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Signal Transduction and Targeted Therapy May 2023Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder in sleep in which the airways narrow or collapse during sleep, causing obstructive sleep apnea.... (Review)
Review
Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder in sleep in which the airways narrow or collapse during sleep, causing obstructive sleep apnea. The prevalence of OSAS continues to rise worldwide, particularly in middle-aged and elderly individuals. The mechanism of upper airway collapse is incompletely understood but is associated with several factors, including obesity, craniofacial changes, altered muscle function in the upper airway, pharyngeal neuropathy, and fluid shifts to the neck. The main characteristics of OSAS are recurrent pauses in respiration, which lead to intermittent hypoxia (IH) and hypercapnia, accompanied by blood oxygen desaturation and arousal during sleep, which sharply increases the risk of several diseases. This paper first briefly describes the epidemiology, incidence, and pathophysiological mechanisms of OSAS. Next, the alterations in relevant signaling pathways induced by IH are systematically reviewed and discussed. For example, IH can induce gut microbiota (GM) dysbiosis, impair the intestinal barrier, and alter intestinal metabolites. These mechanisms ultimately lead to secondary oxidative stress, systemic inflammation, and sympathetic activation. We then summarize the effects of IH on disease pathogenesis, including cardiocerebrovascular disorders, neurological disorders, metabolic diseases, cancer, reproductive disorders, and COVID-19. Finally, different therapeutic strategies for OSAS caused by different causes are proposed. Multidisciplinary approaches and shared decision-making are necessary for the successful treatment of OSAS in the future, but more randomized controlled trials are needed for further evaluation to define what treatments are best for specific OSAS patients.
Topics: Aged; Middle Aged; Humans; COVID-19; Sleep Apnea, Obstructive; Hypoxia; Obesity; Pharynx
PubMed: 37230968
DOI: 10.1038/s41392-023-01496-3 -
HNO Aug 2023Hyperplasia of the pharyngeal tonsils is to be considered pathologic when nasopharyngeal symptoms of mechanical obstruction and/or chronic inflammation occur. Chronic... (Review)
Review
Hyperplasia of the pharyngeal tonsils is to be considered pathologic when nasopharyngeal symptoms of mechanical obstruction and/or chronic inflammation occur. Chronic Eustachian tube dysfunction can result in various middle ear diseases such as conductive hearing loss, cholesteatoma, and recurrent acute otitis media. During examination, attention should be paid to the presence of adenoid facies (long face syndrome), with a permanently open mouth and visible tip of the tongue. In the case of severe symptoms and/or failure of conservative treatment, adenoidectomy is usually performed on an outpatient basis. Conventional curettage remains the established standard treatment in Germany. Histologic evaluation is indicated for clinical evidence of mucopolysaccharidoses. Due to the risk of hemorrhage, the preoperative bleeding questionnaire, which is obligatory before every pediatric surgery, is referred to. Recurrence of adenoids is possible despite correct adenoidectomy. Before discharge home, otorhinolaryngologic inspection of the nasopharynx for secondary bleeding should be performed and anesthesiologic clearance obtained.
Topics: Child; Humans; Adenoids; Adenoidectomy; Otitis Media; Inflammation; Hypertrophy; Otitis Media with Effusion
PubMed: 37491540
DOI: 10.1007/s00106-023-01299-6 -
Virulence Dec 2021Bacterial proteases and peptidases are integral to cell physiology and stability, and their necessity in is no exception. Protein cleavage and processing mechanisms... (Review)
Review
Bacterial proteases and peptidases are integral to cell physiology and stability, and their necessity in is no exception. Protein cleavage and processing mechanisms within the bacterial cell serve to ensure that the cell lives and functions in its commensal habitat and can respond to new environments presenting stressful conditions. For , the human nasopharynx is its natural habitat. In the context of virulence, movement of to the lungs, blood, or other sites can instigate responses by the bacteria that result in their proteases serving dual roles of self-protein processors and virulence factors of host protein targets.
Topics: Animals; Bacterial Proteins; Genome, Bacterial; Humans; Immune Evasion; Lung; Mice; Nasopharynx; Peptide Hydrolases; Streptococcus pneumoniae; Virulence; Virulence Factors
PubMed: 33660565
DOI: 10.1080/21505594.2021.1889812 -
Nature Medicine Jan 2021Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition,...
Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.
Topics: Adjuvants, Immunologic; B-Lymphocytes; COVID-19 Vaccines; Germinal Center; Hemagglutinin Glycoproteins, Influenza Virus; Humans; In Vitro Techniques; Influenza Vaccines; Lymphoid Tissue; Measles-Mumps-Rubella Vaccine; Organoids; Palatine Tonsil; Rabies Vaccines; T-Lymphocytes
PubMed: 33432170
DOI: 10.1038/s41591-020-01145-0 -
Nature Sep 2022Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context. The...
Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry and microfluidic deterministic barcoding. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.
Topics: Animals; Brain; Cell Differentiation; Cell Lineage; Chromatin; Chromatin Assembly and Disassembly; Chromatin Immunoprecipitation Sequencing; Epigenomics; Gene Expression Profiling; Genome; High-Throughput Nucleotide Sequencing; Humans; Mice; Palatine Tonsil
PubMed: 35978191
DOI: 10.1038/s41586-022-05094-1 -
Cellular Microbiology Nov 2019Streptococcus pneumoniae (the pneumococcus) is a human respiratory tract pathogen and a major cause of morbidity and mortality globally. Although the pneumococcus is a... (Review)
Review
Streptococcus pneumoniae (the pneumococcus) is a human respiratory tract pathogen and a major cause of morbidity and mortality globally. Although the pneumococcus is a commensal bacterium that colonizes the nasopharynx, it also causes lethal diseases such as meningitis, sepsis, and pneumonia, especially in immunocompromised patients, in the elderly, and in young children. Due to the acquisition of antibiotic resistance and the emergence of nonvaccine serotypes, the pneumococcus has been classified as one of the priority pathogens for which new antibacterials are urgently required by the World Health Organization, 2017. Understanding molecular mechanisms behind the pathogenesis of pneumococcal infections and bacterial interactions within the host is crucial to developing novel therapeutics. Previously considered to be an extracellular pathogen, it is becoming evident that pneumococci may also occasionally establish intracellular niches within the body to escape immune surveillance and spread within the host. Intracellular survival within host cells also enables pneumococci to resist many antibiotics. Within the host cell, the bacteria exist in unique vacuoles, thereby avoiding degradation by the acidic lysosomes, and modulate the expression of its virulence genes to adapt to the intracellular environment. To invade and survive intracellularly, the pneumococcus utilizes a combination of virulence factors such as pneumolysin (PLY), pneumococcal surface protein A (PspA), pneumococcal adhesion and virulence protein B (PavB), the pilus-1 adhesin RrgA, pyruvate oxidase (SpxB), and metalloprotease (ZmpB). In this review, we discuss recent findings showing the intracellular persistence of Streptococcus pneumoniae and its underlying mechanisms.
Topics: Blood-Brain Barrier; Dendritic Cells; Drug Resistance, Microbial; Heart; Humans; Lung; Macrophages; Myocardium; Nasopharynx; Pneumococcal Infections; Respiratory System; Spleen; Streptococcus pneumoniae; Virulence Factors
PubMed: 31251447
DOI: 10.1111/cmi.13077 -
Signal Transduction and Targeted Therapy Sep 2021Absent in melanoma 2 (AIM2) has been reported to be a component of inflammasomes in innate immune cells. Surprisingly, AIM2 is expressed by B cells, and higher AIM2...
Absent in melanoma 2 (AIM2) has been reported to be a component of inflammasomes in innate immune cells. Surprisingly, AIM2 is expressed by B cells, and higher AIM2 expression is observed in the B cells from lupus patients. To date, the inflammasome-independent function of AIM2 in B cells remains unclear. Here, we report increased expression of AIM2 in human tonsil memory and germinal center (GC) B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients. Conditional knockout of AIM2 in B cells reduces the CD19 B-cell frequency in lymph nodes and spleens, and dampens KLH-induced IgG1-antibody production. In a pristane-induced mouse model of lupus, AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells, T follicular helper (Tfh) cells, plasmablast cells, and plasma cells. Furthermore, the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6. However, the silencing of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression, indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6. In addition, IL-10 is found to upregulate AIM2 expression via DNA demethylation. Together, our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6-Blimp-1 axis, providing a novel target for SLE treatment.
Topics: Adenoids; Animals; Antigens, CD19; Cell Differentiation; DNA Methylation; DNA-Binding Proteins; Disease Models, Animal; Germinal Center; Humans; Immunity, Innate; Lupus Erythematosus, Systemic; Lymph Nodes; Memory B Cells; Mice; Positive Regulatory Domain I-Binding Factor 1; Proto-Oncogene Proteins c-bcl-6; Spleen; Terpenes
PubMed: 34521812
DOI: 10.1038/s41392-021-00725-x -
Immunity Feb 2024Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas...
Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil.
Topics: Humans; Adult; Palatine Tonsil; B-Lymphocytes
PubMed: 38301653
DOI: 10.1016/j.immuni.2024.01.006 -
Oncotarget Feb 2023Since its inception, the Hemoglobin, Albumin, Lymphocyte, Platelet Score (HALP) has gained attention as a new prognostic biomarker to predict several clinical outcomes... (Review)
Review
Since its inception, the Hemoglobin, Albumin, Lymphocyte, Platelet Score (HALP) has gained attention as a new prognostic biomarker to predict several clinical outcomes in a multitude of cancers. In our review, we searched PubMed for articles between the first paper on HALP in 2015 through September 2022, yielding 32 studies in total that evaluated HALP's association with various cancers, including Gastric, Colorectal, Bladder, Prostate, Kidney, Esophageal, Pharyngeal, Lung, Breast, and Cervical cancers, among others. This review highlights the collective association HALP has with demographic factors such as age and sex in addition to TNM staging, grade, and tumor size. Furthermore, this review summarizes HALP's prognostic ability to predict overall survival, progression-free survival, recurrence-free survival, among other outcomes. In some studies, HALP has also been able to predict response to immunotherapy and chemotherapy. This review article also aims to serve as a comprehensive and encyclopedic report on the literature that has evaluated HALP as a biomarker in various cancers, highlighting the heterogeneity surrounding HALP's utilization. Because HALP requires only a complete blood count and albumin - already routinely collected for cancer patients - HALP shows potential as a cost-effective biomarker to aid clinicians in improving outcomes for immuno-nutritionally deficient patients.
Topics: Female; Humans; Male; Albumins; Hemoglobins; Lymphocytes; Prognosis; Neoplasms; Blood Platelets
PubMed: 36848404
DOI: 10.18632/oncotarget.28367