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Journal of Clinical Medicine Jun 2024Advances in perinatal intensive care have significantly enhanced the survival rates of extremely low gestation-al-age neonates but with continued high rates of... (Review)
Review
Advances in perinatal intensive care have significantly enhanced the survival rates of extremely low gestation-al-age neonates but with continued high rates of bronchopulmonary dysplasia (BPD). Nevertheless, as the survival of these infants improves, there is a growing awareness of associated abnormalities in pulmonary vascular development and hemodynamics within the pulmonary circulation. Premature infants, now born as early as 22 weeks, face heightened risks of adverse development in both pulmonary arterial and venous systems. This risk is compounded by parenchymal and airway abnormalities, as well as factors such as inflammation, fibrosis, and adverse growth trajectory. The presence of pulmonary hypertension in bronchopulmonary dysplasia (BPD-PH) has been linked to an increased mortality and substantial morbidities, including a greater susceptibility to later neurodevelopmental challenges. BPD-PH is now recognized to be a spectrum of disease, with a multifactorial pathophysiology. This review discusses the challenges associated with the identification and management of BPD-PH, both of which are important in minimizing further disease progression and improving cardiopulmonary morbidity in the BPD infant.
PubMed: 38929946
DOI: 10.3390/jcm13123417 -
Life (Basel, Switzerland) Jun 2024The RASopathies are a group of syndromes caused by genetic variants that affect the RAS-MAPK signaling pathway, which is essential for cell response to diverse stimuli.... (Review)
Review
Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies: A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib and Selumetinib.
The RASopathies are a group of syndromes caused by genetic variants that affect the RAS-MAPK signaling pathway, which is essential for cell response to diverse stimuli. These variants functionally converge towards the overactivation of the pathway, leading to various constitutional and mosaic conditions. These syndromes show overlapping though distinct clinical presentations and share congenital heart defects, hypertrophic cardiomyopathy (HCM), and lymphatic dysplasia as major clinical features, with highly variable prevalence and severity. Available treatments have mainly been directed to target the symptoms. However, repurposing MEK inhibitors (MEKis), which were originally developed for cancer treatment, to target evolutive aspects occurring in these disorders is a promising option. Animal models have shown encouraging results in treating various RASopathy manifestations, including HCM and lymphatic abnormalities. Clinical reports have also provided first evidence supporting the effectiveness of MEKi, especially trametinib, in treating life-threatening conditions associated with these disorders. Nevertheless, despite notable improvements, there are adverse events that occur, necessitating careful monitoring. Moreover, there is evidence indicating that multiple pathways can contribute to these disorders, indicating a current need to more accurate understand of the underlying mechanism of the disease to apply an effective targeted therapy. In conclusion, while MEKi holds promise in managing life-threatening complications of RASopathies, dedicated clinical trials are required to establish standardized treatment protocols tailored to take into account the individual needs of each patient and favor a personalized treatment.
PubMed: 38929714
DOI: 10.3390/life14060731 -
Medicina (Kaunas, Lithuania) May 2024: Our aim was to perform a retrospective analysis of the volume of cervical screening tests, the number of patients treated with an excision method, and the incidence of...
: Our aim was to perform a retrospective analysis of the volume of cervical screening tests, the number of patients treated with an excision method, and the incidence of invasive and non-invasive cervical during a pandemic and pre-pandemic period of 24 months. : The study compared 404 patients who underwent cervical cone biopsy for cervical cancer. The study examined patients' specimens based on histopathological characteristics and categorized cervical lesions based on pap smear. : There was a statistically significant age difference between the two study periods. The mean difference was 32 years before the pandemic and 35 years during the pandemic (-value > 0.05). The biggest patient loss ratio identified by age group was in the 50-59-year group, with a 14.53% loss in the pre-pandemic period and a 9.1% loss in the pandemic period. In the pandemic period, patients from rural areas presented in the clinical trial with a lower rate of 39.52% (83 patients) vs. 60.47% (127 patients) in urban areas. A higher percentage of patients experiencing cervicorrhagia as a clinical manifestation in the pandemic period vs. the pre-pandemic period, with an increase in more severe lesions in the pandemic period, had a statistical significance of 8% more newly diagnosed compared to the pre-pandemic period. : The addressability of the patients during the COVID period was not affected in a drastic way in our study. We encountered a decrease in appointments in the age group of 50-59 years and a decrease in patients with rural residence. In our study, we found an increase in cervical bleeding as a reason for consultation in the pandemic period with a higher lesion degree, both on a pap smear and on a cervical biopsy.
Topics: Humans; Female; COVID-19; Retrospective Studies; Middle Aged; Uterine Cervical Neoplasms; Adult; SARS-CoV-2; Papanicolaou Test; Early Detection of Cancer; Aged; Pandemics; Vaginal Smears
PubMed: 38929526
DOI: 10.3390/medicina60060909 -
Antioxidants (Basel, Switzerland) Jun 2024Bronchopulmonary dysplasia (BPD) is a chronic condition affecting preterm infants, characterized by lung alveolar simplification/hypoalveolarization and vascular...
Bronchopulmonary dysplasia (BPD) is a chronic condition affecting preterm infants, characterized by lung alveolar simplification/hypoalveolarization and vascular remodeling. The nuclear factor erythroid 2 like 2 (Nfe2l2, or Nrf2) plays a critical role in the cytoprotective response to neonatal hyperoxia, and its global deficiency exacerbates hypoalveolarization in mice. The abnormal recruitment and activation of myeloid cells are associated with the pathogenesis of BPD. Therefore, we employed a genetic approach to investigate the role of myeloid Nrf2 in regulating hyperoxia-induced hypoalveolarization. Pups, both wild-type () and those with a myeloid Nrf2 deletion (abbreviated as ), were exposed to hyperoxia for 72 h at postnatal day 1 (Pnd1), and then sacrificed at either Pnd4 or Pnd18 following a two-week recovery period. We analyzed the hypoalveolarization, inflammation, and gene expression related to cytoprotective and inflammatory responses in the lungs of these pups. The hypoalveolarization induced by hyperoxia was significantly greater in pups compared to their counterparts (35.88% vs. 21.01%, respectively) and was accompanied by increased levels of inflammatory cells and IL-1β activation in the lungs. Antioxidant gene expression in response to neonatal hyperoxia was lower in pups compared to their counterparts. Furthermore, -deficient macrophages exposed to hyperoxia exhibited markedly decreased cytoprotective gene expression and increased IL-1β levels compared to Nrf2-sufficient cells. Our findings demonstrate the crucial role of myeloid Nrf2 in mitigating hyperoxia-induced lung hypoalveolarization and inflammatory responses in neonatal mice.
PubMed: 38929137
DOI: 10.3390/antiox13060698 -
International Journal of Molecular... Jun 2024Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions,... (Review)
Review
Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions, HCs can form gap junction (GJ) channels, providing a direct diffusive path between neighbouring cells. In addition, unpaired HCs provide conduits for the exchange of solutes between the cytoplasm and the extracellular milieu, including messenger molecules involved in paracrine signalling. The synergistic action of membrane potential and Ca ions controls the gating of the large and relatively unselective pore of connexin HCs. The four orders of magnitude difference in gating sensitivity to the extracellular ([Ca]) and the cytosolic ([Ca]) Ca concentrations suggests that at least two different Ca sensors may exist. While [Ca] acts as a spatial modulator of the HC opening, which is most likely dependent on the cell layer, compartment, and organ, [Ca] triggers HC opening and the release of extracellular bursts of messenger molecules. Such molecules include ATP, cAMP, glutamate, NAD, glutathione, D-serine, and prostaglandins. Lost or abnormal HC regulation by Ca has been associated with several diseases, including deafness, keratitis ichthyosis, palmoplantar keratoderma, Charcot-Marie-Tooth neuropathy, oculodentodigital dysplasia, and congenital cataracts. The fact that both an increased and a decreased Ca sensitivity has been linked to pathological conditions suggests that Ca in healthy cells finely tunes the normal HC function. Overall, further investigation is needed to clarify the structural and chemical modifications of connexin HCs during [Ca] and [Ca] variations. A molecular model that accounts for changes in both Ca and the transmembrane voltage will undoubtedly enhance our interpretation of the experimental results and pave the way for developing therapeutic compounds targeting specific HC dysfunctions.
Topics: Connexins; Humans; Calcium; Animals; Gap Junctions; Calcium Signaling
PubMed: 38928300
DOI: 10.3390/ijms25126594 -
Cancers Jun 2024Premalignant lesions within the bronchial epithelium signify the initial phases of squamous cell lung carcinoma, posing challenges for detection via conventional...
Premalignant lesions within the bronchial epithelium signify the initial phases of squamous cell lung carcinoma, posing challenges for detection via conventional methods. Instead of focusing solely on gene expression, in this study, we explore transcriptomic alterations linked to lesion progression, with an emphasis on protein-coding transcripts. We reanalyzed a publicly available RNA-Seq dataset on airway epithelial cells from 82 smokers with and without premalignant lesions. Transcript and gene abundance were quantified using kallisto, while differential expression and transcript usage analysis was performed utilizing sleuth and RATs packages. Functional characterization involved overrepresentation analysis via clusterProfiler, weighted coexpression network analysis (WGCNA), and network analysis via Enrichr-KG. We detected 5906 differentially expressed transcripts and 4626 genes, exhibiting significant enrichment within pathways associated with oxidative phosphorylation and mitochondrial function. Remarkably, transcript-level WGCNA revealed a single module correlated with dysplasia status, notably enriched in cilium-related biological processes. Notable hub transcripts included RABL2B (ENST00000395590), DNAH1 (ENST00000420323), EFHC1 (ENST00000635996), and VWA3A (ENST00000563389) along with transcription factors such as FOXJ1 and ZNF474 as potential regulators. Our findings underscore the value of transcript-level analysis in uncovering novel insights into premalignant bronchial lesion biology, including identification of potential biomarkers associated with early lung carcinogenesis.
PubMed: 38927965
DOI: 10.3390/cancers16122260 -
Cancers Jun 2024The incidences of anogenital HPV-related cancers in women are on the rise; this is especially true for anal cancer. Medical societies are now beginning to recommend anal...
The incidences of anogenital HPV-related cancers in women are on the rise; this is especially true for anal cancer. Medical societies are now beginning to recommend anal cancer screening in certain high-risk populations, including high-risk women with a history of genital dysplasia. The aim of this study is to investigate national anogenital HPV cancer trends as well as the role of demographics, deprivation, and ethnicity on anogenital cancer incidence in England, in an attempt to better understand this cohort of women which is increasingly affected by anogenital HPV-related disease. Demographic data from the Clinical Outcomes and Services Dataset (COSD) were extracted for all patients diagnosed with anal, cervical, vulval and vaginal cancer in England between 2014 and 2020. Outcomes included age, ethnicity, deprivation status and staging. An age over 55 years, non-white ethnicity and high deprivation are significant risk factors for late cancer staging, as per logistic regression. In 2019, the incidences of anal and vulval cancer in white women aged 55-74 years surpassed that of cervical cancer. More needs to be done to educate women on HPV-related disease and their lifetime risk of these conditions.
PubMed: 38927883
DOI: 10.3390/cancers16122177 -
Bioengineering (Basel, Switzerland) May 2024Esophageal carcinoma is the sixth-leading cause of cancer death worldwide. A precursor to esophageal adenocarcinoma (EAC) is Barrett's Esophagus (BE). Early-stage...
Design and Evaluation of ScanCap: A Low-Cost, Reusable Tethered Capsule Endoscope with Blue-Green Illumination Imaging for Unsedated Screening and Early Detection of Barrett's Esophagus.
Esophageal carcinoma is the sixth-leading cause of cancer death worldwide. A precursor to esophageal adenocarcinoma (EAC) is Barrett's Esophagus (BE). Early-stage diagnosis and treatment of esophageal neoplasia (Barrett's with high-grade dysplasia/intramucosal cancer) increase the five-year survival rate from 10% to 98%. BE is a global challenge; however, current endoscopes for early BE detection are costly and require extensive infrastructure for patient examination and sedation. We describe the design and evaluation of the first prototype of ScanCap, a high-resolution optical endoscopy system with a reusable, low-cost tethered capsule, designed to provide high-definition, blue-green illumination imaging for the early detection of BE in unsedated patients. The tethered capsule (12.8 mm diameter, 35.5 mm length) contains a color camera and rotating mirror and is designed to be swallowed; images are collected as the capsule is retracted manually via the tether. The tether provides electrical power and illumination at wavelengths of 415 nm and 565 nm and transmits data from the camera to a tablet. The ScanCap prototype capsule was used to image the oral mucosa in normal volunteers and ex vivo esophageal resections; images were compared to those obtained using an Olympus CV-180 endoscope. Images of superficial capillaries in intact oral mucosa were clearly visible in ScanCap images. Diagnostically relevant features of BE, including irregular Z-lines, distorted mucosa, and dilated vasculature, were clearly visible in ScanCap images of ex vivo esophageal specimens.
PubMed: 38927792
DOI: 10.3390/bioengineering11060557 -
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