Planar Cell Polarity in the Multiciliated Epithelial Lining of the Mouse Eustachian Tube.

OBJECTIVES: Planar cell polarity (PCP) signaling, essential for uniform alignment and directional beating of motile cilia, has been investigated in multiciliated epithelia. As a complex structure connecting the middle ear to the nasopharynx, the eustachian tube (ET) is important in the onset of ear-nose-throat diseases. However, PCP signaling, including the orientation that is important for ciliary motility and clearance function in the ET, has not been studied. We evaluated PCP in the ET epithelium. STUDY DESIGN: Morphometric examination of the mouse ET. METHODS: We performed electron microscopy to assess ciliary polarity in the mouse ET, along with immunohistochemical analysis of PCP protein localization in the ET epithelium. RESULTS: We discovered PCP in the ET epithelium. Motile cilia were aligned in the same direction in individual and neighboring cells; this alignment manifested as ciliary polarity in multiciliated cells. Additionally, PCP proteins were asymmetrically localized between adjacent cells in the plane of the ET. CONCLUSIONS: The multiciliated ET epithelium exhibits polarization, suggesting novel structural features that may be critical for ET function. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3795-3801, 2024.

Cytokine Storm: The Primary Determinant for the Pathophysiological Evolution of COVID-19 Deterioration.

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing major threat to global health and has posed significant challenges for the treatment of severely ill COVID-19 patients. Several studies have reported that cytokine storms are an important cause of disease deterioration and death in COVID-19 patients. Consequently, it is important to understand the specific pathophysiological processes underlying how cytokine storms promote the deterioration of COVID-19. Here, we outline the pathophysiological processes through which cytokine storms contribute to the deterioration of SARS-CoV-2 infection and describe the interaction between SARS-CoV-2 and the immune system, as well as the pathophysiology of immune response dysfunction that leads to acute respiratory distress syndrome (ARDS), multi-organ dysfunction syndrome (MODS), and coagulation impairment. Treatments based on inhibiting cytokine storm-induced deterioration and occurrence are also described.

Influence of aging on deterioration of patients with COVID-19.

Aging is an important factor affecting the deterioration of patients with coronavirus disease 2019 (COVID-19). The aging and degeneration of various tissues and organs in the elderly lead to impaired organ function. Underlying conditions such as chronic lung disease, cardiovascular disease, and diabetes in aged patients are associated with higher mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily interacts with the cell surface receptor angiotensin-converting enzyme (ACE) 2 and other accessory proteins such as 78 kDa glucose-regulated protein 78 (GRP78) and CD147. Thus, altered receptor signals in aging and chronic disease play a role in SARS-CoV-2 infection, and are associated with a higher risk of deterioration in different organs. In this review, after a brief introduction to the link between aging and receptors for SARS-CoV-2, we focus on the risk of deterioration in different organs of COVID-19 patients considering aging as the main factor. We further discuss the structural and/or physiological changes in the immune system and organs (lung, heart, kidney, vessels, nerve system), as well as those associated with diabetes, in aging patients, and speculate on the most likely mechanisms underlying the deterioration of COVID-19 patients.

Meta-analysis of efficacy and adverse events of erlotinib-based targeted therapies for advanced/metastatic non-small cell lung cancer.

A network meta-analysis evaluating efficacy and adverse events of eight erlotinib-based therapies (erlotinib+placebo, erlotinib+tivantinib, erlotinib+celecoxib, erlotinib+onartuzumab, erlotinib+sunitinib, erlotinib+entinostat, erlotinib+sorafenib, and erlotinib+bevacizumab) for advanced/metastatic non-small-cell lung cancer (NSCLC) was performed. PubMed and Cochrane Library were reviewed, and ten randomized controlled trials were identified in which patients receiving at least one erlotinib-based therapy. Efficacy outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse outcomes were evaluated. Patients treated with erlotinib+tivantinib, or erlotinib+celecoxib had longer PFS than patients on erlotinib+placebo; patients on erlotinib+tivantinib had longer OS compared to erlotinib+placebo. For PFS, erlotinib+celecoxib had the highest value of surface under the cumulative ranking curve (SUCRA). For OS, erlotinib+tivantinib had the highest SUCRA. For ORR, erlotinib+bevacizumab had the highest SUCRA, while erlotinib+entinostat ranked the lowest. For DCR, erlotinib+sorafenib had the highest SUCRA. Erlotinib+onartuzumab had the highest SUCRA for diarrhea, nausea, vomiting, decreased appetite, and dyspnea. Erlotinib+sunitinib had the lowest SUCRA for diarrhea, nausea, vomiting, and decreased appetite. Erlotinib + entinostat had the lowest SUCRA for fatigue, asthenia, and dyspnea. Our study suggests erlotinib+tivantinib and erlotinib+celecoxib regimens have the best long-term efficacy, while erlotinib+sunitinib and erlotinib+entinostat have the fewest adverse effects in patients with advanced/metastatic NSCLC.

Per(3-chloro-4-methyl)phenylcarbamate cyclodextrin clicked stationary phase for chiral separation in multiple modes high-performance liquid chromatography.

In this work, a detail study has been performed on the enantioselectivity of per(3-chloro-4-methyl)phenylcarbamate-ß-CD clicked chiral stationary phase (CSP) in high-performance liquid chromatography. Both normal phase and polar organic mobile phases have been explored for the enantioseparation of 39 model racemic pairs including aromatic alcohols, flavonoids, ß-blockers and amino acids. Chiral resolution values over 10 were achieved for flavonoids. The comparison study with reference perphenylcarbamate-ß-CD clicked CSP reveals the significance of 3-chloro-4-methyl functionality in improving the enantioselectivities. This study may provide insight on the multiple interactions between functionalized CD and analytes.

Blueberry Improves the Therapeutic Effect of Etanercept on Patients with Juvenile Idiopathic Arthritis: Phase III Study.

Juvenile idiopathic arthritis (JIA) is the most common arthritis in the adolescents under the age of 16. Etanercept, an inhibitor of tumor necrosis factor, is often used to treat JIA despite its significant side effects. Homeopathic remedies, such as blueberries, have anti-inflammatory properties with fewer unwanted effects and should be considered as a primary treatment. We aimed to explore the efficacy and safety of combination therapy of blueberry and etanercept for JIA. Two hundred and one JIA patients were selected, and randomly and evenly assigned to three groups: ETA (50 mg of etanercept twice weekly), ETABJ (matched etanercept and 50 ml blueberry juice daily) and ETAPJ (matched etanercept and placebo juice). The severity of JIA was measured using American College of Rheumatology scales (ACR) 20, 50 and 70. The levels of pro-inflammatory cytokines, interleukin-1 (IL1) alpha and IL1 beta, and interleukin-1 receptor antagonist (IL1RA) were measured by qRT-PCR and ELISA. After a 6-month follow-up, the ACR20, ACR50 and ACR70 in an ETABJ group were higher than those in other two groups (P < 0.05), suggesting clinically meaningful improvement in JIA. Meanwhile, the symptoms and side effects were reduced significantly or absent in an ETABJ group, including mental diseases, retrobulbar optic neuritis, gaining weight, infection, cutaneous vasculitis, diarrhea, uveitis and pancytopenia. Blueberries reduced the levels of IL1 alpha and beta, and increased the level of IL1RA. Thus, a combination therapy of blueberry and etanercept can reduce the severity of JIA and should be developed as a new method for JIA therapy.

Engineering Cyclodextrin Clicked Chiral Stationary Phase for High-Efficiency Enantiomer Separation.

The separation of racemic molecules is of crucial significance not only for fundamental research but also for technical application. Enantiomers remain challenging to be separated owing to their identical physical and chemical properties in achiral environments. Chromatographic techniques employing chiral stationary phases (CSPs) have been developed as powerful tools for the chiral analysis and preparation of pure enantiomers, most of which are of biological and pharmaceutical interests. Here we report our efforts in developing high-performance phenylcarbamated cyclodextrin (CD) clicked CSPs. Insights on the impact of CD functionalities in structure design are provided. High-efficiency enantioseparation of a range of aryl alcohols and flavanoids with resolution values (Rs) over 10 were demonstrated by per(3-chloro-4-methyl)phenylcarbamated CD clicked CSP. Comparison study and molecular simulations suggest the improved enantioselectivity was attributed to higher interactions energy difference between the complexes of enantiomers and CSPs with phenylcarbamated CD bearing 3-chloro and 4-methyl functionalities.

Enantioseparation tuned by solvent polarity on a ß-cyclodextrin clicked chiral stationary phase.

The efficient enantioseparation of 26 racemates has been achieved with the perphenylcarbamoylated cyclodextrin clicked chiral stationary phase by screening the optimum composition of mobile phase in high-performance liquid chromatography. The chromatographic results indicate that both the retention and chiral resolution of racemates are closely related to the polarity of the mobile phases and the structures of analytes. The addition of alcohols can significantly tune the enantioseparation in normal-phase high-performance liquid chromatography. The addition of methanol and the ratio of ethanol/methanol or isopropanol/methanol played a key role on the resolution of flavonoids in ternary eluent systems. The chiral separation of flavonoids with pure organic solvent as mobile phase indicates the preferential order for chiral resolution is methanol>ethanol>isopropanol>n-propanol>acetonitrile.

Evaluation of perphenylcarbamated cyclodextrin clicked chiral stationary phase for enantioseparations in reversed phase high performance liquid chromatography.

In this study, perphenylcarbamated cyclodextrin clicked chiral stationary phase (CSP) was developed with high column efficiency. The characteristics of the column were evaluated in terms of linearity, limit of detection and limit of quantification. The enantioselectivity of the as-prepared clicked CSP was explored with 26 recemates including aryl alcohols, flavanoids and adrenergic drugs in reversed phase high-performance liquid chromatography. The effect of separation parameters including flow rate, column temperature, organic modifier and buffer on the enantioselectivity of the clicked CSP was investigated in detail. The correlation study of the analytes structure and their chiral resolution revealed the great influence of analytes' structure on the enantioseparations with cyclodextrin CSP. Methanol with 1% of triethylammonium acetate buffer (pH 4) was proved to be the best choice for the chiral separation of basic enantiomers.