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Genes Jun 2024Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly affecting premature infants, with limited therapeutic options and increased long-term consequences....
Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly affecting premature infants, with limited therapeutic options and increased long-term consequences. Adrenomedullin (), a proangiogenic peptide hormone, has been found to protect rodents against experimental BPD. This study aims to elucidate the molecular and cellular mechanisms through which influences BPD pathogenesis using a lipopolysaccharide (LPS)-induced model of experimental BPD in mice. Bulk RNA sequencing of -sufficient (wild-type or ) and -haplodeficient () mice lungs, integrated with single-cell RNA sequencing data, revealed distinct gene expression patterns and cell type alterations associated with deficiency and LPS exposure. Notably, computational integration with cell atlas data revealed that -haplodeficient mouse lungs exhibited gene expression signatures characteristic of increased inflammation, natural killer (NK) cell frequency, and decreased endothelial cell and type II pneumocyte frequency. Furthermore, in silico human BPD patient data analysis supported our cell type frequency finding, highlighting elevated NK cells in BPD infants. These results underscore the protective role of in experimental BPD and emphasize that it is a potential therapeutic target for BPD infants with an inflammatory phenotype.
Topics: Adrenomedullin; Bronchopulmonary Dysplasia; Animals; Mice; Humans; Sequence Analysis, RNA; Disease Models, Animal; Lipopolysaccharides; Lung; Killer Cells, Natural; Transcriptome
PubMed: 38927741
DOI: 10.3390/genes15060806 -
Genes Jun 2024Cardiomyopathies (CMs), one of the main causes of sudden death among the young population, are a heterogeneous group of myocardial diseases, usually with a genetic...
Cardiomyopathies (CMs), one of the main causes of sudden death among the young population, are a heterogeneous group of myocardial diseases, usually with a genetic cause. Next-Generation Sequencing (NGS) has expanded the genes studied for CMs; however, the yield is still around 50%. The systematic study of Copy Number Variants (CNVs) could contribute to improving our diagnostic capacity. These alterations have already been described as responsible for cardiomyopathies in some cases; however, their impact has been rarely assessed. We analyzed the clinical significance of CNVs in cardiomyopathies by studying 11,647 affected patients, many more than those considered in previously published studies. We evaluated the yield of the systematic study of CNVs in a production context using NGS and a novel CNV detection software tool v2.0 that has demonstrated great efficacy, maximizing sensitivity and avoiding false positives. We obtained a CNV analysis yield of 0.8% that fluctuated depending on the type of cardiomyopathy studied (0.29% HCM, 1.41% DCM, 1.88% ARVC, 1.8% LVNC, 1.45% RCM), and we present the frequency of occurrence for 18 genes that agglutinate the 95 pathogenic/likely pathogenic CNVs detected. We conclude the importance of including in diagnostic tests a systematic study of these genetic alterations for the different cardiomyopathies.
Topics: Humans; DNA Copy Number Variations; Cardiomyopathies; High-Throughput Nucleotide Sequencing; Male; Female; Adult; Clinical Relevance
PubMed: 38927710
DOI: 10.3390/genes15060774 -
Genes May 2024HELIX syndrome (Hypohidrosis-Electrolyte disturbances-hypoLacrimia-Ichthyosis-Xerostomia) (MIM#617671) (ORPHA:528105), described in 2017, is due to an abnormal claudin...
HELIX syndrome (Hypohidrosis-Electrolyte disturbances-hypoLacrimia-Ichthyosis-Xerostomia) (MIM#617671) (ORPHA:528105), described in 2017, is due to an abnormal claudin 10 b protein, secondary to pathogenic variants. So far, only ten families have been described. We aim to describe the phenotype in the first Spanish family identified, highlight the skin anomalies as an important clue, and expand the genotypic spectrum. Two adult brothers from consanguineous parents with suspected ectodermal dysplasia (ED) since early childhood were re-evaluated. A comprehensive phenotypic exam and an aCGH + SNP4 × 180 K microarray followed by Sanger sequencing of the gene were performed. They presented hypohidrosis, xerosis, mild ichthyosis, plantar keratosis, palm hyperlinearity, alacrima, and xerostomia. In adulthood, they also developed a salt-losing nephropathy with hypokalemia and hypermagnesemia. The molecular study in both patients revealed a novel pathogenic homozygous deletion of 8 nucleotides in exon 2 of the gene [ (NM_0006984.4): c.322_329delGGCTCCGA, p.Gly108fs*] leading to a premature truncation of the protein. Both parents were heterozygous carriers. Hypohidrosis, ichthyosis, and plantar keratosis associated with alacrima and xerostomia should raise suspicion for HELIX syndrome, which also includes nephropathy and electrolyte disturbances in adults. Given the potential for ED misdiagnosis in infancy, it is important to include the gene in a specific genodermatosis next-generation sequencing (NGS) panel to provide early diagnosis, accurate management, and genetic counseling.
Topics: Humans; Male; Claudins; Adult; Ichthyosis; Hypohidrosis; Ectodermal Dysplasia; Pedigree; Phenotype
PubMed: 38927623
DOI: 10.3390/genes15060687 -
Biomedicines May 2024Exposure to hyperoxia is an important factor in the development of bronchopulmonary dysplasia (BPD) in preterm newborns. MicroRNAs (miRs) have been implicated in the...
Exposure to hyperoxia is an important factor in the development of bronchopulmonary dysplasia (BPD) in preterm newborns. MicroRNAs (miRs) have been implicated in the pathogenesis of BPD and provide a potential therapeutic target. This study was conducted utilizing a postnatal animal model of experimental hyperoxia-induced murine BPD to investigate the expression and function of miR-195 as well as its molecular signaling targets within developing mouse lung tissue. miR-195 expression levels increased in response to hyperoxia in male and female lungs, with the most significant elevation occurring in 40% O (mild) and 60% O (moderate) BPD. The inhibition of miR-195 improved pulmonary morphology in the hyperoxia-induced BPD model in male and female mice with females showing more resistance to injury and better recovery of alveolar chord length, septal thickness, and radial alveolar count. Additionally, we reveal miR-195-dependent signaling pathways involved in BPD and identify PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) as a novel specific target protein of miR-195. Our data demonstrate that high levels of miR-195 in neonatal lungs cause the exacerbation of hyperoxia-induced experimental BPD while its inhibition results in amelioration. This finding suggests a therapeutic potential of miR-195 inhibition in preventing BPD.
PubMed: 38927415
DOI: 10.3390/biomedicines12061208 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2024In infants with severe bronchopulmonary dysplasia (sBPD), severe pulmonary lobar emphysema may occur as a complication, contributing to significant impairment in...
In infants with severe bronchopulmonary dysplasia (sBPD), severe pulmonary lobar emphysema may occur as a complication, contributing to significant impairment in ventilation. Clinical management of these infants is extremely challenging and some may require lobectomy to improve ventilation. However, prior to the lobectomy, it is very difficult to assess whether the remaining lung parenchyma would be able to sustain adequate ventilation postoperatively. In addition, preoperative planning and perioperative management are also quite challenging in these patients. This paper reports the utility of selective bronchial occlusion in assessing the safety and efficacy of lobectomy in a case of sBPD complicated by severe right upper lobar emphysema. Since infants with sBPD already have poor lung development and significant lung injury, lobectomy should be viewed as a non-traditional therapy and be carried out with extreme caution. Selective bronchial occlusion test can be an effective tool in assessing the risks and benefits of lobectomy in cases with sBPD and lobar emphysema. However, given the technical difficulty, successful application of this technique requires close collaboration of an experienced interdisciplinary team.
Topics: Humans; Pulmonary Emphysema; Bronchopulmonary Dysplasia; Infant, Newborn; Infant, Premature; Bronchi; Male; Pneumonectomy; Female
PubMed: 38926385
DOI: 10.7499/j.issn.1008-8830.2403014 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2024To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early...
OBJECTIVES
To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early identification of BPD in twin preterm infants in clinical practice.
METHODS
A retrospective analysis was performed for the twin preterm infants with a gestational age of <34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020. According to their conditions, they were divided into group A (both twins had BPD), group B (only one twin had BPD), and group C (neither twin had BPD). The risk factors for BPD in twin preterm infants were analyzed. Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins.
RESULTS
A total of 904 pairs of twins with a gestational age of <34 weeks were included in this study. The multivariate logistic regression analysis showed that compared with group C, birth weight discordance of >25% between the twins was an independent risk factor for BPD in one of the twins (=3.370, 95%: 1.500-7.568, <0.05), and high gestational age at birth was a protective factor against BPD (<0.05). The conditional logistic regression analysis of group B showed that small-for-gestational-age (SGA) birth was an independent risk factor for BPD in individual twins (=5.017, 95%: 1.040-24.190, <0.05).
CONCLUSIONS
The development of BPD in twin preterm infants is associated with gestational age, birth weight discordance between the twins, and SGA birth.
Topics: Humans; Bronchopulmonary Dysplasia; Risk Factors; Infant, Newborn; Female; Retrospective Studies; Male; Infant, Premature; Twins; Gestational Age; Birth Weight; Logistic Models
PubMed: 38926378
DOI: 10.7499/j.issn.1008-8830.2312005 -
The Role of the Airway and Gut Microbiome in the Development of Chronic Lung Disease of Prematurity.Pathogens (Basel, Switzerland) Jun 2024Chronic lung disease (CLD) of prematurity, a common cause of morbidity and mortality in preterm-born infants, has a multifactorial aetiology. This review summarizes the... (Review)
Review
Chronic lung disease (CLD) of prematurity, a common cause of morbidity and mortality in preterm-born infants, has a multifactorial aetiology. This review summarizes the current evidence for the effect of the gut and airway microbiota on the development of CLD, highlighting the differences in the early colonisation patterns in preterm-born infants compared to term-born infants. Stool samples from preterm-born infants who develop CLD have less diversity than those who do not develop CLD. Pulmonary inflammation, which is a hallmark in the development of CLD, may potentially be influenced by gut bacteria. The respiratory microbiota is less abundant than the stool microbiota in preterm-born infants. There is a lack of clear evidence for the role of the respiratory microbiota in the development of CLD, with results from individual studies not replicated. A common finding is the presence of a single predominant bacterial genus in the lungs of preterm-born infants who develop CLD. Probiotic preparations have been proposed as a potential therapeutic strategy to modify the gut or lung microbiota with the aim of reducing rates of CLD but additional robust evidence is required before this treatment is introduced into routine clinical practice.
PubMed: 38921770
DOI: 10.3390/pathogens13060472 -
Cells Jun 2024Background Recently, mesenchymal stromal cells (MSCs) have gained recognition for their clinical utility in transplantation to induce tolerance and to improve/replace...
UNLABELLED
Background Recently, mesenchymal stromal cells (MSCs) have gained recognition for their clinical utility in transplantation to induce tolerance and to improve/replace pharmacological immunosuppression. Cord blood (CB)-derived MSCs are particularly attractive for their immunological naivety and peculiar anti-inflammatory and anti-apoptotic properties.
OBJECTIVES
The objective of this study was to obtain an inventory of CB MSCs able to support large-scale advanced therapy medicinal product (ATMP)-based clinical trials.
STUDY DESIGN
We isolated MSCs by plastic adherence in a GMP-compliant culture system. We established a well-characterized master cell bank and expanded a working cell bank to generate batches of finished MSC(CB) products certified for clinical use. The MSC(CB) produced by our facility was used in approved clinical trials or for therapeutic use, following single-patient authorization as an immune-suppressant agent.
RESULTS
We show the feasibility of a well-defined MSC manufacturing process and describe the main indications for which the MSCs were employed. We delve into a regulatory framework governing advanced therapy medicinal products (ATMPs), emphasizing the need of stringent quality control and safety assessments. From March 2012 to June 2023, 263 of our Good Manufacturing Practice (GMP)-certified MSC(CB) preparations were administered as ATMPs in 40 subjects affected by Graft-vs.-Host Disease, nephrotic syndrome, or bronco-pulmonary dysplasia of the newborn. There was no infusion-related adverse event. No patient experienced any grade toxicity. Encouraging preliminary outcome results were reported. Clinical response was registered in the majority of patients treated under therapeutic use authorization.
CONCLUSIONS
Our 10 years of experience with MSC(CB) described here provides valuable insights into the use of this innovative cell product in immune-mediated diseases.
Topics: Humans; Mesenchymal Stem Cells; Fetal Blood; Quality Control; Female; Mesenchymal Stem Cell Transplantation; Male; Adult; Middle Aged; Adolescent; Aged; Young Adult; Child
PubMed: 38920694
DOI: 10.3390/cells13121066 -
Medical Review (2021) Jun 2024The majority of esophageal squamous dysplasia (ESD) patients progress slowly, while a subset of patients can undergo recurrence rapidly or progress to invasive cancer...
OBJECTIVES
The majority of esophageal squamous dysplasia (ESD) patients progress slowly, while a subset of patients can undergo recurrence rapidly or progress to invasive cancer even after proper treatment. However, the molecular mechanisms underlying these clinical observations are still largely unknown.
METHODS
By sequencing the genomic data of 160 clinical samples from 49 tumor-free ESD patients and 88 esophageal squamous cell carcinoma (ESCC) patients, we demonstrated lower somatic mutation and copy number alteration (CNA) burden in ESD compared with ESCC.
RESULTS
Cross-species screening and functional assays identified as a novel driver gene for ESD progression. Furthermore, we revealed that miR-4292 promoted ESD progression and could serve as a non-invasive diagnostic marker for ESD.
CONCLUSIONS
These findings largely expanded our understanding of ESD genetics and tumorigenesis, which possessed promising significance for improving early diagnosis, reducing overtreatment, and identifying high-risk ESD patients.
PubMed: 38919397
DOI: 10.1515/mr-2024-0008 -
The Iowa Orthopaedic Journal 2024Acetabular dysplasia has a wide range of prevalence reported in the literature. This variation is likely due to differences in the population under investigation and...
BACKGROUND
Acetabular dysplasia has a wide range of prevalence reported in the literature. This variation is likely due to differences in the population under investigation and studies focusing on cohorts with hip pain and osteoarthritis. There are reports of radiographic hip dysplasia prevalence for adults without hip pain but there is no systematic review of these studies to document the incidence in the general population. The purpose of this systematic review was to provide a full summary of all studies that report prevalence of hip dysplasia in adults without hip pain.
METHODS
PRISMA guidelines were utilized as an outline for this systematic review. Articles were pulled from PubMed, OVID Medline, Embase, SCOPUS, Cochrane Central Register of Clinical Trials, and clinicaltrials.gov from their inception dates to 1/7/24. Studies were included if participants were asymptomatic and reported rates of prevalence.
RESULTS
Fourteen studies were included in this systematic review. There were 10,998 hips from 5,506 participants included in this analysis. The overall prevalence of radiographic hip dysplasia was 2.3%. Eight studies of 5,930 hips reported the prevalence of hip dysplasia by sex. The prevalence rate in these studies was 3.8% in females and 2.7% in males.
CONCLUSION
Acetabular dysplasia based on radiographic measurements is relatively common in the general adult population. Furthermore, females have a higher prevalence rate when compared to males. It is important to recognize the incidence of hip dysplasia in the asymptomatic adult population as we recommend surgical treatment for patients who present with hip pain and dysplasia. Further studies should investigate the natural history of untreated and treated hip dysplasia. .
Topics: Humans; Prevalence; Adult; Radiography; Hip Dislocation; Male; Female
PubMed: 38919354
DOI: No ID Found