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Bosnian Journal of Basic Medical... Oct 2022Immune cell infiltration plays an essential role in the occurrence and development of colon cancer. However, the main tumor-associated immune cell infiltration and its...
Immune cell infiltration plays an essential role in the occurrence and development of colon cancer. However, the main tumor-associated immune cell infiltration and its gene regulation in colon cancer still need to be further clarified in order to provide a new perspective for diagnosing and treating this disease. For this study, single-cell RNA sequencing (scRNA-seq) expression profiles and TCGA colon cancer data sets were first acquired from the GEO database. Then, Seurat, Monocle, LIMMA, Clusterprofile, GSVA and GSEABase algorithms were used to systematically examine the data. Potential target drugs corresponding to target genes were analyzed in the Drugbank database and detected by molecular docking. Immunohistochemistry was used to assess the level of C1QC expression in the tissue microarray. Single cell analysis suggested that neutrophil activation might be the critical regulatory pathway in colon cancer and that macrophages were the main cell population involved. Subsequent functional enrichment analysis on differential genes in macrophages suggested that C1QC may be a critical regulatory factor in the occurrence and progression of colon cancer, and was closely related to the survival of patients. According to the drug target prediction, palivizumab is a targeted drug for C1QC, and molecular docking demonstrated that palivizumab binds to C1QC. Additionally, tissue-microarray based immunohistochemical analysis showed that C1QC was highly expressed in colon cancer tissue, and the prognosis of colon cancer patients with high C1QC expression was worse, closely related to age, lymphatic metastasis and the TNM stage (Tumor, Nodes and Metastases). Our findings suggest that C1QC may regulate the macrophages in colon cancer immune infiltration, which is expected to be a potential immunotherapy target for colon cancer, and beneficial for the diagnosis and prognosis of colon cancer patients.
Topics: Humans; Prognosis; Gene Expression Regulation, Neoplastic; Molecular Docking Simulation; Palivizumab; Neoplasm Staging; Colonic Neoplasms; Sequence Analysis, RNA; Carcinoma
PubMed: 35765947
DOI: 10.17305/bjbms.2022.7309 -
Analytica Chimica Acta Jul 2022Full characterization of the attached carbohydrate moieties of glycoproteins is of high importance for both the rapidly growing biopharmaceutical industry and the...
Full characterization of the attached carbohydrate moieties of glycoproteins is of high importance for both the rapidly growing biopharmaceutical industry and the biomedical field. In this paper we report the design and production of three important 6HIS-tagged exoglycosidases (neuraminidase, β-galactosidase and hexosaminidase) to support rapid solid phase N-glycan sequencing with high robustness using immobilized enzymes. The exoglycosidases were generated in bacterial expression systems with high yield. Oriented immobilization via the 6HIS-tag portion of the molecules supported easy accessibility to the active sites and consequently high digestion performance. The three exoglycosidases were premixed in an appropriate matrix format and processed in a low-salt buffer to support long term storage. The digestion efficiencies of the immobilized enzymes were demonstrated by using solid phase sequencing in conjunction with capillary electrophoresis analysis of the products on a commercial glycoprotein therapeutic (palivizumab) and human serum derived fluorophore labeled glycans.
Topics: Electrophoresis, Capillary; Enzymes, Immobilized; Glycoproteins; Glycoside Hydrolases; Humans; Polysaccharides
PubMed: 35680335
DOI: 10.1016/j.aca.2022.339906 -
Anales de Pediatria Jun 2022The aim of the study was to assess the incidence of hospital admission due to severe acute respiratory infection by respiratory syncytial virus (RSV-ARI) in children...
INTRODUCTION
The aim of the study was to assess the incidence of hospital admission due to severe acute respiratory infection by respiratory syncytial virus (RSV-ARI) in children with primary immunodeficiencies (PIDs) and the severity of RSV-ARI in these patients.
METHODS
We conducted a nationwide cross-sectional retrospective and prospective multicentre study in the 2011-2017 period. The study was performed in 15 Spanish hospitals and included children with PID who required hospital admission due to RSV-ARI.
RESULTS
Out of 439 patients with PID followed up at participating hospitals, 13 (3%) required hospital admission due to RSV-ARI. The median age of admitted patients was 1.6 years (interquartile range, 0.5-2.2), and 7 were male. The types of PID most frequently associated with admission due to RSV-ARI were combined immunodeficiency (CID; 4/71; 6%) and CID with associated or syndromic features (CIDwASF; 6/147; 4%). Two of the 13 patients were receiving palivizumab for RSV prophylaxis, and 3 received potentially active therapies against RSV during the hospital stay. Viral coinfection was detected in 6 patients, 5 (39%) developed complications, and 4 (31%) required admission to the paediatric intensive care unit. There were no documented RSV-related deaths.
CONCLUSIONS
In the group of patients with PID, severe RSV infection requiring hospitalization is more frequent in patients with CID and CIDwASF, in whom special efforts should be made to prevent RSV infection. Further studies are needed to confirm these results.
Topics: Child; Cross-Sectional Studies; Female; Hospitalization; Humans; Infant; Male; Prospective Studies; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Retrospective Studies
PubMed: 35637145
DOI: 10.1016/j.anpede.2022.03.002 -
Global Pediatric Health 2022In recent years, epidemics of respiratory syncytial virus (RSV) have been seen in the summer in Japan. Patients hospitalized in the summer used a high-flow oxygen...
In recent years, epidemics of respiratory syncytial virus (RSV) have been seen in the summer in Japan. Patients hospitalized in the summer used a high-flow oxygen administration device more frequently than patients hospitalized in the winter. This study was a retrospective study to examine the variables associated with duration of oxygen therapy and severe cases. Subjects were pediatric patients diagnosed with RSV infection and hospitalized for treatment during the 5 years from April 2014 to March 2019. Data from 292 patients were analyzed. Duration of oxygen therapy was significantly associated with bronchial asthma (partial regression coefficient: 0.897, = .004). Hospitalization in summer was significantly associated with severe condition (adjusted odds ratio: 4.07, 95% confidence interval: 1.16-14.27). The present study showed that bronchial asthma is a risk factor for prolonged oxygen therapy and infection in summer is a risk factor for progression to severe condition in cases of RSV infection.
PubMed: 35601928
DOI: 10.1177/2333794X221100950 -
Journal of Proteins and Proteomics 2022Viral infections are progressively becoming a global health burden, as witnessed in the ongoing COVID-19 pandemic. Respiratory Syncytial Virus (RSV) is another highly...
UNLABELLED
Viral infections are progressively becoming a global health burden, as witnessed in the ongoing COVID-19 pandemic. Respiratory Syncytial Virus (RSV) is another highly contagious negative-sense RNA virus that causes lower respiratory tract infections and high mortality in infants. Palivizumab (Synagis) is the only humanized monoclonal antibody (mAb) approved by the FDA against RSV. The virus neutralization efficacy often depends on the nature and abundance of the glycoforms in therapeutic mAbs. Therefore, a thorough estimation of their PTM profile, especially glycosylation, is relevant. Here, we describe the intact and released glycan analysis of palivizumab (Synagis) using HILIC chromatography and mass spectrometry. We detected five glycoforms (Man5/G0FB, G0F/G1F, G1F/G1F, G0FB/G0FB, and G2F/G2F) in deconvoluted MS spectra of intact glycosylated palivizumab. The mapping of the peptide and glycopeptides using LC-ESI-MS led to the detection of associated PTMs and the direct identification of a glycopeptide, GlcNAcMan. EEQYNSTYR, derived from the heavy chain of palivizumab.Release glycan analysis using UHPLC-HILIC revealed a typical glycan profile consisting of major glycans, G0F (33.94%), G1F (35.50%), G2F (17.24%) also reported previously and minor G1F' (5.81%), Man5 (3.96%) and G0FB (2.26%) forms with the superior resolution of isomeric G1F/G1F'. Next, we provide the first experimental evidence of Neu5Gc in the commercial palivizumab formulation using DMB labelling. The estimated monosaccharide composition was consistent with previous studies. The findings of the study highlight the efficiency of the release glycan method in providing a correct measure of the total palivizumab glycan pool compared to the intact glycoprotein/glycopeptide approach. The UHPLC-RPLC/HILIC and MS combinations provide a more comprehensive glycoprofile assessment due to the parallel use of fluorescent labels for the analysis of the release of -glycan, sialic acid, and monosaccharide composition. This approach is suitable for quick quality testing and market surveillance of therapeutic mAbs. Alongside a well-perceived need for cost-effective immunoprophylaxis and the ongoing fast-paced development of next-generation variants of palivizumab, such as MEDI8897, the study reiterates glycosylation as a critical parameter that needs monitoring for drug characterization and quality control.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s42485-022-00086-1.
PubMed: 35572846
DOI: 10.1007/s42485-022-00086-1 -
Frontiers in Immunology 2022Respiratory syncytial virus (RSV) causes a spectrum of respiratory illnesses in infants and young children that may lead to hospitalizations and a substantial number of... (Review)
Review
Respiratory syncytial virus (RSV) causes a spectrum of respiratory illnesses in infants and young children that may lead to hospitalizations and a substantial number of outpatient visits, which result in a huge economic and healthcare burden. Most hospitalizations happen in otherwise healthy infants, highlighting the need to protect all infants against RSV. Moreover, there is evidence on the association between early-life RSV respiratory illness and recurrent wheezing/asthma-like symptoms As such, RSV is considered a global health priority. However, despite this, the only prevention strategy currently available is palivizumab, a monoclonal antibody (mAb) indicated in a subset of preterm infants or those with comorbidities, hence leaving the majority of the infant population unprotected against this virus. Therefore, development of prevention strategies against RSV for all infants entering their first RSV season constitutes a large unmet medical need. The aim of this review is to explore different immunization approaches to protect all infants against RSV. Prevention strategies include maternal immunization, immunization of infants with vaccines, immunization of infants with licensed mAbs (palivizumab), and immunization of infants with long-acting mAbs (e.g., nirsevimab, MK-1654). Of these, palivizumab use is restricted to a small population of infants and does not offer a solution for all-infant protection, whereas vaccine development in infants has encountered various challenges, including the immaturity of the infant immune system, highlighting that future pediatric vaccines will most likely be used in older infants (>6 months of age) and children. Consequently, maternal immunization and immunization of infants with long-acting mAbs represent the two feasible strategies for protection of all infants against RSV. Here, we present considerations regarding these two strategies covering key areas which include mechanism of action, "consistency" of protection, RSV variability, duration of protection, flexibility and optimal timing of immunization, benefit for the mother, programmatic implementation, and acceptance of each strategy by key stakeholders. We conclude that, based on current data, immunization of infants with long-acting mAbs might represent the most effective approach for protecting all infants entering their first RSV season.
Topics: Aged; Antibodies, Monoclonal; Antiviral Agents; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Palivizumab; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 35572550
DOI: 10.3389/fimmu.2022.880368 -
Molecules (Basel, Switzerland) Mar 2022Respiratory syncytial virus infection (RSVI) is an acute medical and social problem in many countries globally. Infection is most dangerous for infants under one year... (Review)
Review
Respiratory syncytial virus infection (RSVI) is an acute medical and social problem in many countries globally. Infection is most dangerous for infants under one year old and the elderly. Despite its epidemiological relevance, only two drugs are registered for clinical use against RSVI: ribavirin (approved in a limited number of countries due to side effects) and palivizumab (Synagis), which is intended only for the prevention, but not the treatment, of infection. Currently, various research groups are searching for new drugs against RSV, with three main areas of research: small molecules, polymeric drugs (proteins and peptides), and plant extracts. This review is devoted to currently developed protein and peptide anti-RSV drugs.
Topics: Aged; Antiviral Agents; Humans; Infant; Palivizumab; Peptides; Respiratory Syncytial Virus Infections; Respiratory Tract Infections
PubMed: 35408661
DOI: 10.3390/molecules27072263 -
Medicine Mar 2022Given the high disability rate of multiple sclerosis (MS), there is a need for safer and more effective therapeutic agents. Existing literature highlights the prominent...
Given the high disability rate of multiple sclerosis (MS), there is a need for safer and more effective therapeutic agents. Existing literature highlights the prominent roles of miRNA in MS pathophysiology. Nevertheless, there are few studies that have explored the usefulness of existing drugs in treating MS through potential miRNA-modulating abilities.The current investigation identifies genes that may exacerbate the risk of MS due to their respective miRNA associations. These findings were then used to determine potential drug candidates through the construction of miRNA-regulated drug-pathway network through genes. We uncovered a total of 48 MS risk pathways, 133 MS risk miRNAs, and 186 drugs that can affect these pathways. Potential MS risk miRNAs that are also regulated by therapeutic candidates were hsa05215 and hsa05152. We analyzed the properties of the miRNA-regulated drug-pathway network through genes and uncovered a number of novel MS agents by assessing their respective Z-values.A total of 20 likely drug candidates were identified, including human immunoglobulin, aspirin, alemtuzumab, minocycline, abciximab, alefacept, palivizumab, bevacizumab, efalizumab, tositumomab, minocycline, etanercept, catumaxomab, and sarilumab. Each of these agents were then explored with regards to their likely mechanism of action in treating MS.The current investigation provides a fresh perspective on MS biological mechanisms as well as likely treatment strategies.
Topics: Alemtuzumab; Antineoplastic Agents; Drug Repositioning; Humans; MicroRNAs; Multiple Sclerosis
PubMed: 35356949
DOI: 10.1097/MD.0000000000029107 -
MBio Feb 2021There is an unmet need for preclinical models to understand the pathogenesis of human respiratory viruses and predict responsiveness to immunotherapies. Airway organoids...
The Human Nose Organoid Respiratory Virus Model: an Human Challenge Model To Study Respiratory Syncytial Virus (RSV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Pathogenesis and Evaluate Therapeutics.
There is an unmet need for preclinical models to understand the pathogenesis of human respiratory viruses and predict responsiveness to immunotherapies. Airway organoids can serve as an human airway model to study respiratory viral pathogenesis; however, they rely on invasive techniques to obtain patient samples. Here, we report a noninvasive technique to generate human nose organoids (HNOs) as an alternative to biopsy-derived organoids. We made air-liquid interface (ALI) cultures from HNOs and assessed infection with two major human respiratory viruses, respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infected HNO-ALI cultures recapitulate aspects of RSV and SARS-CoV-2 infection, including viral shedding, ciliary damage, innate immune responses, and mucus hypersecretion. Next, we evaluated the feasibility of the HNO-ALI respiratory virus model system to test the efficacy of palivizumab to prevent RSV infection. Palivizumab was administered in the basolateral compartment (circulation), while viral infection occurred in the apical ciliated cells (airways), simulating the events in infants. In our model, palivizumab effectively prevented RSV infection in a concentration-dependent manner. Thus, the HNO-ALI model can serve as an alternative to lung organoids to study respiratory viruses and test therapeutics. Preclinical models that recapitulate aspects of human airway disease are essential for the advancement of novel therapeutics and vaccines. Here, we report a versatile airway organoid model, the human nose organoid (HNO), that recapitulates the complex interactions between the host and virus. HNOs are obtained using noninvasive procedures and show divergent responses to SARS-CoV-2 and RSV infection. SARS-CoV-2 induces severe damage to cilia and the epithelium, no interferon-λ response, and minimal mucus secretion. In striking contrast, RSV induces hypersecretion of mucus and a profound interferon-λ response with ciliary damage. We also demonstrated the usefulness of our HNO model of RSV infection to test the efficacy of palivizumab, an FDA-approved monoclonal antibody to prevent severe RSV disease in high-risk infants. Our study reports a breakthrough in both the development of a novel nose organoid model and in our understanding of the host cellular response to RSV and SARS-CoV-2 infection.
Topics: Infant; Humans; SARS-CoV-2; Palivizumab; COVID-19; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Lung; Organoids
PubMed: 35164569
DOI: 10.1128/mbio.03511-21 -
Wellcome Open Research 2021: Bronchiolitis (most frequently caused by respiratory syncytial virus; RSV) is a common winter disease predominantly affecting children under one year of age. It is a...
Study Pre-protocol for "BronchStart - The Impact of the COVID-19 Pandemic on the Timing, Age and Severity of Respiratory Syncytial Virus (RSV) Emergency Presentations; a Multi-Centre Prospective Observational Cohort Study".
: Bronchiolitis (most frequently caused by respiratory syncytial virus; RSV) is a common winter disease predominantly affecting children under one year of age. It is a common reason for presentations to an emergency department (ED) and frequently results in hospital admission, contributing to paediatric units approaching or exceeding capacity each winter. During the SARS-CoV-2 pandemic, the circulation of RSV was dramatically reduced in the United Kingdom and Ireland. Evidence from the Southern Hemisphere and other European countries suggests that as social distancing restrictions for SARS-CoV-2 are relaxed, RSV infection returns, causing delayed or even summer epidemics, with different age distributions. : The ability to track, anticipate and respond to a surge in RSV cases is critical for planning acute care delivery. There is an urgent need to understand the onset of RSV spread at the earliest opportunity. This will influence service planning, to inform clinicians whether the population at risk is a wider age range than normal, and whether there are changes in disease severity. This information is also needed to inform decision on the timing of passive immunisation of children at higher risk of hospitalisation, intensive care admission or death with RSV infection, which is a public health priority. : This multi-centre prospective observational cohort study will use a well-established research network (Paediatric Emergency Research in the UK and Ireland, PERUKI) to report in real time cases of RSV infection in children aged under two years, through the collection of essential, but non-identifying patient information. Forty-five centres will gather initial data on age, index of multiple deprivation quintile, clinical features on presentation, and co-morbidities. Each case will be followed up at seven days to identify treatment, viral diagnosis and outcome. Information be released on a weekly basis and used to support clinical decision making.
PubMed: 34458589
DOI: 10.12688/wellcomeopenres.16778.2