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om the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design.
A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways.
TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. learn more The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation.
Trials Registration ISRCTN, ISRCTN36667085 . Registered on September 26, 2014.
Trials Registration ISRCTN, ISRCTN36667085 . Registered on September 26, 2014.
The immune pathways in Alzheimer's disease (AD) remain incompletely understood. Our recent study indicates that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the brain barriers of aged mice and that their activation alleviates aging-associated cognitive decline. The regulation and function of ILC2 in AD, however, remain unknown.
In this study, we examined the numbers and functional capability of ILC2 from the triple transgenic AD mice (3xTg-AD) and control wild-type mice. We investigated the effects of treatment with IL-5, a cytokine produced by ILC2, on the cognitive function of 3xTg-AD mice.
We demonstrate that brain-associated ILC2 are numerically and functionally defective in the triple transgenic AD mouse model (3xTg-AD). The numbers of brain-associated ILC2 were greatly reduced in 7-month-old 3xTg-AD mice of both sexes, compared to those in age- and sex-matched control wild-type mice. The remaining ILC2 in 3xTg-AD mice failed to efficiently produce the type 2 cytokine IL-5 but gained the capability to express a number of proinflammatory genes. Administration of IL-5, a cytokine produced by ILC2, transiently improved spatial recognition and learning in 3xTg-AD mice.
Our results collectively indicate that numerical and functional deficiency of ILC2 might contribute to the cognitive impairment of 3xTg-AD mice.
Our results collectively indicate that numerical and functional deficiency of ILC2 might contribute to the cognitive impairment of 3xTg-AD mice.
The design of stable and biocompatible black phosphorus-based theranostic agents with high photothermal conversion efficiency and clear mechanism to realize MRI-guided precision photothermal therapy (PTT) is imminent.
Herein, black phosphorus nanosheets (BPs) covalently with mono-dispersed and superparamagnetic ferrous selenide (FeSe
) to construct heteronanostructure nanoparticles modified with methoxy poly (Ethylene Glycol) (mPEG-NH
) to obtain good water solubility for MRI-guided photothermal tumor therapy is successfully designed. The mechanism reveals that the enhanced photothermal conversion achieved by BPs-FeSe
-PEG heteronanostructure is attributed to the effective separation of photoinduced carriers. Besides, through the formation of the P-Se bond, the oxidation degree of FeSe
is weakened. The lone pair electrons on the surface of BPs are occupied, which reduces the exposure of lone pair electrons in air, leading to excellent stability of BPs-FeSe
-PEG. Furthermore, the BPs-FeSe
-PEG heteronanostructure could realize enhanced T
-weighted imaging due to the aggregation of FeSe
on BPs and the formation of hydrogen bonds, thus providing accurate PTT guidance and generating hyperthermia to inhabit tumor growth under NIR laser with negligible toxicity in vivo.
Collectively, this work offers an opportunity for fabricating BPs-based heteronanostructure nanomaterials that could simultaneously enhance photothermal conversion efficiency and photostability to realize MRI-guided cancer therapy.
Collectively, this work offers an opportunity for fabricating BPs-based heteronanostructure nanomaterials that could simultaneously enhance photothermal conversion efficiency and photostability to realize MRI-guided cancer therapy.
Autoreactive B cells are well recognized as key participants in the pathogenesis of systemic lupus erythematosus (SLE). However, elucidating the particular subset of B cells in producing anti-dsDNA antibodies is limited due to their B cell heterogeneity. This study aimed to identify peripheral B cell subpopulations that display autoreactivity to DNA and contribute to lupus pathogenesis.
Flow cytometry was used to detect total B cell subsets (n = 20) and DNA autoreactive B cells (n = 15) in SLE patients' peripheral blood. Clinical disease activities were assessed in SLE patients using modified SLEDAI-2 K and used for correlation analyses with expanded B cell subsets and DNA autoreactive B cells.
The increases of circulating double negative 2 (DN2) and activated naïve (aNAV) B cells were significantly observed in SLE patients. Expanded B cell subsets and DNA autoreactive B cells represented a high proportion of aNAV B cells with overexpression of CD69 and CD86. The frequencies of aNAV B cells in total B cell populations were significantly correlated with modified SLEDAI-2 K scores.
