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Clinical Cancer Research : An Official... Mar 2023Acute and chronic GVHD remain major causes of transplant-related morbidity and mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). We have...
PURPOSE
Acute and chronic GVHD remain major causes of transplant-related morbidity and mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). We have shown CD83 chimeric antigen receptor (CAR) T cells prevent GVHD and kill myeloid leukemia cell lines. In this pilot study, we investigate CD83 expression on GVHD effector cells, correlate these discoveries with clinical outcomes, and evaluate critical therapeutic implications for transplant recipients.
EXPERIMENTAL DESIGN
CD83 expression was evaluated among circulating CD4+ T cells, B-cell subsets, T follicular helper (Tfh) cells, and monocytes from patients with/without acute or chronic GVHD (n = 48 for each group), respectively. CD83 expression was correlated with survival, TRM, and relapse after alloHCT. Differential effects of GVHD therapies on CD83 expression was determined.
RESULTS
CD83 overexpression on CD4+ T cells correlates with reduced survival and increased TRM. Increased CD83+ B cells and Tfh cells, but not monocytes, are associated with poor posttransplant survival. CD83 CAR T eliminate autoreactive CD83+ B cells isolated from patients with chronic GVHD, without B-cell aplasia as observed with CD19 CAR T. We demonstrate robust CD83 antigen density on human acute myeloid leukemia (AML), and confirm potent antileukemic activity of CD83 CAR T in vivo, without observed myeloablation.
CONCLUSIONS
CD83 is a promising diagnostic marker of GVHD and warrants further investigation as a therapeutic target of both GVHD and AML relapse after alloHCT.
Topics: Humans; Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute; Pilot Projects; Receptors, Chimeric Antigen; Recurrence; Transplantation, Homologous
PubMed: 36622700
DOI: 10.1158/1078-0432.CCR-22-2837 -
Journal of Cellular and Molecular... Feb 2022Cold-inducible RNA-binding protein (CIRP) is a stress-response protein that is expressed in various types of cells and acts as an RNA chaperone, modifying the stability... (Review)
Review
Cold-inducible RNA-binding protein (CIRP) is a stress-response protein that is expressed in various types of cells and acts as an RNA chaperone, modifying the stability of its targeted mRNA. Intracellular CIRP could also be released into extracellular space and once released, extracellular CIRP (eCIRP) acts as a damage-associated molecular pattern (DAMP) to induce and amplify inflammation. Recent studies have found that eCIRP could promote acute lung injury (ALI) via activation of macrophages, neutrophils, pneumocytes and lung vascular endothelial cells in context of sepsis, haemorrhagic shock, intestinal ischemia/reperfusion injury and severe acute pancreatitis. In addition, CIRP is also highly expressed in the bronchial epithelial cells and its expression is upregulated in the bronchial epithelial cells of patients with chronic obstructive pulmonary diseases (COPD) and rat models with chronic bronchitis. CIRP is a key contributing factor in the cold-induced exacerbation of COPD by promoting the expression of inflammatory genes and hypersecretion of airway mucus in the bronchial epithelial cells. Besides, CIRP is also involved in regulating pulmonary fibrosis, as eCIRP could directly activate and induce an inflammatory phenotype in pulmonary fibroblast. This review summarizes the findings of CIRP investigation in respiratory diseases and the underlying molecular mechanisms.
Topics: Acute Disease; Animals; Endothelial Cells; Humans; Lung; Lung Diseases; Pancreatitis; RNA-Binding Proteins; Rats
PubMed: 34953031
DOI: 10.1111/jcmm.17142 -
EBioMedicine Sep 2023Patients diagnosed with environmental/occupational bronchiolitis obliterans (BO) over the last 2 decades often present with an indolent evolution of respiratory symptoms... (Review)
Review
Patients diagnosed with environmental/occupational bronchiolitis obliterans (BO) over the last 2 decades often present with an indolent evolution of respiratory symptoms without a history of high-level, acute exposure to airborne toxins. Exertional dyspnea is the most common symptom and standard clinical and radiographic evaluation can be non-diagnostic. Lung biopsies often reveal pathological abnormalities affecting all distal lung compartments. These modern cases of BO typically exhibit the constrictive bronchiolitis phenotype of small airway remodeling, along with lymphocytic inflammation. In addition, hypertensive-type remodeling of intrapulmonary vasculature, diffuse fibroelastosis of alveolar tissue, and fibrous thickening of visceral pleura are frequently present. The diagnosis of environmental/occupational BO should be considered in patients who present with subacute onset of exertional dyspnea and a history compatible with prolonged or recurrent exposure to environmental toxins. Important areas for future studies include development of less invasive diagnostic approaches and testing of novel agents for disease prevention and treatment.
Topics: Humans; Bronchiolitis Obliterans; Biopsy; Dyspnea; Phenotype
PubMed: 37598462
DOI: 10.1016/j.ebiom.2023.104760 -
Respiratory Care Jul 2022High-frequency percussive ventilation (HFPV) is an alternative mode of mechanical ventilation that has been shown to improve gas exchange in subjects with severe...
BACKGROUND
High-frequency percussive ventilation (HFPV) is an alternative mode of mechanical ventilation that has been shown to improve gas exchange in subjects with severe respiratory failure. We hypothesized that HFPV use would improve ventilation and oxygenation in intubated children with acute bronchiolitis.
METHODS
In this single-center prospective cohort study we included mechanically ventilated children in the pediatric ICU with bronchiolitis 1-24 months old who were transitioned to HFPV from conventional invasive mechanical ventilation from November 2018-April 2020. Patients with congenital heart disease, on extracorporeal membrane oxygenation (ECMO), and with HFPV duration < 12 h were excluded. Subject gas exchange metrics and ventilator parameters were compared before and after HFPV initiation.
RESULTS
Forty-one of 192 (21%) patients intubated with bronchiolitis underwent HFPV, and 35 met inclusion criteria. Median age of cohort was 4 months, and 60% were previously healthy. All subjects with available oxygenation saturation index (OSI) measurements pre-HFPV met pediatric ARDS criteria (31/35, 89%). Mean CO decreased from 65.4 in the 24 h pre-HFPV to 51 ( < .001) in the 24 h post initiation. S /F was significantly improved at 24 h post-HFPV (153.3 to 209.7, = .001), whereas the decrease in mean OSI at 24 h did not meet statistical significance (11.9 to 10.2, = .15). The mean peak inspiratory pressure (PIP) decreased post-HFPV from 29.7 to 25.0 at 24 h ( < .001). No subjects developed an air leak or hemodynamic instability secondary to HFPV. Two subjects required ECMO, and of these, one subject died.
CONCLUSIONS
HFPV was associated with significant improvement in ventilation and decreased exposure to high PIPs for mechanically ventilated children with bronchiolitis in our cohort and had a potential association with improved oxygenation. Our study shows that HFPV may be an effective alternative mode of ventilation in patients with bronchiolitis who have poor gas exchange on conventional invasive mechanical ventilation.
Topics: Bronchiolitis, Viral; Child; Child, Preschool; High-Frequency Ventilation; Humans; Infant; Prospective Studies; Respiration, Artificial; Respiratory Distress Syndrome
PubMed: 35580910
DOI: 10.4187/respcare.09350 -
Molecular Therapy : the Journal of the... Nov 2023Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine...
Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4 T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of T helper (Th)17 cells, germinal center B cells, and plasma cells. The PRMT1 inhibitor also controlled acute GVHD (aGVHD) in mice by decreasing the percentage of Th17 cells. Moreover, inhibiting PRMT1 also weakened Th17 cell differentiation, B cell proliferation, and antibody production in cells from cGVHD patients. Additionally, further studies revealed that PRMT1 regulated B cell proliferation and antibody secretion by methylating isocitrate dehydrogenase 2 (IDH2). We observed asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 promoted IDH2 homodimerization, which enhanced IDH2 activity, further increasing B cell proliferation and antibody production. Collectively, this study provides a rationale for the application of PRMT1 inhibitors in the prevention of aGVHD and cGVHD.
Topics: Humans; Animals; Mice; Bronchiolitis Obliterans Syndrome; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; B-Lymphocytes; Plasma Cells; Methyltransferases; Protein-Arginine N-Methyltransferases; Repressor Proteins
PubMed: 37735873
DOI: 10.1016/j.ymthe.2023.09.011 -
Saudi Medical Journal May 2023Approximately 25% of all pediatric consultations are due to respiratory conditions, 10% of which are for asthma. Regarding prevalence, bronchiolitis, acute bronchitis,... (Review)
Review
Approximately 25% of all pediatric consultations are due to respiratory conditions, 10% of which are for asthma. Regarding prevalence, bronchiolitis, acute bronchitis, and respiratory infections are other leading pediatric respiratory illnesses. Compared to the aforementioned diseases, pediatric acute respiratory distress syndrome (PARDS) is rare but lethal in the Intensive Care Unit patients. According to global studies, the mortality in PARDS ranges from 13.3% to 60.7%. Before the Pediatric Acute Lung Injury Consensus Conference (PALICC), adult acute respiratory distress syndrome (ARDS) management guidelines were used for PARDS. The PALICC set new criteria to identify PARDS with a different treatment and management approach. Steroids have been used to treat ARDS in some cases, although their effectiveness in treating pediatric patients is highly debated in the scientific community. This review examines steroid use in treating PARDS, emphasizes current developments in the field, and gives a broad overview of PARDS management.
Topics: Child; Humans; Respiratory Distress Syndrome; Respiration, Artificial; Adrenal Cortex Hormones; Asthma
PubMed: 37182909
DOI: 10.15537/smj.2023.44.5.20220672 -
Enfermedades Infecciosas Y... Dec 2022The autumn and winter bronchiolitis epidemics have virtually disappeared in the first year of the COVID-19 pandemic. Our objectives were characterised bronchiolitis...
INTRODUCTION
The autumn and winter bronchiolitis epidemics have virtually disappeared in the first year of the COVID-19 pandemic. Our objectives were characterised bronchiolitis during fourth quarter of 2020 and the role played by SARS-CoV-2.
METHODS
Prospective multi-centre study performed in Madrid (Spain) between October and December 2020 including all children admitted with acute bronchiolitis. Clinical data were collected and multiplex PCR for respiratory viruses were performed.
RESULTS
Thirty-three patients were hospitalised with bronchiolitis during the study period: 28 corresponded to rhinovirus (RV), 4 to SARS-CoV-2, and 1 had both types of infection. SAR-CoV-2 bronchiolitis were comparable to RV bronchiolitis except for a shorter hospital stay. A significant decrease in the admission rate for bronchiolitis was found and no RSV was isolated.
CONCLUSION
SARS-CoV-2 infection rarely causes acute bronchiolitis and it is not associated with a severe clinical course. During COVID-19 pandemic period there was a marked decrease in bronchiolitis cases.
Topics: Child; Humans; COVID-19; SARS-CoV-2; Pandemics; Prospective Studies; Bronchiolitis; Enterovirus Infections
PubMed: 36464475
DOI: 10.1016/j.eimce.2021.06.005 -
Chronic Obstructive Pulmonary Diseases... Jul 2020Neutrophils have been implicated in the pathogenesis of alpha-1 antitrypsin deficiency (AATD) since the first descriptions of the disease. Neutrophil proteinases can... (Review)
Review
Neutrophils have been implicated in the pathogenesis of alpha-1 antitrypsin deficiency (AATD) since the first descriptions of the disease. Neutrophil proteinases can cause all lung manifestations of AATD, from small airways destruction, to emphysema, to chronic bronchitis and airflow obstruction. Initially, it was proposed that neutrophil functions were normal in AATD, responding in an initially physiological manner to a high burden of pulmonary inflammation. More recent studies have shed new light on this, describing changes in neutrophil responses (a modulation of usual cellular functions) in the presence of inflammation or infection which might enhance tissue damage while impeding bacterial clearance, providing some evidence to support there being an AATD neutrophil phenotype. Many facets of neutrophil function in AATD can be explained by the loss of alpha-1 antitrypsin (AAT) in diverse biological processes. If this were the only reason for altered neutrophil functions, one would predict similar disease presentation across affected people. However, this is not the case. Despite similar (low) levels of AAT, lung disease is extremely variable in AATD, with some patients suffering a significant burden of lung disease and some much less, irrespective of smoking habits and, in some cases, despite augmentation therapy. This review will explore how complex neutrophil responses are and how they are altered with age, inflammation and AATD. Further, it will discuss the need to understand more completely which aspects of AATD-associated disease are driven by neutrophils and how patients more susceptible to neutrophil dysfunction could be identified to potentially stratify treatment approaches.
PubMed: 32697897
DOI: 10.15326/jcopdf.7.3.2019.0164 -
Jornal Brasileiro de Pneumologia :... 2020
Topics: Azithromycin; Bronchiolitis; Bronchiolitis Obliterans; Humans; Respiratory Sounds
PubMed: 32638841
DOI: 10.36416/1806-3756/e20200285 -
ZFA. Zeitschrift Fur Allgemeinmedizin 2022Acute cough (< 8 weeks) is a frequent complaint in family practice consultations. The most common cause are respiratory infections. The Guideline "Acute and chronic...
BACKGROUND
Acute cough (< 8 weeks) is a frequent complaint in family practice consultations. The most common cause are respiratory infections. The Guideline "Acute and chronic cough" of the German College of General Practitioners and Family Physicians (DEGAM) was updated in 2021 and contains recommendations for an evidence-based approach for the management of acute cough in primary care.
METHODS
The guideline has been updated in accordance with the findings of a systematic search of the literature for international guidelines and systematic reviews. All recommendations were developed by an interdisciplinary guideline committee and agreed by formal consensus.
RESULTS
History-taking, exclusion of red flags and a physical examination are the basis of diagnostic evaluation. If an acute, uncomplicated bronchitis is likely, no laboratory tests, sputum diagnostics, or chest x-rays should be performed, and antibiotics should not be administered. Evidence based strategies to avoid antibiotic therapy (delayed prescribing, shared decision making, point-of-care-tests) can be used. There is inadequate evidence for the efficacy of antitussive or expectorant drugs against acute cough. The state of the evidence for phytotherapeutic agents is heterogeneous; clinical importance is minimal. COVID-19 should currently be considered in cases of acute respiratory symptoms. If specific symptoms or red flags occur, further diagnoses in the context of acute cough such as community-acquired pneumonia, influenza disease and exacerbations of chronic respiratory diseases (bronchial asthma, COPD) should be taken into consideration.
CONCLUSIONS
These evidence-based recommendations are intended to reduce the use of antibiotics to treat colds and acute bronchitis, for which they are not indicated. Further clinical trials of symptomatic treatments for cough should be performed in order to extend the evidence base.
PubMed: 37274352
DOI: 10.53180/zfa.2022.0169-0177