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Disease Progression , Female , Humans , Immunity, Innate/genetics , Longitudinal Studies , Male , Middle Aged , Risk Factors , SARS-CoV-2/isolation & purification , Transcriptome , Young Adult
14.
Angew Chem Int Ed Engl ; 61(9): e202112995, 2022 02 21.
Article in English | MEDLINE | ID: covidwho-1633678

ABSTRACT

The transmission of SARS-CoV-2 coronavirus has led to the COVID-19 pandemic. Nucleic acid testing while specific has limitations for mass surveillance. One alternative is the main protease (Mpro ) due to its functional importance in mediating the viral life cycle. Here, we describe a combination of modular substrate and gold colloids to detect Mpro via visual readout. The strategy involves zwitterionic peptide that carries opposite charges at the C-/N-terminus to exploit the specific recognition by Mpro . Autolytic cleavage releases a positively charged moiety that assembles the nanoparticles with rapid color changes (t<10 min). We determine a limit of detection for Mpro in breath condensate matrices <10 nM. We further assayed ten COVID-negative subjects and found no false-positive result. In the light of simplicity, our test for viral protease is not limited to an equipped laboratory, but also is amenable to integrating as portable point-of-care devices including those on face-coverings.


Subject(s)
COVID-19/diagnosis , Coronavirus 3C Proteases/metabolism , Peptides/metabolism , SARS-CoV-2/metabolism , Biomarkers/metabolism , Breath Tests , COVID-19/virology , Colorimetry/methods , Humans , Limit of Detection , Proteolysis
15.
Cytokine ; 149: 155755, 2022 01.
Article in English | MEDLINE | ID: covidwho-1632232

ABSTRACT

This study analyzed the levels at admission of biomarkers for their association with and ability to predict risk of severe outcomes, including admission to the ICU, need for invasive mechanical ventilation (IMV), need for vasopressor use (VU), and in-hospital mortality (IHM) in 700 patients hospitalized with COVID-19. Biomarker data split by outcomes was compared using Mann-Whitney U tests; frequencies of biomarker values were compared using Chi-square tests and multivariable logistic regression analysis was performed to look at the impact of biomarkers by outcome. Patients that suffered IHM were more likely to have reduced platelet numbers and high blood urea nitrogen (BUN) levels among patients admitted to the ICU. Risk factors for mortality were related to hyper-coagulability (low platelet count and increased D-dimer) and decreased respiratory (PaO2/FiO2 ratio) and kidney function (BUN). Association with risks of other severe outcomes were as follows: ICU with hyper-inflammation (IL-6) and decreased respiratory function; IMV with low platelet count, abnormal neutrophil-lymphocyte ratio with reduced respiratory function, VU with inflammatory markers (IL-6), and low platelet count with respiratory function. Our studies confirmed the association of biomarkers of hematological, inflammatory, coagulation, pulmonary and kidney functions with disease severity. Whether these biomarkers have any mechanistic or causal role in the disease progress requires further investigation.


Subject(s)
Biomarkers/metabolism , COVID-19/metabolism , COVID-19/pathology , Aged , Female , Hospital Mortality , Hospitalization , Humans , Inflammation/metabolism , Inflammation/pathology , Intensive Care Units , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/pathogenicity , Severity of Illness Index
16.
Elife ; 112022 01 17.
Article in English | MEDLINE | ID: covidwho-1626761

ABSTRACT

Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.


Developing a new drug that is both safe and effective is a complex and expensive endeavor. An alternative approach is to 'repurpose' existing, safe compounds ­ that is, to establish if they could treat conditions others than the ones they were initially designed for. To achieve this, methods that can predict the activity of thousands of established drugs are necessary. These approaches are particularly important for conditions for which it is hard to find promising treatment. This includes, for instance, heart failure, dementia and other diseases that are linked to the activity of the hormone insulin becoming modified throughout the body, a defect called insulin resistance. Unfortunately, it is difficult to model the complex actions of insulin using cells in the lab, because they involve intricate networks of proteins, tissues and metabolites. Timmons et al. set out to develop a way to better assess whether a drug could be repurposed to treat insulin resistance. The aim was to build a biological signature of the disease in multiple human tissues, as this would help to make the findings more relevant to the clinic. This involved examining which genes were switched on or off in thousands of tissue samples from patients with different degrees of insulin resistance. Importantly, some of the patients had their condition reversed through lifestyle changes, while others did not respond well to treatment. These 'non-responders' provided crucial new clues to screen for active drugs. Carefully piecing the data together revealed the molecules and pathways most related to the severity of insulin resistance. Cross-referencing these results with the way existing drugs act on gene activity, highlighted 138 compounds that directly bind 73 proteins responsible for regulating insulin resistance pathways. Some of the drugs identified are suitable for short-term clinical studies, and it may even be possible to rank similar compounds based on their chemical activity. Beyond giving a glimpse into the complex molecular mechanisms of insulin resistance in humans, Timmons et al. provide a fresh approach to how drugs could be repurposed, which could be adapted to other conditions.


Subject(s)
Drug Repositioning , Metabolic Diseases/drug therapy , Adipose Tissue/metabolism , Biomarkers/metabolism , Humans , Insulin Resistance , Metabolic Diseases/genetics , Muscles/metabolism , Transcriptome
17.
Pharmacol Res Perspect ; 10(1): e00911, 2022 02.
Article in English | MEDLINE | ID: covidwho-1625316

ABSTRACT

Infection of humans with SARS-CoV-2 virus causes a disease known colloquially as "COVID-19" with symptoms ranging from asymptomatic to severe pneumonia. Initial pathology is due to the virus binding to the ACE-2 protein on endothelial cells lining blood vessels and entering these cells in order to replicate. Viral replication causes oxidative stress due to elevated levels of reactive oxygen species. Many (~60%) of the infected people appear to have eliminated the virus from their body after 28 days and resume normal activity. However, a significant proportion (~40%) experience a variety of symptoms (loss of smell and/or taste, fatigue, cough, aching pain, "brain fog," insomnia, shortness of breath, and tachycardia) after 12 weeks and are diagnosed with a syndrome named "LONG COVID." Longitudinal clinical studies in a group of subjects who were infected with SARS-CoV-2 have been compared to a non-infected matched group of subjects. A cohort of infected subjects can be identified by a battery of cytokine markers to have persistent, low level grade of inflammation and often self-report two or more troubling symptoms. There is no drug that will relieve their symptoms effectively. It is hypothesized that drugs that activate the intracellular transcription factor, nuclear factor erythroid-derived 2-like 2 (NRF2) may increase the expression of enzymes to synthesize the intracellular antioxidant, glutathione that will quench free radicals causing oxidative stress. The hormone melatonin has been identified as an activator of NRF2 and a relatively safe chemical for most people to ingest chronically. Thus, it is an option for consideration of re-purposing studies in "LONG COVID" subjects experiencing insomnia, depression, fatigue, and "brain fog" but not tachycardia. Appropriately designed clinical trials are required to evaluate melatonin.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/complications , Biomarkers/metabolism , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/virology , Endothelium, Vascular/virology , Humans , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Virus Replication
18.
Sci Rep ; 12(1): 696, 2022 01 13.
Article in English | MEDLINE | ID: covidwho-1621270

ABSTRACT

Despite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.


Subject(s)
Acute Chest Syndrome/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , NF-kappa B/metabolism , Nicotinamide Phosphoribosyltransferase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiology , Animals , Antibodies, Neutralizing/metabolism , Biomarkers/metabolism , COVID-19/metabolism , Disease Models, Animal , Inflammation/metabolism , Lipopolysaccharides/metabolism , Lung/metabolism , Male , Rats , Rats, Sprague-Dawley , SARS-CoV-2/pathogenicity , Swine
19.
PLoS One ; 17(1): e0262342, 2022.
Article in English | MEDLINE | ID: covidwho-1622361

ABSTRACT

PURPOSE: Coronavirus disease-2019 (COVID-19) is associated with a wide spectrum of clinical symptoms including acute respiratory failure. Biomarkers that can predict outcomes in patients with COVID-19 can assist with patient management. The aim of this study is to evaluate whether procalcitonin (PCT) can predict clinical outcome and bacterial superinfection in patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). METHODS: Adult patients diagnosed with SARS-CoV-2 by nasopharyngeal PCR who were admitted to a tertiary care center in Boston, MA with SARS-CoV-2 infection between March 17 and April 30, 2020 with a baseline PCT value were studied. Patients who were presumed positive for SARS-CoV-2, who lacked PCT levels, or who had a positive urinalysis with negative cultures were excluded. Demographics, clinical and laboratory data were extracted from the electronic medical records. RESULTS: 324 patient charts were reviewed and grouped by clinical and microbiologic outcomes by day 28. Baseline PCT levels were significantly higher for patients who were treated for true bacteremia (p = 0.0005) and bacterial pneumonia (p = 0.00077) compared with the non-bacterial infection group. Baseline PCT positively correlated with the NIAID ordinal scale and survival over time. When compared to other inflammatory biomarkers, PCT showed superiority in predicting bacteremia. CONCLUSIONS: Baseline PCT levels are associated with outcome and bacterial superinfection in patients hospitalized with SARS-CoV-2.


Subject(s)
Bacterial Infections/metabolism , COVID-19/metabolism , Procalcitonin/metabolism , Aged , Aged, 80 and over , Biomarkers/metabolism , Boston , Case-Control Studies , Female , Humans , Inflammation/metabolism , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/pathogenicity
20.
Lancet Oncol ; 23(2): 270-278, 2022 02.
Article in English | MEDLINE | ID: covidwho-1616869

ABSTRACT

BACKGROUND: Endoscopic surveillance is recommended for patients with Barrett's oesophagus because, although the progression risk is low, endoscopic intervention is highly effective for high-grade dysplasia and cancer. However, repeated endoscopy has associated harms and access has been limited during the COVID-19 pandemic. We aimed to evaluate the role of a non-endoscopic device (Cytosponge) coupled with laboratory biomarkers and clinical factors to prioritise endoscopy for Barrett's oesophagus. METHODS: We first conducted a retrospective, multicentre, cross-sectional study in patients older than 18 years who were having endoscopic surveillance for Barrett's oesophagus (with intestinal metaplasia confirmed by TFF3 and a minimum Barrett's segment length of 1 cm [circumferential or tongues by the Prague C and M criteria]). All patients had received the Cytosponge and confirmatory endoscopy during the BEST2 (ISRCTN12730505) and BEST3 (ISRCTN68382401) clinical trials, from July 7, 2011, to April 1, 2019 (UK Clinical Research Network Study Portfolio 9461). Participants were divided into training (n=557) and validation (n=334) cohorts to identify optimal risk groups. The biomarkers evaluated were overexpression of p53, cellular atypia, and 17 clinical demographic variables. Endoscopic biopsy diagnosis of high-grade dysplasia or cancer was the primary endpoint. Clinical feasibility of a decision tree for Cytosponge triage was evaluated in a real-world prospective cohort from Aug 27, 2020 (DELTA; ISRCTN91655550; n=223), in response to COVID-19 and the need to provide an alternative to endoscopic surveillance. FINDINGS: The prevalence of high-grade dysplasia or cancer determined by the current gold standard of endoscopic biopsy was 17% (92 of 557 patients) in the training cohort and 10% (35 of 344) in the validation cohort. From the new biomarker analysis, three risk groups were identified: high risk, defined as atypia or p53 overexpression or both on Cytosponge; moderate risk, defined by the presence of a clinical risk factor (age, sex, and segment length); and low risk, defined as Cytosponge-negative and no clinical risk factors. The risk of high-grade dysplasia or intramucosal cancer in the high-risk group was 52% (68 of 132 patients) in the training cohort and 41% (31 of 75) in the validation cohort, compared with 2% (five of 210) and 1% (two of 185) in the low-risk group, respectively. In the real-world setting, Cytosponge results prospectively identified 39 (17%) of 223 patients as high risk (atypia or p53 overexpression, or both) requiring endoscopy, among whom the positive predictive value was 31% (12 of 39 patients) for high-grade dysplasia or intramucosal cancer and 44% (17 of 39) for any grade of dysplasia. INTERPRETATION: Cytosponge atypia, p53 overexpression, and clinical risk factors (age, sex, and segment length) could be used to prioritise patients for endoscopy. Further investigation could validate their use in clinical practice and lead to a substantial reduction in endoscopy procedures compared with current surveillance pathways. FUNDING: Medical Research Council, Cancer Research UK, Innovate UK.


Subject(s)
Adenocarcinoma/pathology , Barrett Esophagus/pathology , COVID-19 , Esophageal Neoplasms/pathology , Patient Selection , Watchful Waiting/methods , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/metabolism , Aged , Barrett Esophagus/diagnostic imaging , Barrett Esophagus/metabolism , Barrett Esophagus/therapy , Biomarkers/metabolism , COVID-19/prevention & control , Clinical Decision-Making , Clinical Trials as Topic , Cross-Sectional Studies , Decision Trees , Disease Progression , Esophageal Neoplasms/diagnostic imaging , Esophageal Neoplasms/metabolism , Esophagoscopy , Feasibility Studies , Female , Humans , Male , Middle Aged , Pilot Projects , Prospective Studies , Retrospective Studies , Risk Assessment , Risk Factors , SARS-CoV-2 , Trefoil Factor-3/metabolism , Tumor Suppressor Protein p53/metabolism
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