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1.
Journal of Public Health in Africa ; 13:23-24, 2022.
Article in English | EMBASE | ID: covidwho-2006772

ABSTRACT

Introduction/ Background: The risk of hospitalisation/death from Covid-19 in the UK is disproportionately high in black populations. In people of African ancestry, variants of the APOL1 gene (G1 and G2) are associated with risk of noncommunicable diseases, and sleeping sickness. We hypothesise that adverse Covid-19 outcomes are also associated with these variants. Methods: The UK Biobank contains genetic, lifestyle, and health information from 7,643 individuals who self-report as being of black ethnicity. Within this cohort there had been 142 hospitalisations and 36 deaths attributed to Covid-19 as of September 2021. Taking risk factors previously associated with poor Covid-19 outcomes (age, sex, chronic kidney disease, atrial fibrillation, hypertension, depression, chronic obstructive pulmonary disease, dementia, type 2 diabetes, obesity, and Townsend deprivation index) as covariates, we used Firth's Bias Reduced Logistic Regression in R to identify APOL1 genotypes that were associated with hospitalisation and death. Results: Individuals who are heterozygous for variants at both the G1 and the G2 loci are termed G1/G2 compound heterozygotes. G1/G2 compound heterozygosity was associated with hospitalisation (odds ratio = 2.4, 95% confidence interval: 1.2-4.5, p = 0.010) and death (odds ratio = 5.4, 95% confidence interval: 1.8-15.4, p = 0.004). This association has not previously been detected in genome wide association studies, as they usually examine individual loci separately rather than considering combinations of loci. Impact: This has implications at the individual and population level by identifying those at higher risk of severe Covid-19 who would benefit from early vaccination and treatment. This is especially relevant to geographical regions where APOL1 G1 and G2 variants are common, such as West and Central Africa and their diaspora. Conclusion: This data supports hypotheses proposing APOL1 genotype (and specifically G1/G2 compound heterozygosity) as a significant contributory factor in the increased rates of poor Covid-19 outcomes observed in people of African ancestry.

2.
Front Oncol ; 12: 915628, 2022.
Article in English | MEDLINE | ID: covidwho-1997473

ABSTRACT

Lung cancer patients with high programmed cell death-ligand 1 (PD-L1) expression in tumor cells and epidermal growth factor receptor (EGFR) mutations are rare, but there is no clinical standard for which treatment such patients should receive. Here, we report a 52-year-old male smoker who was diagnosed with stage IIIB lung adenocarcinoma. A rare EGFR G719A mutation was detected in the lymph node samples by next-generation sequencing (NGS), and a high PD-L1 expression was found by immunohistochemistry (IHC). After 10 cycles of induction therapy (toripalimab plus pemetrexed plus nedaplatin plus apatinib), surgery was successfully performed, followed by 2 cycles of consolidation therapy (toripalimab plus pemetrexed) and 4 cycles of maintenance therapy (toripalimab). A progression-free survival (PFS) of 7 months was achieved. In this case, we showed that the programmed cell death protein 1 (PD-1) inhibitor toripalimab plus chemotherapy and apatinib was effective and tolerable in a locally advanced EGFR-mutant non-small cell lung cancer (NSCLC) patient with a positive PD-L1 expression.

3.
American Journal of Kidney Diseases ; 79(4):S2-S3, 2022.
Article in English | EMBASE | ID: covidwho-1996877

ABSTRACT

Inheritance of the APOL1 G1 or G2 risk alleles in the homozygous or compound heterozygous state, are associated with a ~7-30X increased risk of development of chronic kidney disease (CKD), and with collapsing glomerulopathies in individuals with viral infections including COVID-19 or HIV. Identification of APOL1 high risk genotypes (HRG) can impact patient treatment, prognosis and kidney donor selection. Approximately 13% of African Americans (AA) have an APOL1 HRG, indicating genetic testing in this population can identify those at-risk for CKD development, leading to appropriate patient counseling and management. Here we sought to understand the clinical presentation and variability among patients with APOL1 HRGs, following the implementation of genetic testing for kidney disease with a broad panel at a Louisiana Nephrology clinic. Clinical genetic testing of patient samples was performed using a >380 kidney gene panel (the RenasightTM test, Natera, Inc.) A retrospective review of clinical data for individuals positive for an APOL1 HRG (G1/G1, G2/G2, G1/G2) was performed. We identified 12 patients that were positive for an APOL1 HRG, with all genotypes represented: G1/G1 (n=8), G1/G2 (n=3), and G2/G2 (n=1). Among this cohort, 100% (12/12) were of AA descent. At the time of testing 91% (11/12) of the patients were diagnosed with CKD or ESRD with proteinuria. Biopsy confirmed focal segmental glomerulosclerosis (FSGS) in two patients and collapsing glomerulopathy in one patient. The most common comorbidities among this cohort were hypertension (9/12) and diabetes mellitus (2/12). Four patients had a history of infection with COVID-19 (n=3) or HIV (n=1), three of whom had renal involvement (acute kidney injury or CKD and proteinuria). Use of a broad kidney gene panel enabled the identification of APOL1 HRGs in individuals for which hypertension or diabetes may have otherwise been attributed as the primary cause of CKD. APOL1 HRGs could also provide context for the renal involvement seen in the patients with COVID-19 or HIV infection. Broad panel genetic testing provides an accessible tool for nephrology clinics to help identify individuals at risk for positivity for an APOL1 HRG, including those of AA descent with hypertensive, proteinuric CKD.

4.
Future Microbiol ; 17: 985-988, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1963289

ABSTRACT

Tweetable abstract Severe COVID-19 patients display dysregulated expression of checkpoint molecules PD-1 and its ligand PD-L1, suggesting that these checkpoint molecules could be considered as prognostic markers and therapeutic targets in severe cases of COVID-19.


Subject(s)
B7-H1 Antigen , COVID-19 , B7-H1 Antigen/metabolism , Humans , Programmed Cell Death 1 Receptor/metabolism
5.
Health Risk Analysis ; 2022(2):174-184, 2022.
Article in Russian | Scopus | ID: covidwho-1964936

ABSTRACT

Long-term or permanent chemical ambient air pollution in residential areas is among priority factors that cause medical and demographic losses. It is necessary to achieve greater precision when assessing risks of changes in homeostasis at their early reversible stage (molecular level). These changes are highly likely to transform into pathological processes at an older age in case the exposure persists. Our research goal was to create a bioinformatics matrix of molecular markers to predict risk-associated health disorders (exemplified by a marker of exposure). We introduced a stepwise research algorithm that involved using the proteome technology to identify expressed proteins and cause-effect relations between them and influencing factors;revealing molecular-cellular and functional relationships within the “exposure factor – gene – protein – negative outcome” system to predict risk-associated health disorders. The algorithm was implemented to examine the proteomic blood plasma profile of children aged 3–6 years living under long-term aerogenic exposure to fluoride-containing compounds. We established certain changes in the proteomic profiles of the exposed children in comparison with non-exposed ones as per 27 identified proteins. A bioinformatics matrix was created on the example of cathepsin L1;we established that changes in the level of this protein had a cause-effect relationship with fluoride ion concentrations in urine. Qualitative synthesis of molecular-cellular localization, functional and tissue belonging showed that cathepsin L1 expression caused by elevated fluoride ion levels in urine could affect extracellular matrix remodeling, degradation and post-translation modification of proteins in cells of the lungs, large intestine, and pancreas, in cardiomyocytes and in glomerular podocytes. It also mediated proteolysis of the subunits of the SARS-CoV-2 S1 protein necessary for the virus penetration into a cell and its replication. This created bioinformatics matrix exemplified by cathepsin L1 made it possible to predict risk-associated negative outcomes in exposed people including cardiomyopathy, colitis, glomerulonephritis, diabetes mellitus, atherosclerosis, and coronavirus infection. These predictive estimates raise effectiveness of early detection and development of preventive measures aimed at minimizing possible negative outcomes. © Zemlyanova M.A., Zaitseva N.V., Koldibekova Yu.V., Peskova E.V., Bulatova N.I., 2022

6.
Int J Mol Sci ; 23(13)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1934133

ABSTRACT

Casein kinase 2 (CK2) is a ubiquitously expressed serine/threonine kinase and is upregulated in human obesity. CX-4945 (Silmitasertib) is a CK2 inhibitor with anti-cancerous and anti-adipogenic activities. However, the anti-adipogenic and pro-lipolytic effects and the mode of action of CX-4945 in (pre)adipocytes remain elusive. Here, we explored the effects of CX-4945 on adipogenesis and lipolysis in differentiating and differentiated 3T3-L1 cells, a murine preadipocyte cell line. CX-4945 at 15 µM strongly reduced lipid droplet (LD) accumulation and triglyceride (TG) content in differentiating 3T3-L1 cells, indicating the drug's anti-adipogenic effect. Mechanistically, CX-4945 reduced the expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and perilipin A in differentiating 3T3-L1 cells. Strikingly, CX-4945 further increased the phosphorylation levels of cAMP-activated protein kinase (AMPK) and liver kinase B-1 (LKB-1) while decreasing the intracellular ATP content in differentiating 3T3-L1 cells. In differentiated 3T3-L1 cells, CX-4945 had abilities to stimulate glycerol release and elevate the phosphorylation levels of hormone-sensitive lipase (HSL), pointing to the drug's pro-lipolytic effect. In addition, CX-4945 induced the activation of extracellular signal-regulated kinase-1/2 (ERK-1/2), and PD98059, an inhibitor of ERK-1/2, attenuated the CX4945-induced glycerol release and HSL phosphorylation in differentiated 3T3-L1 cells, indicating the drug's ERK-1/2-dependent lipolysis. In summary, this investigation shows that CX-4945 has strong anti-adipogenic and pro-lipolytic effects on differentiating and differentiated 3T3-L1 cells, mediated by control of the expression and phosphorylation levels of CK2, C/EBP-α, PPAR-γ, FAS, ACC, perilipin A, AMPK, LKB-1, ERK-1/2, and HSL.


Subject(s)
Adipogenesis , Casein Kinase II , Naphthyridines , Phenazines , 3T3-L1 Cells , AMP-Activated Protein Kinases/metabolism , Animals , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/metabolism , Cell Differentiation/drug effects , Cyclic AMP-Dependent Protein Kinases/metabolism , Glycerol/pharmacology , Humans , Lipolysis/drug effects , Mice , Naphthyridines/pharmacology , PPAR gamma/metabolism , Perilipin-1/metabolism , Phenazines/pharmacology , Sterol Esterase/metabolism
7.
Nephrology Dialysis Transplantation ; 37(SUPPL 3):i171-i172, 2022.
Article in English | EMBASE | ID: covidwho-1915689

ABSTRACT

BACKGROUND AND AIMS: Cases of collapsing glomerulopathy in association with COVID-19 infection have been reported worldwide, frequently referred to as COVAN (COVID-19 Associated Nephropathy). Affected patients are almost exclusively of Black ethnicity, likely associated with APOL-1 renal risk variants. There remains a paucity of data on patient outcomes, however, and it is unclear how the natural history of this disease may vary from HIV-associated nephropathy (HIVAN) and other non-viral causes of collapsing FSGS. Here, we present a case series of seven patients with presumed COVAN from a single tertiary UK renal centre;highlighting patient demography, biopsy findings, clinical management and short-term renal outcomes. METHOD: We identified all adult patients presenting to our centre with nephrotic syndrome and a renal biopsy demonstrating collapsing glomerulopathy, in association with a positive COVID-19 PCR swab result. Detailed case note reviews were undertaken using electronic health records to extract data relevant to patient demography, co-morbidities, COVID -19 symptoms, renal biopsy findings, treatment and biochemical parameters, both at the time of presentation and during follow-up at 1, 3, 6 and 12 months respectively (where available). RESULTS: In total, we identified seven patients with presumed COVAN. Three of the seven patients were male, median age was 60 years (range 25-80 years). Six of the seven patients were of Black ethnicity and one patient was of South Asian ethnicity (renal transplant recipient with donor ethnicity unknown). All seven patients had a background of hypertension, 5/7 had known chronic kidney disease (CKD), 5/7 had type 2 diabetes mellitus (T2DM) and 4/7 were obese (BMI > 30). In the vast majority of cases, associated COVID-19 symptoms were mild. All patients had profound nephrotic syndrome at the time of renal biopsy, with median urine ACR 1085 mg/mmol (range 682-1380 mg/mmol) and median serum albumin 15 g/L (range 8-20 g/L). Two of seven patients had mild AKI (stage 1) and 5/7 patients had severe AKI (stage 3), with 3 of these patients receiving acute haemodialysis therapy. Management of glomerulopathy was supportive in all cases, including diuresis and anticoagulation (two patients received a short course of oral dexamethasone for their COVID-19 symptoms). ACE inhibitors/angiotensin receptor blockers were re-introduced in two patients and newly commenced in two further patients during follow-up. At 6 months follow-up, one patient remained dialysis dependant and one patient had ongoing decline in renal function (renal transplant recipient);all other patients achieved at least partial remission, with > 50% reduction in urine ACR and some (but not complete) recovery in renal function (Fig. 1). There were no viral particles identified on direct examination of renal biopsy specimens, but 4/7 biopsies exhibited tubulo-reticular inclusions, suggesting an interferon-driven systemic inflammatory process. CONCLUSION: In this case series of seven COVAN cases from a single tertiary UK centre, we noted that in keeping with reports from North America, Black ethnicity patients were disproportionately affected. Partial remission was achieved in most of our cases with supportive treatment only;however, ongoing monitoring of this cohort is required to better understand longer-term patient outcomes. Testing for APOL-1 gene mutations and molecular testing of biopsy samples for this cohort is also ongoing to facilitate better insights into pathophysiology and risk factors associated with this novel disease. (Figure Presented).

8.
Nephrology Dialysis Transplantation ; 37(SUPPL 3):i139-i140, 2022.
Article in English | EMBASE | ID: covidwho-1915679

ABSTRACT

BACKGROUND AND AIMS: The COVID-19 pandemic has brought to the forefront a wide spectrum of renal injuries that included glomerulopathies, some of which were recently highlighted in various case reports. These consist of focal and segmental glomerulosclerosis (FSGS) and minimal change disease (MCD).1 These changes were found among seemingly vulnerable populations such as the African American and Caucasian ethnicities with paucity of reports among other races. We present two cases of biopsy-confirmed MCD secondary to COVID-19 infection among adult Filipino patients. METHODS: Case Report RESULTS: Case 1 A 40-year-old Filipino female with a history of right total mastectomy 2 years prior for a low-grade phyllodes tumor and no other medical comorbidities was admitted due to stillbirth. She was noted to have bipedal edema with a positive COVID-19 RT-PCR swab. Further workup revealed a serum creatinine 1.04 mg/dL, urine RBC 1/HPF and a 24-h urine protein of 9.22 g with hypoalbuminemia and dyslipidemia. Serologic workup was noted to be negative. She was started on Losartan, Atorvastatin, and Furosemide. A kidney biopsy was performed which demonstrated unremarkable light microscopy and immunofluorescence and widespread podocyte-foot process effacement. These biopsy findings were interpreted to be consistent with minimal change disease. She was started on Prednisone at 1 mg/kg/day with continuation of both Losartan and Atorvastatin. Six weeks after, the patient achieved complete remission with resolution of both hypoalbuminemia and dyslipidemia. She also reports no further recurrence of edema. Case 2 A 61-year-old Filipino male with a history of type 2 diabetes mellitus, hypertension, dyslipidemia and mild COVID-19 infection 4 months prior now presented with diarrhea. A routine COVID-19 RT-PCR swab revealed a re-infection. Physical examination noted bipedal edema. Further workup demonstrated a serum creatinine 3.39 mg/dL, urine RBC 2/HPF and urine ACR 2.6 g/g. Serologic tests were negative. He was diagnosed with Nephrotic Syndrome and underwent kidney biopsy. Findings showed an unremarkable light microscopy and immunofluorescence with widespread podocyte-foot process effacement. These findings were found to be consistent with minimal change disease and acute tubular injury. He was started on Prednisone (1 mg/kg/day), Losartan, Furosemide and Atorvastatin. Eight weeks later, the patient achieved complete remission with resolution of edema. CONCLUSION: It is currently suspected that APOL1 risk variants found in reported cases of COVID-19-associated glomerulopathies are underlying toxic gain-of-function mutations that drive kidney disease.2 It is interesting to note that APOL1 renal risk variants are found exclusively in African-derived chromosomes and are rarely found among European or Asian chromosomes.3 Even though an APOL1 genotyping was not performed, our case reports provide the first examples of MCD among individuals without a high-risk genotype (APOL1) by epidemiology and enlarge the literature on MCD in COVID-19. We posit that there may be other underlying predispositions or mechanisms that may be driving glomerulopathy formation among COVID-19 patients aside from their inherent APOL 1 risk. Both of our patients were started on steroid therapy with a tapering regimen and achieved complete remission on subsequent follow-up. Existing reports suggest that most cases of COVID-19-associated MCD will often achieve resolution of AKI and proteinuria with steroid therapy, even in those with high-risk APOL1 genotype, emphasizing the need for an accurate histologic classification.4 (Figure Presented).

9.
Elife ; 112022 06 23.
Article in English | MEDLINE | ID: covidwho-1903840

ABSTRACT

Coronavirus disease 2019 (COVID-19) is the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2; SC2), which has caused a worldwide pandemic with striking morbidity and mortality. Evaluation of SC2 strains demonstrated impressive genetic variability, and many of these viral variants are now defined as variants of concern (VOC) that cause enhanced transmissibility, decreased susceptibility to antibody neutralization or therapeutics, and/or the ability to induce severe disease. Currently, the delta (δ) and omicron (ο) variants are particularly problematic based on their impressive and unprecedented transmissibility and ability to cause breakthrough infections. The delta variant also accumulates at high concentrations in host tissues and has caused waves of lethal disease. Because studies from our laboratory have demonstrated that chitinase 3-like-1 (CHI3L1) stimulates ACE2 and Spike (S) priming proteases that mediate SC2 infection, studies were undertaken to determine if interventions that target CHI3L1 are effective inhibitors of SC2 viral variant infection. Here, we demonstrate that CHI3L1 augments epithelial cell infection by pseudoviruses that express the alpha, beta, gamma, delta, or omicron S proteins and that the CHI3L1 inhibitors anti-CHI3L1 and kasugamycin inhibit epithelial cell infection by these VOC pseudovirus moieties. Thus, CHI3L1 is a universal, VOC-independent therapeutic target in COVID-19.


Subject(s)
COVID-19 , Chitinases , Angiotensin-Converting Enzyme 2 , COVID-19/drug therapy , Chitinases/genetics , Humans , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2/genetics , Virus Internalization
10.
Int J Environ Res Public Health ; 19(10)2022 05 12.
Article in English | MEDLINE | ID: covidwho-1875623

ABSTRACT

Acquired immune deficiency syndrome (AIDS) is a serious public health problem. This study aims to establish a combined model of seasonal autoregressive integrated moving average (SARIMA) and Prophet models based on an L1-norm to predict the incidence of AIDS in Henan province, China. The monthly incidences of AIDS in Henan province from 2012 to 2020 were obtained from the Health Commission of Henan Province. A SARIMA model, a Prophet model, and two combined models were adopted to fit the monthly incidence of AIDS using the data from January 2012 to December 2019. The data from January 2020 to December 2020 was used to verify. The mean square error (MSE), mean absolute error (MAE), and mean absolute percentage error (MAPE) were used to compare the prediction effect among the models. The results showed that the monthly incidence fluctuated from 0.05 to 0.50 per 100,000 individuals, and the monthly incidence of AIDS had a certain periodicity in Henan province. In addition, the prediction effect of the Prophet model was better than SARIMA model, the combined model was better than the single models, and the combined model based on the L1-norm had the best effect values (MSE = 0.0056, MAE = 0.0553, MAPE = 43.5337). This indicated that, compared with the L2-norm, the L1-norm improved the prediction accuracy of the combined model. The combined model of SARIMA and Prophet based on the L1-norm is a suitable method to predict the incidence of AIDS in Henan. Our findings can provide theoretical evidence for the government to formulate policies regarding AIDS prevention.


Subject(s)
Acquired Immunodeficiency Syndrome , Acquired Immunodeficiency Syndrome/epidemiology , China/epidemiology , Forecasting , Humans , Incidence , Models, Statistical
11.
Am J Physiol Lung Cell Mol Physiol ; 323(1): L14-L26, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1861686

ABSTRACT

Critically ill patients manifest many of the same immune features seen in coronavirus disease 2019 (COVID-19), including both "cytokine storm" and "immune suppression." However, direct comparisons of molecular and cellular profiles between contemporaneously enrolled critically ill patients with and without severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited. We sought to identify immune signatures specifically enriched in critically ill patients with COVID-19 compared with patients without COVID-19. We enrolled a multisite prospective cohort of patients admitted under suspicion for COVID-19, who were then determined to be SARS-CoV-2-positive (n = 204) or -negative (n = 122). SARS-CoV-2-positive patients had higher plasma levels of CXCL10, sPD-L1, IFN-γ, CCL26, C-reactive protein (CRP), and TNF-α relative to SARS-CoV-2-negative patients adjusting for demographics and severity of illness (Bonferroni P value < 0.05). In contrast, the levels of IL-6, IL-8, IL-10, and IL-17A were not significantly different between the two groups. In SARS-CoV-2-positive patients, higher plasma levels of sPD-L1 and TNF-α were associated with fewer ventilator-free days (VFDs) and higher mortality rates (Bonferroni P value < 0.05). Lymphocyte chemoattractants such as CCL17 were associated with more severe respiratory failure in SARS-CoV-2-positive patients, but less severe respiratory failure in SARS-CoV-2-negative patients (P value for interaction < 0.01). Circulating T cells and monocytes from SARS-CoV-2-positive subjects were hyporesponsive to in vitro stimulation compared with SARS-CoV-2-negative subjects. Critically ill SARS-CoV-2-positive patients exhibit an immune signature of high interferon-induced lymphocyte chemoattractants (e.g., CXCL10 and CCL17) and immune cell hyporesponsiveness when directly compared with SARS-CoV-2-negative patients. This suggests a specific role for T-cell migration coupled with an immune-checkpoint regulatory response in COVID-19-related critical illness.


Subject(s)
COVID-19 , Respiratory Insufficiency , B7-H1 Antigen , Chemokines , Critical Illness , Humans , Prospective Studies , SARS-CoV-2 , Tumor Necrosis Factor-alpha
12.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-335563

ABSTRACT

Risk of hospitalisation or death from COVID-19 in the UK is disproportionately high in people of African ancestry. Two APOL1 haplotypes (G1 and G2) found at high frequency only in populations of African descent are associated with increased risk of non-communicable and infectious diseases. Here, we test the hypothesis that adverse COVID-19 outcomes are also associated with these APOL1 high-risk variants. Within 9,433 individuals with African ancestry in the UK Biobank, there were 172 hospitalisations and 47 deaths attributed to COVID-19 as of December 2021. We examined APOL1 genotypes for association with hospitalisation and death while controlling for risk factors previously associated with poor COVID-19 outcomes. We identified an association between carriage of two APOL1 high-risk variants and death from COVID-19 (OR=2.7, 95% CI: 1.2-6.4). Stratified by genotype, those with G1/G2 had a higher odds of COVID-19 hospitalisation (OR=2.1, 95% CI: 1.1-3.8) and death (OR=5.9, 95% CI: 2.2-15.3) than G0/G0. There was no significant association detected in carriers of G1/G1 and G2/G2. These data suggest that the APOL1 G1/G2 genotype contributes to the increased rates of hospitalisation and mortality from COVID-19 in people of African ancestry, and could help to identify those at higher risk of severe COVID-19. This is especially relevant to geographical regions where APOL1 G1 and G2 high-risk variants are common, such as West and Central Africa and their diaspora.

13.
Front Immunol ; 13: 869825, 2022.
Article in English | MEDLINE | ID: covidwho-1809406

ABSTRACT

Phage display is a well-established technology for in vitro selection of monoclonal antibodies (mAb), and more than 12 antibodies isolated from phage displayed libraries of different formats have been approved for therapy. We have constructed a large size (10^11) human antibody VH domain library based on thermo-stable, aggregation-resistant scaffolds. This diversity was obtained by grafting naturally occurring CDR2s and CDR3s from healthy donors with optimized primers into the VH library. This phage-displayed library was used for bio-panning against various antigens. So far, panels of binders have been isolated against different viral and tumor targets, including the SARS-CoV-2 RBD, HIV-1 ENV protein, mesothelin and FLT3. In the present study, we discuss domain library construction, characterize novel VH binders against human CD22 and PD-L1, and define our design process for antibody domain drug conjugation (DDC) as tumoricidal reagents. Our study provides examples for the potential applications of antibody domains derived from library screens in therapeutics and provides key information for large size human antibody domain library construction.


Subject(s)
COVID-19 , Immunoglobulin Heavy Chains , Antibodies, Monoclonal , B7-H1 Antigen , Humans , Peptide Library , SARS-CoV-2 , Sialic Acid Binding Ig-like Lectin 2/metabolism
14.
15.
Genes (Basel) ; 13(5)2022 Apr 20.
Article in English | MEDLINE | ID: covidwho-1792755

ABSTRACT

The major advantage of mRNA vaccines over more conventional approaches is their potential for rapid development and large-scale deployment in pandemic situations. In the current COVID-19 crisis, two mRNA COVID-19 vaccines have been conditionally approved and broadly applied, while others are still in clinical trials. However, there is no previous experience with the use of mRNA vaccines on a large scale in the general population. This warrants a careful evaluation of mRNA vaccine safety properties by considering all available knowledge about mRNA molecular biology and evolution. Here, I discuss the pervasive claim that mRNA-based vaccines cannot alter genomes. Surprisingly, this notion is widely stated in the mRNA vaccine literature but never supported by referencing any primary scientific papers that would specifically address this question. This discrepancy becomes even more puzzling if one considers previous work on the molecular and evolutionary aspects of retroposition in murine and human populations that clearly documents the frequent integration of mRNA molecules into genomes, including clinical contexts. By performing basic comparisons, I show that the sequence features of mRNA vaccines meet all known requirements for retroposition using L1 elements-the most abundant autonomously active retrotransposons in the human genome. In fact, many factors associated with mRNA vaccines increase the possibility of their L1-mediated retroposition. I conclude that is unfounded to a priori assume that mRNA-based therapeutics do not impact genomes and that the route to genome integration of vaccine mRNAs via endogenous L1 retroelements is easily conceivable. This implies that we urgently need experimental studies that would rigorously test for the potential retroposition of vaccine mRNAs. At present, the insertional mutagenesis safety of mRNA-based vaccines should be considered unresolved.


Subject(s)
COVID-19 Vaccines , COVID-19 , Animals , Biology , COVID-19/prevention & control , COVID-19 Vaccines/genetics , Humans , Long Interspersed Nucleotide Elements , Mice , RNA, Messenger/genetics , Retroelements , Vaccines, Synthetic/genetics , mRNA Vaccines
16.
Viruses ; 14(4)2022 04 15.
Article in English | MEDLINE | ID: covidwho-1792417

ABSTRACT

Monocytes play a role in viral biology, but little is known about the monocyte subpopulation in the course of COVID-19 disease. The aim of the study was the analysis of classical, intermediate and non-classical monocytes with expression of PD-L1 and CD62L, TIM-3 and CD86 molecules in peripheral blood (PB) to distinguish patients with SARS-CoV-2 infection from convalescent patients. The study group consisted of 55 patients with SARS-CoV-2 infection and 51 convalescent patients. The cells were analyzed by flow cytometry. The number and proportion of monocytes were lower in patients with COVID-19 than convalescent patients. We observed a lower proportion of non-classical monocytes in COVID-19 patients than convalescent ones. There was a higher proportion of PDL-1-positive intermediate monocytes in COVID-19 patients than convalescent ones. We noticed a higher geometric mean fluorescence intensity (GeoMean) of PD-L1 on intermediate monocytes in COVID-19 patients than convalescent patients, and a higher proportion of CD62L-positive monocytes in COVID-19 patients in comparison with convalescent ones. We found a higher GeoMean of CD62L on monocytes in COVID-19 patients than convalescent ones. Assessment of PD-L1- and CD62L-positive monocyte subsets may identify patients with a possible predisposition for rapid recovery. The monitoring of monocyte subsets in PB might be a useful test in COVID-19 patients.


Subject(s)
B7-H1 Antigen , COVID-19 , L-Selectin , Monocytes , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , COVID-19/genetics , COVID-19/metabolism , Flow Cytometry , Humans , L-Selectin/genetics , L-Selectin/metabolism , Monocytes/metabolism , SARS-CoV-2
17.
Biological Psychiatry ; 91(9):S28, 2022.
Article in English | EMBASE | ID: covidwho-1777994

ABSTRACT

Background: There are no blood screening tests to assess brain molecular alterations linked to neurological alterations in human coronavirus disease 2019 (COVID-19). Evidence indicates long-term brain abnormalities associated with SARS-CoV-2 infection, including cognitive impairment, which may develop into an emerging health problem as many patients are emerging with cognitive abnormalities that may be associated to an increased risk of AD. Promising results from the field of blood-based biomarkers are emerging with the use of extracellular vesicles (EVs). Neuronal-derived EVs (NDEVs) can be isolated from the total pool of EVs in the blood to investigate biomarkers of brain diseases. Methods: Isolation of NDEVs was performed using the ExoQuick ULTRA EV Isolation System, followed by immunoprecipitation with L1CAM antibody. EVs were characterized by nanoparticle tracking analysis, electron microscopy, Exo-Check Array, and ELISA/immunoblotting to detect exosome proteins. Biomarker measurements in the plasma, CSF and EVs from plasma was done by ELISA. A broader analysis of isolated EVs was done by Mass spectrometry. Results: Levels of cytokines were increased in the blood samples from a cohort of 100 COVID-19 patients compared to controls. We had the opportunity to investigate biomarkers in the CSF of 38 patients and observed that the levels of cytokines and biomarkers of neurodegeneration in CSF samples were increased. Conclusions: COVID-19 was associated with increases in CSF and blood cytokines and markers of neurodegeneration. A close follow up in patients that developed COVID-19 symptoms is important to determine the long-term consequences of infection Funding Source: CNPq, FAPERJ, CIHR Keywords: Extracellular Vesicles, Biomarkers, COVID-19

18.
Genetics in Medicine ; 24(3):S170-S171, 2022.
Article in English | EMBASE | ID: covidwho-1768092

ABSTRACT

Introduction: Chronic kidney disease (CKD) is a debilitating disorder associated with significant morbidity and mortality. CKD diagnoses can have overlapping, non-specific clinical symptoms and histology findings, and the underlying etiology can remain unknown. Recent studies have shown that 1 in 10 adults with CKD has a genetic component to their disease. However, genetic services are limited in this patient population and disproportionally impact those from medically underserved communities. Therefore, an adult kidney genetics clinic was developed within the Division of Nephrology at a large urban academic medical center to increase access to genetic services and testing in adults with kidney disease. Methods: In June 2019, the Division of Nephrology at Columbia University Irving Medical Center created a Kidney Genetics Clinic staffed by genetic counselors (GC) and nephrologists. Initially, appointments were held in-person but transitioned to telemedicine beginning in May 2020 due to the COVID-19 pandemic. The clinic utilized two appointment types: full genetic consults (staffed by a GC and nephrologist) and genetic counseling visits (staffed by a GC only). Genetic counselors implemented several genetic education initiatives to increase clinic referrals and increase provider interest. These included bi-monthly genetic case seminars, monthly genetic research sign-out rounds, a continuing education course focusing on clinical genetics, and genetic counseling student rotations. Results: Between June 2019 and June 2021, the clinic received 277 referrals, averaging 11 per month. Of those referred, 83% were scheduled, and 212 patients underwent genetic evaluation. The median wait time from referral to appointment was 37 days, and the no-show rate was 8%. The majority (89%) of appointments were via telehealth, either by phone or video, while the rest occurred in person. Genetic counseling visits accounted for 21% of patient appointments, and the remaining ones were full genetic consults. Most patients who attended their genetics appointment were in the NY tri-state area (87%), but 12% resided in nine additional states, three other countries, and one US territory. The primary insurance was Medicare in 10% of patients and Medicaid in 17%. Most patients described themselves as white (n=126), while 47 patients reported Hispanic or Latino ethnicity, 36 identified as Black, 15 Asian, and 4 Native Hawaiian or Pacific Islander. The average age of the patient population was 44 years old (ranging from 18 to 87). Patients seen in the genetics clinic were referred for a variety of indications and included several different kidney diagnoses, including: CAKUT (n=6), tubulointerstitial disease (n=26), suspected or clinical diagnosis of a collagenopathy (n=38), focal segmental glomerulosclerosis (FSGS) (n=28), tubulopathy or electrolyte disorder (n=16), cystic kidney disease (including PKD) (n=24), hematuria and/or proteinuria (n=31), complement dysregulation (n=8), tumor or cancer (n=4), and CKD of unknown etiology (n=23). Six patients had a known genetic diagnosis, and 23 were healthy relatives of individuals with a known genetic diagnosis or potential kidney donors. Of patients seen in the kidney genetics clinic, 42% reported a family history of CKD or a personal or family history of a genetic diagnosis. A total of 186 clinical genetic tests were ordered on 174 patients;nine tests still have results pending, and ten were canceled. Genetic tests that were ordered included: small (>50) and large gene panels (n=146), exome sequencing (n=6), microarrays (n=4), and single gene and targeted variant testing (n=20). In patients that did not undergo genetic testing, reasons included: not clinically indicated, testing already ordered, and financial concerns. A diagnostic or candidate diagnostic positive result was reported in 29% of patients, involving 18 different genes. Pathogenic or likely pathogenic variants were most common in COL4A4 (n=11), followed by PKD1 (n=8). Similarly, the highest diagnostic yield was in patients with a referral ndication of a suspected collagenopathy (diagnosis in 50%) or cystic disease (diagnosis in 50%). A non-diagnostic positive finding was identified in 9% of patients and included results such as secondary findings (n=1), carrier status (n=5), and risk factors, such as an APOL1 high-risk genotype (n=9). The identification of a genetic diagnosis in patients impacted several areas of clinical care, including referrals to specialists, kidney donor selection, clinical trial eligibility (for example, in patients with a genetic Alport diagnosis), and increased access to medications (such as tolvaptan in patients with PKD1 variants). In addition, those with non-diagnostic findings were referred to ongoing research studies at the medical center to elucidate the genetics of kidney disease. Conclusion: Here, we describe the successful creation and implementation of an adult kidney genetics clinic at a large medical center. By utilizing a combination of in-person appointments and telemedicine, the clinic was able to provide access to genomic services across a broad geographic region and to a diverse patient population of adults with kidney disease. Genetic education efforts were an integral component of the clinic's success, as it increased visibility and helped providers identify patients who would benefit from genetic services, as evidenced by the high percentage of referred patients scheduling appointments and high diagnostic yield in patients undergoing testing. Identifying genetic diagnoses in this patient population has several clinical implications, including changes in management, eligibility for genetically stratified clinical trials, and treatment decisions. Continued and ongoing access to genomic services is a fundamental component of patient care in adults with kidney disease.

19.
Gastro Hep Adv ; 1(2): 194-209, 2022.
Article in English | MEDLINE | ID: covidwho-1747991

ABSTRACT

BACKGROUND AND AIMS: The SARS-CoV-2 pandemic has overwhelmed the treatment capacity of the health care systems during the highest viral diffusion rate. Patients reaching the emergency department had to be either hospitalized (inpatients) or discharged (outpatients). Still, the decision was taken based on the individual assessment of the actual clinical condition, without specific biomarkers to predict future improvement or deterioration, and discharged patients often returned to the hospital for aggravation of their condition. Here, we have developed a new combined approach of omics to identify factors that could distinguish coronavirus disease 19 (COVID-19) inpatients from outpatients. METHODS: Saliva and blood samples were collected over the course of two observational cohort studies. By using machine learning approaches, we compared salivary metabolome of 50 COVID-19 patients with that of 270 healthy individuals having previously been exposed or not to SARS-CoV-2. We then correlated the salivary metabolites that allowed separating COVID-19 inpatients from outpatients with serum biomarkers and salivary microbiota taxa differentially represented in the two groups of patients. RESULTS: We identified nine salivary metabolites that allowed assessing the need of hospitalization. When combined with serum biomarkers, just two salivary metabolites (myo-inositol and 2-pyrrolidineacetic acid) and one serum protein, chitinase 3-like-1 (CHI3L1), were sufficient to separate inpatients from outpatients completely and correlated with modulated microbiota taxa. In particular, we found Corynebacterium 1 to be overrepresented in inpatients, whereas Actinomycetaceae F0332, Candidatus Saccharimonas, and Haemophilus were all underrepresented in the hospitalized population. CONCLUSION: This is a proof of concept that a combined omic analysis can be used to stratify patients independently from COVID-19.

20.
Cells ; 11(5)2022 02 25.
Article in English | MEDLINE | ID: covidwho-1742338

ABSTRACT

Programmed death-ligand 1 (PD-L1) plays a key role in maintaining immune tolerance and also in immune evasion of cancers and pathogens. Though the identity of stimuli that induce PD-L1 in various human innate cells and their function are relatively well studied, data on the basophils remain scarce. In this study, we have identified one of the factors, such as IFN-γ, that induces PD-L1 expression in human basophils. Interestingly, we found that basophil priming by IL-3 is indispensable for IFN-γ-induced PD-L1 expression in human basophils. However, priming by other cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF) and thymic stromal lymphopoietin (TSLP) was dispensable. Analyses of a published microarray data set on IL-3-treated basophils indicated that IL-3 enhances IFNGR2, one of the chains of the IFNGR heterodimer complex, and CD274, thus providing a mechanistic insight into the role of IL-3 priming in IFN-γ-induced PD-L1 expression in human basophils.


Subject(s)
B7-H1 Antigen , Basophils , Humans , Interferon-gamma/pharmacology , Interleukin-3/pharmacology , Leukocyte Count
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