ABSTRACT
Background: Glioblastoma multiforme (GBM) may be susceptible to metabolic strategies such as fasting and ketogenic diets, which lower blood glucose and elevate ketones. Combining these two strategies may be an ideal approach for sustaining a potentially therapeutic glucose ketone index (GKI). In this prospective case series, we observed whether a combined metabolic strategy was feasible, safe, and capable of sustaining a GKI <6 in patients with GBM. Methods: We provided recommendations and guidelines to 10 GBM patients at various stages of tumour progression and treatment that enabled them to complete a 5-7-day fast every 1-2 months combined with a modified ketogenic diet during the intervening weeks. Patients monitored their blood glucose and ketone levels and body weight. Adverse effects were assessed. Results: Patients completed a mean of 161 ± 74 days of the combined metabolic strategy, with 34 ± 18 (21%) days of prolonged fasting (mean fast duration: 6.0 ± 1.4 days) and 127 ± 59 (79%) days on the ketogenic diet. The mean GKI for all 10 patients was 3.22 (1.28 during the fasts, 5.10 during the ketogenic diet). Body weight decreased by 8.4 ± 6.9 kg (11.2% decrease in baseline weight). The most common adverse effects attributed to the fasts and ketogenic diet were fatigue, irritability, and feeling lightheaded. The metabolic strategy did not interfere with standard oncological treatments. Conclusion: This is the first study to observe the feasibility and safety of repeated, prolonged fasting combined with a modified ketogenic diet in patients with GBM. Using minimal support, patients maintained the combined metabolic strategy for 5-6 months while sustaining a potentially therapeutic mean GKI of 3.22. Weight loss was considerable. Adverse effects attributed to the metabolic strategy were mild, and it did not interfere with standard oncological treatments. Study Registration: This study is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12620001310954. The study was registered on 4 December 2020.
ABSTRACT
The interleukin-5 receptor alpha chain (IL-5Ralpha) is known to regulate the development and function of B cells and eosinophils. Although the functions of IL-5Ralpha cytoplasmic domain subregions have been studied extensively using cultured cell lines, this approach has limitations when studying the functions of distinct primary B-cell subpopulations and their responsiveness to IL-5. In the present study, we generated mice on an IL-5Ralpha null background, each expressing a mutant form of an IL-5Ralpha transgene ligated to a mu enhancer and VH promoter, either lacking the cytoplasmic DC3 region or substituting two proline residues for alanine (ApvA) in the membrane-proximal ppvp motif of the cytoplasmic domain. The ppvp motif, which mediates activation of JAK2/STAT5 and Btk, also contributes to c-fos, c-jun and c-myc expression. IL-5Ralpha null mutant mice showed impaired B-1-cell development, reduced serum immunoglobulin G3 (IgG3) and IgM, no IL-5-induced enhancement of B-cell proliferation and IL-5-induced switch recombination from the mu gene to gamma1 gene; these were not recovered following the expression of the ApvA mutant. In contrast, absence of the DC3 region affected the IL-5-induced switch recombination from the mu to the gamma1 gene and B-1-cell development, while IL-5-induced proliferation and IgM production were at levels similar to those of B cells expressing wild-type IL-5Ralpha transgene. The results clearly indicated that the ppvp motif and the DC3 region of IL-5Ralpha played distinct roles in B-cell proliferation and differentiation. Thus, this present approach offers new insights into the functions of the cytoplasmic subregions of IL-5Ralpha, in particular its carboxy-terminal region.
Subject(s)
B-Lymphocyte Subsets/immunology , Immunoglobulin Class Switching/immunology , Immunoglobulin G/biosynthesis , Receptors, Interleukin/immunology , Amino Acid Sequence , Animals , Cell Culture Techniques , Cell Differentiation/immunology , Cell Division/immunology , Cytoplasm/immunology , Immunoglobulin M/biosynthesis , Interleukin-5/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Molecular Sequence Data , Mutation , Receptors, Interleukin/genetics , Receptors, Interleukin-5 , Structure-Activity RelationshipABSTRACT
The title compound, (S)-(+)-4-[5-(2-oxo-4, 5-dihydroimidazol-1-ylsulfonyl)indolin-1 -ylcarbonyl ]anilinium chloride (S)-(+)-1-[1-(4-aminobenzoyl)indoline-5- sulfonyl]-4-phenyl-4, 5-dihydroimidazol-2-one, C(24)H(23)N(4)O(4)S(+).Cl(-). C(24)H(22)N(4)O(4)S, crystallizes in space group C2 from a CH(3)OH/CH(2)Cl(2) solution. In the crystal structure, there are two different conformers with their terminal C(6) aromatic rings mutually oriented at angles of 67.69 (14) and 61.16 (15) degrees. The distances of the terminal N atoms (of the two conformers) from the chloride ion are 3.110 (4) and 3.502 (4) A. There are eight distinct hydrogen bonds, i.e. four N-H...Cl, three N-H...O and one N-H...N, with one N-H group involved in a bifurcated hydrogen bond with two acceptors sharing the H atom. C-H...O contacts assist in the overall hydrogen-bonding process.