Vitamin D supplementation has been suggested to enhance immunity during respiratory infection season. We tested the effect of active vitamin D (calcitriol) supplementation on key airway innate immune ...mechanisms in vitro.
Primary human airway epithelial cells (hAECs) grown at the air liquid interface were supplemented with 10-7 M calcitriol for 24 hours (or a time course) and their antimicrobial airway surface liquid (ASL) was tested for pH, viscoscity, and antibacterial and antiviral properties. We also tested hAEC ciliary beat frequency (CBF). Next, we assessed alterations to hAEC gene expression using RNA sequencing, and based on results, we measured neutrophil migration across hAECs.
Calcitriol supplementation enhanced ASL bacterial killing of Staphylococcus aureus (p = 0.02) but did not enhance its antiviral activity against 229E-CoV. It had no effect on ASL pH or viscosity at three timepoints. Lastly, it did not affect hAEC CBF or neutrophil migration, although there was a trend of enhanced migration in the presence of a neutrophil chemokine (p = 0.09). Supplementation significantly altered hAEC gene expression, primarily of AMP-related genes including CAMP and TREM1.
While vitamin D supplementation did not have effects on many airway innate immune mechanisms, it may provide a useful tool to resolve respiratory bacterial infections.
IntroductionVitamin D supplementation has been suggested to enhance immunity during respiratory infection season. We tested the effect of active vitamin D (calcitriol) supplementation on key airway ...innate immune mechanisms in vitro.MethodsPrimary human airway epithelial cells (hAECs) grown at the air liquid interface were supplemented with 10-7 M calcitriol for 24 hours (or a time course) and their antimicrobial airway surface liquid (ASL) was tested for pH, viscoscity, and antibacterial and antiviral properties. We also tested hAEC ciliary beat frequency (CBF). Next, we assessed alterations to hAEC gene expression using RNA sequencing, and based on results, we measured neutrophil migration across hAECs.ResultsCalcitriol supplementation enhanced ASL bacterial killing of Staphylococcus aureus (p = 0.02) but did not enhance its antiviral activity against 229E-CoV. It had no effect on ASL pH or viscosity at three timepoints. Lastly, it did not affect hAEC CBF or neutrophil migration, although there was a trend of enhanced migration in the presence of a neutrophil chemokine (p = 0.09). Supplementation significantly altered hAEC gene expression, primarily of AMP-related genes including CAMP and TREM1.ConclusionWhile vitamin D supplementation did not have effects on many airway innate immune mechanisms, it may provide a useful tool to resolve respiratory bacterial infections.
Neuronal cytoskeletal proteins like the microtubule associated protein 2 (MAP2) are objected to pathological proteolysis in case of Alzheimer's disease and brain ischemia. The neurotrophic ...peptidergic drug Cerebrolysin (EBEWE Arzneimittel, Austria, Europe) is produced by a standardized enzymatic break-down of lipid free porcine brain proteins. Cerebolysin protected MAP2 in primary neuronal cultures after a brief histotoxic hypoxia and in a rat model of acute brain ischemia. Furthermore the drug was shown to inhibit the proteases mu- and m-calpain dose dependently in several cell free protease activity assays. The question if the higher MAP2 levels are due to an alleviation of proteolysis, to a higher synthesis rate or both is addressed in the current investigation: Monitoring the MAP2 content of primary neuronal cell cultures over a period of eight days revealed MAP2 to reach a peak level on day six in vitro followed by a degradation phase. In other experiments the protein synthesis of Cerebrolysin treated and untreated cells was blocked with cycloheximide at that moment when all cells exhibited the same MAP2 content. After the following MAP2 degradation phase--i.e. after eight days in vitro--the MAP2 contents were determined by western blotting. Cerebrolysin treated cells contained more MAP2 than untreated controls proving that the drug protects MAP2 independently from de novo synthesis, although further work is in progress to investigate if the drug supplementary boosts this effect by increasing MAP2 synthesis.
We study the class of univariate polynomials βk(X), introduced by Carlitz, with coefficients in the algebraic function field Fq(t) over the finite field Fq with q elements. It is implicit in the work ...of Carlitz that these polynomials form an Fqt-module basis of the ring Int(Fqt)={f∈Fq(t)X|f(Fqt)⊆Fqt} of integer-valued polynomials on the polynomial ring Fqt. This stands in close analogy to the famous fact that a Z-module basis of the ring Int(Z) is given by the binomial polynomials (Xk).
We prove, for k=qs, where s is a non-negative integer, that βk is irreducible in Int(Fqt) and that it is even absolutely irreducible, that is, all of its powers βkm with m>0 factor uniquely as products of irreducible elements of this ring. As we show, this result is optimal in the sense that βk is not even irreducible if k is not a power of q.
ABSTRACT
Purpose
Following two cases of neutralizing antibodies to epoetin alfa in an investigational clinical study, a small number of individual syringes of two drug product batches were found to ...contain unusually high levels of aggregation at the end of the clinical trial.
Methods
We undertook an extensive analytical approach to determine the root-cause of the increased aggregation in the affected batches.
Results
Soluble tungsten was found in the syringes, most likely derived from the pins used to manufacture the syringes. Spiking of epoetin alfa with sodium polytungstate or an extract of tungsten pins used to manufacture the syringes induced the formation of aggregates, both dimers that appeared to be covalently linked by disulphide bonds as well as higher-order aggregates. Sodium polytungstate had also a strong denaturing effect on the protein.
Conclusions
We propose tungsten-mediated unfolding and aggregation of epoetin alfa in pre-filled syringes as a potential root cause for increased immunogenicity. This finding may be more broadly applicable to this and other classes of therapeutic proteins.
Systemic Sclerosis (SSc) is a clinically heterogeneous disease that includes an upregulation of type I interferons (IFNs). The aim of this observational study was to investigate the IFN-regulated ...protein Sialic Acid−Binding Ig-like Lectin 1 (SIGLEC-1) as a biomarker for disease phenotype, therapeutic response, and differential diagnosis in SSc. Levels of SIGLEC-1 expression on monocytes of 203 SSc patients were determined in a cross-sectional and longitudinal analysis using multicolor flow cytometry, then compared to 119 patients with other rheumatic diseases and 13 healthy controls. SSc patients higher SIGLEC-1 expression on monocytes (2097.94 ± 2134.39) than HCs (1167.45 ± 380.93; p = 0.49), but significantly lower levels than SLE (8761.66 ± 8325.74; p < 0.001) and MCTD (6414.50 ± 1846.55; p < 0.001) patients. A positive SIGELC-1 signature was associated with reduced forced expiratory volume (p = 0.007); however, we were unable to find an association with fibrotic or vascular disease manifestations. SIGLEC-1 remained stable over time and was independent of changes in immunosuppressive therapy. However, SIGLEC-1 is suitable for differentiating SSc from other connective tissue diseases. SIGLEC-1 expression on monocytes can be useful in the differential diagnosis of connective tissue disease but not as a biomarker for SSc disease manifestations or activity.
: To summarize the available literature on using machine learning (ML) for the detection and segmentation of benign tumors of the central nervous system (CNS) and to assess the adherence of published ...ML/diagnostic accuracy studies to best practice.
: The MEDLINE database was searched for the use of ML in patients with any benign tumor of the CNS, and the records were screened according to PRISMA guidelines.
: Eleven retrospective studies focusing on meningioma (n = 4), vestibular schwannoma (n = 4), pituitary adenoma (n = 2) and spinal schwannoma (n = 1) were included. The majority of studies attempted segmentation. Links to repositories containing code were provided in two manuscripts, and no manuscripts shared imaging data. Only one study used an external test set, which raises the question as to whether some of the good performances that have been reported were caused by overfitting and may not generalize to data from other institutions.
: Using ML for detecting and segmenting benign brain tumors is still in its infancy. Stronger adherence to ML best practices could facilitate easier comparisons between studies and contribute to the development of models that are more likely to one day be used in clinical practice.
(1) Background: Prostate cancer is the most common cancer in men and can be treated with radical prostatectomy (RPE) or radiotherapy in the primary setting. Stereotactic radiotherapy (SBRT) has ...proven to be effective and well tolerated in this setting. However, if SBRT is an equally promising treatment option if applied in the adjuvant or salvage setting after RPE remains unknown. (2) Methods: We searched the PubMed and Embase databases with the following full-text queries in August 2021 for any combination of the terms "SBRT", "prostate", "adjuvant", "postoperative", "salvage", "stereotactic radiotherapy", "prostate bed". There were no limitations regarding publication date or language. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. (3) Results: We identified 11 individual studies that were included in this systematic review. Three publications included patients without prior radiotherapy and the remaining eight patients with prior radiotherapy. In all but two publications the radiation target was the macroscopic recurrence. SBRT was overall well tolerated with acceptable rates of acute and late gastrointestinal or genitourinary toxicity. Quality of life was published for two phase I trials with good results. There was a very heterogeneous reporting on biochemical control after SBRT. (4) Conclusions: At this point, ultra-hypofractionated RT using SBRT to the prostate bed remains experimental and its use should be restricted to clinical trials. Given the biological rationale for extreme hypofractionation in patients with prostate cancer and the acceptable toxicity rates that have been reported, further exploration of this field is warranted.
The Laser Ranging Interferometer (LRI) instrument on the Gravity Recovery and Climate Experiment (GRACE) Follow-On mission has provided the first laser interferometric range measurements between ...remote spacecraft, separated by approximately 220 km. Autonomous controls that lock the laser frequency to a cavity reference and establish the 5 degrees of freedom two-way laser link between remote spacecraft succeeded on the first attempt. Active beam pointing based on differential wave front sensing compensates spacecraft attitude fluctuations. The LRI has operated continuously without breaks in phase tracking for more than 50 days, and has shown biased range measurements similar to the primary ranging instrument based on microwaves, but with much less noise at a level of 1 nm/sqrtHz at Fourier frequencies above 100 mHz.
To summarize the available literature on using machine learning (ML) for palliative care practice as well as research and to assess the adherence of the published studies to the most important ML ...best practices.
The MEDLINE database was searched for the use of ML in palliative care practice or research, and the records were screened according to PRISMA guidelines.
In total, 22 publications using machine learning for mortality prediction (n = 15), data annotation (n = 5), predicting morbidity under palliative therapy (n = 1), and predicting response to palliative therapy (n = 1) were included. Publications used a variety of supervised or unsupervised models, but mostly tree-based classifiers and neural networks. Two publications had code uploaded to a public repository, and one publication uploaded the dataset.
Machine learning in palliative care is mainly used to predict mortality. Similarly to other applications of ML, external test sets and prospective validations are the exception.
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