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Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg.kg-1), and positive control sildenafil group (100 mg.kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% +/- 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF- kappaB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF- kappaB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-kappaB and signal transducer and activator of transcription 3 (STAT3) by DYY.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.
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Objective: Immunohistochemistry of post-mortem lung tissue from Covid-19 patients with diffuse alveolar damage demonstrated marked increases in chondroitin sulfate and CHST15 and decline in N-acetylgalactosamine-4-sulfatase. Studies were undertaken to identify the mechanisms involved in these effects. Method(s): Human primary small airway epithelial cells (PCS 301-010;ATCC) were cultured and exposed to the SARSCoV- 2 spike protein receptor binding domain (SPRBD;AA: Lys310-Leu560;Amsbio). Expression of the spike protein receptor, angiotensin converting enzyme 2 (ACE2), was enhanced by treatment with Interferon-beta. Promoter activation, DNA-binding, RNA silencing, QPCR, Western blots, ELISAs, and specific enzyme inhibitors were used to elucidate the underlying molecular mechanisms. Result(s): Treatment of the cultured cells by the SPRBD led to increased CHST15 and CHST11 expression and decline in ARSB expression. Sulfotransferase activity, total chondroitin sulfate, and sulfated glycosaminoglycan (GAG) content were increased. Phospho-T180/T182-p38-MAPK and phospho- S423/S425-Smad3 were required for the activation of the CHST15 and CHST11 promoters. Inhibition by SB203580, a phospho-p38 MAPK inhibitor, and by SIS3, a Smad3 inhibitor, blocked the CHST15 and CHST11 promoter activation. SB203580 reversed the SPRBD-induced decline in ARSB expression, but SIS3 had no effect on ARSB expression or promoter activation. Phospho-p38 MAPK was shown to reduce retinoblastoma protein (RB) S807/S811 phosphorylation and increase RB S249/T252 phosphorylation. E2F-DNA binding declined following exposure to SPRBD, and SB203580 reversed this effect. This indicates a mechanism by which SPRBD, phospho-p38 MAPK, E2F, and RB can regulate ARSB expression and thereby impact on chondroitin 4-sulfate and dermatan sulfate and molecules that bind to these sulfated GAGs, including Interleukin-8, bone morphogenetic protein-4, galectin-3 and SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2). Conclusion(s): The enzyme ARSB is required for the degradation of chondroitin 4-sulfate and dermatan sulfate, and accumulation of these sulfated GAGs can contribute to lung pathophysiology, as evident in Covid-19. Some effects of the SPRBD may be attributable to unopposed Angiotensin II, when Ang1-7 counter effects are diminished due to binding of ACE2 with the SARS-CoV-2 spike protein and reduced production of Ang1-7. Aberrant cell signaling and activation of the phospho-p38 MAPK and Smad3 pathways increase CHST15 and CHST11 production, which can contribute to increased chondroitin sulfate in infected cells. Decline in ARSB may occur as a consequence of effects of phospho-p38 MAPK on RB phosphorylation and E2F1 availability. Decline in ARSB and the resulting impaired degradation of sulfated GAGs have profound consequences on cellular metabolic, signaling, and transcriptional events. Funding is VA Merit Award.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.
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The COVID-19 pandemic has altered people's lifestyles around the world. Prevention of recurrent episodes of the disease and mitigation of its consequences are especially associated with effective post-COVID-19 rehabilitation in patients. The aim of the study was to evaluate the effects of the drug Likopid (glucosaminylmuramyl dipeptide, GMDP) for post-COVID-19 rehabilitation in patients. Material and methods. Patients who recovered from mild to moderate COVID-19 (n=60, mean age 54+/- 11.7 years) were randomized into the observation group (n=30, 15 men and 15 women) who received 2 courses of Licopid (1 mg twice a day) and the comparison group (n=30, 15 men and 15 women). Analysis of the phenotypic and functional characteristics of the innate immune cellular factors was carried out before the start of immunomodulatory therapy, immediately after the end of the course, and also after 6 months observations. In order to assess the quality of life of all patients, we used the SF-36 Health Status Survey and the Hospital Anxiety and Depression Scale questionnaires. Results. During assessing the effect of immunomodulatory therapy on the parameters of innate immunity of patients at the stage of rehabilitation after COVID-19, an increase in the protective cytolytic activity of CD16+ and CD8+Gr+ cells, as well as a persistent increase in TLR2, TLR4 and TLR9 expression was found, which indicates the antigen recognition recovery and presentation at the level of the monocytic link of the immune system. The use of GMDP as an immunomodulatory agent resulted in an 8-fold reduction in the frequency and severity of respiratory infections due to an increase in the total monocyte count. As a result of assessing patients' quality of life against the background of the therapy, a positive dynamic in role functioning was revealed in patients. In the general assessment of their health status, an increase in physical and mental well-being was noted during 6 months of observation. The comparison group showed no improvement in the psychoemotional state. Discussion. The study demonstrated the effectiveness of GMDP immunomodulatory therapy in correcting immunological parameters for post-COVID-19 rehabilitation in patients. The data obtained are consistent with the previously discovered ability of GMDP to restore impaired functions of phagocytic cells and induce the expression of their surface activation markers, which in turn contributes to an adequate response to pathogens. Conclusion. The study revealed that the correction of immunological parameters with the use of GMDP in COVID-19 convalescents contributed not only to a decrease in the frequency and severity of respiratory infections, but also to an improvement in the psycho-emotional state of patients, and a decrease in anxiety and depression.Copyright © Eco-Vector, 2023. All rights reserved.
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Coronavirus disease has many systemic disease symptoms and has severe consequences for the cardiovascular system. Objective. To assess the role of clinical and laboratory indicators in determining the risk of chronic heart failure (CHF) in COV-ID-19 survivors. Material and methods. In total, 151 patients treated in a monoinfectious hospital from 03.11.20 to 10.02.21 with a confirmed diagnosis of COVID-19 were retrospectively selected. Medical history and laboratory data were collected by reviewing electronic medical records. The data included age, gender, body mass index, smoking status, and comorbidities. The laboratory data included the results of hematology and blood chemistry, coagulation, and the levels of acute-phase proteins. The CHF occurrence was used as the study endpoint. Results and discussion. The study patients were divided into two groups depending on the presence of CHF: group 1 included 46 patients with CHF, and group 2 included 105 patients without CHF. The median age was 66.2 (50-92) years;91 (60.3%) were females. Laboratory tests, such as levels of the hs-C-reactive protein, lactate dehydrogenase, procalcitonin, creatinine, and bilirubin, were statistically significantly different in patients of the study groups, and the median values were higher in patients with CHF. Neutrophil-lymphocyte ratio (NLR) showed statistically significant differences between groups: in patients with CHF, the median was 4.97% compared to 3.62% (p=0.011) in those without CHF. The most significant predictors of an increased risk of CHF were age >=66 years (OR=8.038, p<0.001), procalcitonin level >=0.09 ng/mL (increased the CHF risk by 3.8 times, p<0.001), thrombocy-topenia <=220x109/L (p=0.010), an NLR ratio >=4.11% (p=0.010), and a history of chronic kidney disease (p=0.018). Conclusion. A model has been developed to determine the factors closely associated with the risk of chronic heart failure in CO-VID-19 survivors.Copyright © 2023, Media Sphera Publishing Group. All rights reserved.
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The coronavirus SARS-CoV-2 was detected in isolates of pneumonia patients in January 2020. The virus cannot multiply extracellularly but requires access to the cells of a host organism. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor, to which it docks with its spikes. ACE2 belongs to the renin angiotensin system (RAS), whose inhibitors have been used for years against high blood pressure. Renin is an endopeptidase that is predominantly formed in the juxtaglomerular apparatus of the kidney and cleaves the decapeptide angiotensin I (Ang I) from angiotensinogen. Through the angiotensin-converting enzyme (ACE), another 2 C-terminal amino acids are removed from Ang I, so that finally the active octapeptide angiotensin II (Ang II) is formed. The biological effect of Ang II via the angiotensin II receptor subtype 1 (AT1-R) consists of vasoconstriction, fibrosis, proliferation, inflammation, and thrombosis formation. ACE2 is a peptidase that is a homolog of ACE. ACE2 is predominantly expressed by pulmonary alveolar epithelial cells in humans and has been detected in arterial and venous endothelial cells. In contrast to the dicarboxy-peptidase ACE, ACE2 is a monocarboxypeptidase that cleaves only one amino acid from the C-terminal end of the peptides. ACE2 can hydrolyze the nonapeptide Ang-(1-9) from the decapeptide Ang I and the heptapeptide Ang-(1-7) from the octapeptide Ang II. Ang-(1-7) acts predominantly antagonistically (vasodilatory, anti-fibrotic, anti-proliferative, anti-inflammatory, anti-thrombogenetically) via the G protein-coupled Mas receptor to the AT1-R-mediated effects of Ang II. In the pathogenesis of COVID-19 infection, it is therefore assumed that there is an imbalance due to overstimulation of the AT1 receptor in conjunction with a weakening of the biological effects of the Mas receptor.Copyright © 2022 Dustri-Verlag Dr. K. Feistle.
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Background: Several pro- and anti-inflammatory cytokines involved in COVID-19 and it is reasonable to speculate that their removal from blood might limit organ damage. Hemoperfusion with CytoSorb is a technique developed to adsorb molecules in the middle molecular weight range (up to 55 kDa). Studies in vitro and in vivo have shown that HP is highly effective in clearing blood from a number of cytokines. Method(s): We report a case series of 9 consecutive COVID-patients admitted to our COVID Intensive Care Unit (ICU). Five of them were treated with HP using CytoSorb (T), due to the heavy emergency overload it was impossible to deliver blood purification in the other 4 patients (C), who were also considered as potential candidates by the attending medical team. All patients had pneumonia and respiratory failure requiring continuous positive airway pressure. Different antibacterial prophylaxes, antiviral, and anti-inflammatory therapies including steroids were delivered. Result(s): Our results show a better clinical course of T compared to control patients (C), in fact all T except 1 survived, and only 2 of them were intubated, while all C required intubation and died. CRP decreased in both groups, but to a greater extent after HP. Lymphocytopenia worsened in control patient but not in treated patient after HP. Procalcitonin increased in 2 of the not treated patients. In all survived patients (n = 4) HP reduced pro-inflammatory cytokines, as IL-6, TNF-alpha, and IL-8. Notably, a striking effect was observed on IL-6 levels that at the end of the second session were decreased by a 40% than before the first treatment. Serum levels of IL-8 and TNF-alpha were lowered within normal range. In all patients the treatment was safe and there were no complications. Conclusion(s): Our study suggests a potential efficacy of HP in an early phase of viral infection not only for improving survival in the treated patients but also by the remodeling treatment-associated cytokine levels.
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Problem: COVID-19 placentitis is a rare complication of maternal SARS-CoV-2 respiratory infection associated with serious adverse obstetric outcomes, including intra-uterine death. The precise role of SARS-CoV-2 in COVID-19 placentitis is uncertain, as trophoblast infection is only observed in around one-half of the affected placenta. Method of Study: Through multi-omic spatial profiling, including Nanostring GeoMX digital spatial profiling and Lunaphore COMET multiplex IHC, we provide a deep characterization of the immunopathology of placentitis from obstetrically complicated maternal COVID-19 infection. Result(s):We show that SARS-CoV-2 infection of placental trophoblasts is associated with a distinct innate and adaptive immune cell infiltrate, florid cytokine expression and upregulation of viral restriction factors. Quantitative spatial analyses reveal a unique microenvironment surrounding virus-infected trophoblasts characterizedd by multiple immune evasion mechanisms, including immune checkpoint expression, cytotoxic T-cell exclusion, and interferon blunting. Placental viral loads inversely correlated with the duration of maternal infection consistent with progressive virus clearance, potentially explaining the absence of virus in some cases. Conclusion(s): Our results demonstrate a central role for placental SARS-CoV-2 infection in driving the unique immunopathology of COVID-19 placentitis.
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Remdesivir (RDV) is an antiviral medication used most recently for the treatment of COVID-19. Although no adverse effects were observed on perinatal parameters in reproductive and development toxicology studies at doses up to four-fold clinical area under the curve (AUC) exposures, some researchers have reported that therapeutic levels of RDV may impair early embryogenesis, as observed by in vitro studies. In addition, the influence of prenatal RDV exposure on maternal IgG transfer in the placenta is still unknown. Administration of RDV in pregnant humanized mouse model (Tg32), which expresses the human Fc gamma receptor and transporter (FCGRT) gene, was used to further evaluate potential effects on IgG transfer and concurrent perinatal endpoints. Animals were dosed daily from gestational days (GDs) 10- 14 with 25 mg/kg RDV (GS-5734) via intravenous injection (n=3-5 per group). Concurrent vehicle control animals were dosed intravenously with 12% sulfobutyl ether- beta-cyclodextrin in water (pH3.5;NaOH/HCl). All animals were administered 2 mg/kg human IgG via intravenous injection on GD 14. Placentae and fetuses were collected from dams on GD 14, 15, 16, and 18 and evaluated using histopathology and qPCR for inflammation markers. No abnormal morphologies (necrosis/apoptosis) of placentae were observed between the concurrent control and RDVdosed groups. Additionally, no differences in maternal body weights were observed. There were no statistically significant differences in placenta weights. There were no statistically significant changes in pregnancy parameters (implantation sites and dead fetuses/litter) and fetal weights between the RDV-dosed group and concurrent controls at GD 14, 15, 16, and 18. No changes were observed in transcript levels of inflammation markers in the RDV-dosed group when compared to the concurrent control group. There was a slightly lower ratio of fetal IgG level to maternal IgG levels in the RDV-dosed group;however, no statistically significant differences were observed between the RDV-dosed group and concurrent controls on GD 14, 15, 16, and 18. Our results suggest that a daily dose of 25 mg/kg RDV on GDs 10-14 in humanized mice did not cause adverse effects on placenta and fetal development. (Funded by the Perinatal Health Center of Excellence: E0300201.).
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In addition to the classical functions of the musculoskeletal system and calcium homeostasis, the function of vitamin D as an immune modulator is well established. The vitamin D receptors and enzymes that metabolize vitamin D are ubiquitously expressed in most cells in the body, including T and B lymphocytes, antigen-presenting cells, monocytes, macrophages and natural killer cells that trigger immune and antimicrobial responses. Many in vitro and in vivo studies revealed that vitamin D promotes tolerogenic immunological action and immune modulation. Vitamin D adequacy positively influences the expression and release of antimicrobial peptides, such as cathelicidin, defensin, and anti-inflammatory cytokines, and reduces the expression of proinflammatory cytokines. Evidence suggestss that vitamin D's protective immunogenic actions reduce the risk, complications, and death from COVID-19. On the contrary, vitamin D deficiency worsened the clinical outcomes of viral respiratory diseases and the COVID-19-related cytokine storm, acute respiratory distress syndrome, and death. The study revealed the need for more preclinical studies and focused on well-designed clinical trials with adequate sizes to understand the role of vitamin D on the pathophysiology of immune disorders and mechanisms of subduing microbial infections, including COVID-19.Copyright © 2023 Bentham Science Publishers.
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Background: Sepsis is a life-threatening condition that needs immediate diagnosis and treatment to maximize the chances of survival. Bacterial superinfection is a severe and frequent complication among COVID-19 patients and its diagnosis is challenging. Previous reports suggested that Pancreatic Stone Protein (PSP) may be a predictive biomarker for sepsis in critically ill patients. We report a case series of three COVID- 19 patients admitted to our intensive care unit (ICU) with risk of sepsis. Method(s): We daily monitored PSP, procalcitonin (PCT), and C-reactive protein (CRP) levels in three COVID- 19 patients admitted to our ICU. Microbiological sampling and antibiotic treatment were performed according to the ward organization and in case of clinical suspects for infection. Positive cultures and antibiotic treatment were retrieved from clinical charts and patients were followed from ICU admission up to a maximum of 20 days. Result(s): Patient 1 (male, 55 years-old, overweight, no other comorbidity) was admitted to the ICU in treatment with Ceftriaxone then interrupted on day 7. On day 2 he was intubated and piperacillin/tazobactam was started on day 12 for suspected hospital acquired pneumonia. PSP levels markedly increased on day 10 with no significant changes in CRP and PCT levels. On day 13 a positive bronchospirate for Klebsiella pneumoniae was found. Similarly, patient 2 (male, 70 years-old, mild emphysema and diabetes) was admitted to ICU without antibiotic and with a PSP level of 287 ng/ml. His conditions rapidly worsened in severe septic shock requiring intubation. CRP markedly raised 48-72 hours after PSP with only mild increase of PCT. Patient 3 (male, 78 years-old, no comorbidities) was admitted to ICU with high levels of PSP and piperacillin/tazobactam therapy was started. After 48-72 hours CRP levels increased with no significant changes of PCT. A positive bronchospirate for Ps. aeruginosa was collected on day 3. Conclusion(s): Our findings suggest a potential role of PSP as early biomarker of sepsis in critically ill COVID-19 patients. Daily PSP monitoring may anticipate an appropriate treatment of COVID-19 patients with a septic complication in comparison with the actual laboratory markers. Further studies are needed to confirm our hypothesis.
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Background & Aim: The pro-angiogenic, immunoregulatory and anti- inflammatory properties of MSCs are being exploited for the development of cellular therapies, including the treatment of graft versus host disease (GvHD), inflammatory bowel disease and COVID-19. SNBTS have developed a GMP process to bank umbilical cord MSCs (UC-MSCs) whereby we can reliably bank 100 vials of 10 million P2 UC-MSCs per cord. Each of these vials can be extensively expanded and stored for specific applications. The ultimate aim of the bank is for off-the-shelf clinical use, e.g., in GvHD or as an adjuvant therapy in Islet transplantations. Methods, Results & Conclusion(s): During process development, different basal media and supplements were screened for proliferation and MSC marker expression. Cells grown in promising media combinations were then tested for tri-lineage differentiation (identity), their chemokine/cytokine expression and T-cell inhibition (function) assessed. Medium selected for further GMP development and scale up was ultimately determined by all round performance and regulatory compliance. GMP-like UC-MSCs were shown to have immune-modulatory activity in T-cell proliferation assays at 4:1 or 16:1 ratios. Co-culture of UC-MSCs and freshly isolated leukocytes, +/- the immune activating agent LPS, show a dose dependent survival effect on leukocytes. In particular, neutrophils, which are normally very short lived in vitro demonstrated increased viability when co-cultured with UCMSCs. The survival effect was partially reproduced when UC-MSC were replaced with conditioned medium or cell lysate indicating the involvement of soluble factors. This improved neutrophil survival also correlates with results from leukocyte migration studies that demonstrate neutrophils to be the main cell type attracted to MSCs in in vitro and in vivo. Genetic modification of UC-MSC may improve their therapeutic potential. We have tested gene editing by CRISPR/Cas9 technology in primary UC-MSCS. The CXCL8 gene, highly expressed in UC-MSC, was targeted in isolates from several different donors with editing efficiencies of 78-96% observed. This translated to significant knockdown of CXCL8 protein levels in resting cells, however after stimulation levels of CXCL8 were found to be very similar in edited and non-edited UC-MSCs. This observation requires further study, but overall the results show the potential to generate future banks of primary UC-MSCS with genetically enhanced pro-angiogenic, immunoregulatory and/or anti-inflammatory activities.Copyright © 2023 International Society for Cell & Gene Therapy
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Background/Objectives: Rosmarinus Officinalis L.(Rosemary) extract Carnosic acid(CA) has been investigated for its antimicrobial and antioxidative properties(1). Only limited number of publications reported the utilization of this extract in SARSCoV-2 infection. Also, the mechanistic understanding of CA remains to be determined. Our goal was to elucidate the potential role of CA in COVID19. To obtain mechanistic insight of pharmacogenomic action of CA, comprehensive in silico analyses were performed. Further in vitro experiments were done to illustrate the cytotoxicity of CA and confirm in silico findings. Method(s): CA was extracted from Rosmarinus Officinalis L. by HPLC. Stimulation assays were performed using the COVID19 samples. In silico pharmacogenomic properties of CA were performed by using SwissADME. SwissTargetPrediction tool was utilized to define the possible targets. SARS-CoV-2-interacting proteins were evaluated using STRING(2). To verify in silico findings, gene expression levels were analyzed using qPCR. Result(s): Among the top 15 SwissTargetPrediction target molecules(out of 100), Prostaglandin E synthase(PTGES) had the highest probability for CA. Among 332 proteins identified using the STRING, PGES2 was found to be interacting with the nsp7, important molecule for viral replication. The stimulation assays and gene expression analyses confirmed the viral inhibitory role of CA through PTGES pathway. Conclusion(s): To our knowledge, our work is the first to reveal the inhibitory role of CA in COVID19 through PTGES pathway. Given the crucial role of PTGES in inflammation, it is noteworthy to examine CA as potential anti-SARS-CoV2 therapeutics.
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Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (>= 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-offlight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Result(s): We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICIinsensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusion(s): Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer.
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Background/Objectives: SARS-CoV2 causes the COVID-19 disease, capable of producing a severe acute respiratory syndrome. Several clinical variables and genetic variants have been related to a worse prognosis. The aim of this study is to measure if difference in the gene expression are associated with COVID-19 severity. Method(s): We performed RNA-seq Transcriptome in RNA extracted from lymphoblastoid cell line in 20 patients who require hospitalization (10 from the intensive care unit) in a GeneStudio S5 Plus Sequencer (Ion Torrent Technology). FASTQ files were obtained and trimmed using BBtools, BBduk for cutting, filtering and masking the data, and Dedupe for the elimination of duplicates. Mapping and counting matrix was done in bash using the Salmon program. Differential expression analysis and subsequent functional enrichment was performed using Rstudio (DESeq2, ClusterProfiler, GO and KEGG). Result(s): We observed that 2042 differentially expressed genes (1996 overexpressed, LFC>0 and 406 underexpressed, LFC<0) were obtained between patients who require hospitalization versus those in the intensive care unit. We found some genes previously SARS-CoV-2 associated (PGLYRP1, HDAC9 and FUT4). Furthermore, genes involved in the activity of the immune system and in inflammatory processes showed significant differences between cohorts (ABCF1 (LFC = -25.14, padj = 1.05e-13), ABHD16A (LFC = 25.00, padj = 1.05e-13) and IER3 (LFC = -24.45, padj = 2.43e-13)). Conclusion(s): We described differential expression in genes of the immune system and inflammatory processes that might be have a role in the risk of develop severe symptoms of COVID-19, including admission in the intensive care unit. This results should be validated by additional functional studies.
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Objective: The factors affecting the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies from mother to newborn and the duration of seropositivity rates in these infants have not yet been clearly demonstrated. The objectives of this study were (1) to assess the levels of SARS-CoV-2 spike-specific immunoglobulin G (IgG) in women infected in the pregnancy period and newborns born to these women and (2) to search the transplacental transfer ratio of spike-specific IgG. Method(s): Seventy pregnant women with symptomatic SARS-CoV-2 infection and their newborns were prospectively followed. Anti-SARS-CoV-2 immunoassay was used for the detection of the in vitro quantitative determination of total antibodies to the SARS-CoV-2 spike protein. Discussion(s): Spike-specific IgG was demonstrated in 89.1% (44 of 46) of pregnant women infected more than 14 days before delivery and in 92.6% (43 of 44) of their newborns. Median transfer ratio of spike-specific Ig was 0.87 (interquartile range [IQR], 0.34-0.90), 1.0 (IQR, 0.9-0.29), and 0.81 (IQR, 0.02-1.0) in first trimester (n = 4), second trimester (n = 14), and third trimester (n = 28) pregnant women, respectively. Antibody transfer ratio was correlated with time elapsed from infection (p < 0.001). Peak antibody transfer ratio above 1 was observed at a median 60 to 120 days after the infection from delivery. Antibody transfer ratio was high in pregnant women infected more than 60 days before delivery (p < 0.001). Transfer ratio was significantly higher in the severe-critically symptomatic women (n = 15) than the mild-moderately symptomatic women (n = 55) (p = 0.001). At 3 months, 18 of 25 infants (72%) had spike-specific IgG. Conclusion(s): Timing from infection to delivery and severity of maternal infection are critical in assessing the antibody generation and transport. Higher antibody transfer ratio can be detected in neonates when SARS-CoV-2 infection is present for more than 60 days before birth. Maternally derived antibody can persist for 3 months after birth.Copyright © 2023. The Author(s).
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Cumulative data regardingCOVID-19 infection during pregnancy have demonstrated the ability of SARS-CoV-2 to infect the placenta. However, the mechanisms of SARS-CoV-2 placental viral entry are yet to be defined. SARS-CoV-2 infects cells by binding to the ACE2 receptor. However, SARS-CoV-2 cell entry also requires co-localization of spike protein cleavage by the serine protease TMPRSS2. However, the co-expression of ACE2 and TMPRSS2 in placental cells is debated, raising the question of whether potential non-canonical molecular mechanismsmay be involved in SARS-CoV-2 placental cells' viral entry. Although published data regarding the ability of the SARS-CoV- 2 to infect the fetus are contradicting, the placenta appears to be an immunological barrier to active SARS-CoV-2 infection and vertical transmission;however, the mechanism is unclear. Our experiments demonstrated the ability of the SARS-CoV-2 virus to directly infect the placenta and induce transcriptomic responses in COVID-positive mothers. These transcriptomic responses were characterized by differential expression of specific mRNAs and miRNAs associated with SARS-CoV-2 infection, with induction of specific placental miRNAs that can inhibit viral replication. Failure in such mechanisms may be associated with vertical transmission. Since the start of the COVID-19 pandemic, the COVID-19 mRNA vaccines have been widely used to reduce the morbidity and mortality of SARS-CoV-2 infection. Historically, non-live vaccines have not caused any harm to pregnant mothers;however, it is unclear whether our current understanding of the effects of non-live vaccines serves as a reliable precedent owing to the novel technology used to create these mRNA vaccines. Since there are no definitive data on the possible biodistribution of mRNA vaccines to the placenta, the likelihood of vaccine mRNA reaching the fetus remains uncertain. Little has been reported on the tissue localization of the lipid nanoparticles (LNPs) after intramuscular (IM) administration of the mRNA vaccine. The biodistribution of LNPs containing the mRNA vaccine has been investigated in animal models but not humans. In the murine model, the vaccine LNPs were rapidly disseminated to several organs, including the heart, liver, kidney, lung, and spleen, following IM administration. However, no traditional pharmacokinetic or biodistribution studies have been performed with the mRNA vaccines, including possible biodistribution to breast milk or the placenta.
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The current outbreak of COVID-19 is caused by the SARS-CoV-2 virus that has affected > 210 countries. Various steps are taken by different countries to tackle the current war-like health situation. In India, the Ministry of AYUSH released a self-care advisory for immunomodulation measures during the COVID-19 and this review article discusses the detailed scientific rationale associated with this advisory. Authors have spotted and presented in-depth insight of advisory in terms of immunomodulatory, antiviral, antibacterial, co-morbidity associated actions, and their probable mechanism of action. Immunomodulatory actions of advised herbs with no significant adverse drug reaction/toxicity strongly support the extension of advisory for COVID-19 prevention, prophylaxis, mitigations, and rehabilitation capacities. This advisory also emphasized Dhyana (meditation) and Yogasanas as a holistic approach in enhancing immunity, mental health, and quality of life. The present review may open-up new meadows for research and can provide better conceptual leads for future researches in immunomodulation, antiviral-development, psychoneuroimmunology, especially for COVID-19.Copyright © 2021, Institute of Korean Medicine, Kyung Hee University.
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Background/Objectives: Genetic factors influence COVID-19 susceptibility and outcomes, including the development of pulmonary fibrosis (i.e. lung scarring). Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease and the most common cause of pulmonary fibrosis in the general population. Genome-wide association studies (GWAS) of COVID-19 and IPF revealed genes associated with both diseases, suggesting these share genetic risk factors. Here we performed a genetic overlap study between COVID-19 and IPF. Method(s): Summary statistics from an IPF 5-way meta-GWAS and from the COVID-19 Host Genetics initiative GWAS metaanalysis (v6) were used. We performed genetic correlation analyses and assessed individual genetic signals to identify those variants shared between both traits. We conducted colocalisation analyses to determine whether the same causal variant was driving both traits. Finally, the association of overlapping variants with gene expression was assessed and a phenome-wide association study was performed. Result(s): There was a positive genetic correlation between severe COVID-19 and IPF. We found four genetic loci with likely shared causal variants between both traits, including one novel risk locus at 7q22.1 that colocalised with decreased ZKSCAN1 and TRIM4 expression in blood. The other three loci colocalised with MUC5B, ATP11A and DPP9 expression. The locus associated with increased ATP11A expression was also associated with higher Hb1AC levels, a biomarker used in diabetes. Conclusion(s): Results suggest there are shared biological processes driving IPF and severe COVID-19 phenotypes.
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Objective: evaluation of the clinical and economic efficiency of using Levilimab in the treatment of moderate and severe COVID-19 based on real world data (RWD). Material and methods. A single-center observational retrospective case-control study was performed. According to the matching algorithm, 834 pairs of patients with moderate and 347 pairs with severe infection were selected, similar in gender, age, vaccination status, severity of the disease and the level of C-reactive protein. Results. The clinical efficiency of Levilimab with respect to in-hospital mortality was demonstrated both for the moderate course (6% in the Levilimab group and 10% in the standard therapy group;odds ratio (OR) 1.71;95% confidence interval (CI) 1.19-2.47;p<0.01) and for the severe course of COVID-19 (63% and 82%, respectively;OR 2.70;95% CI 1.90-3.82;p<0.01). The costs per 1 treated patient were also higher in the Levilimab therapy groups: the difference in costs compared to the standard therapy group for patients with moderate disease was 54 665.30 rubles, with severe disease - 91 285.85 rubles. The estimated cost of the additional effectiveness of Levilimab for the moderate course of the disease was 13, 666.32 rubles, for the severe course - 4, 804.51 rubles. Conclusion. The use of Levilimab for the treatment of moderate and severe COVID-19 is feasible both from a clinical and economic points of view. Conducting RWD trials is an important tool to understand the effectiveness of medical technologies in real clinical practice.Copyright © 2023 IRBIS LLC. All Rights Reserved.