The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and longterm toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups.
A series of 4-phenethynyldihydrocinnamic acid agonists of the free fatty acid receptor 1 (FFA(1)) has been discovered and explored. The preferred compound 20 (TUG-424, EC(50) = 32 nM) significantly increased glucose-stimulated insulin secretion at 100 nM and may serve to explore the role of FFA(1) in metabolic diseases such as diabetes or obesity.
Malignancies occur with a higher incidence rate and manifest earlier in life in patients with primary immunodeficiency disorders (PIDs) than in the general population. However, no universal mechanism of malignancy predisposition in patients with PIDs has been determined. Despite strong support for the physiologic role of tumor immunosurveillance and the increasing success of strategies in immunologic tumor therapy, which include checkpoint inhibition, mAbs, and engineered T-cell antigen receptors, the incidence and pattern of malignancies in patients with PIDs do not reflect an increased tumor immune escape per se. In contrast, malignancies appear to be restricted to either (1) tissue types bearing the same molecular defect that underlies the PID, such as syndromes of DNA repair deficiency or immune cell-specific maturation or functional defects that suggest a cell-intrinsic oncogenic basis, or (2) other tissues when they are infected by transforming viruses or chronically inflamed, pointing toward extrinsic causes for transformation that are potentially facilitated by but not predominantly caused by a lack of immunosurveillance. Based on recent studies of pre-existing conditions in patients with malignancies and on malignancies in large PID cohorts, we conclude that a large part of tumor predisposition in patients with PIDs is derived from the same molecular defect as the immunodeficiency itself. The presented concept elucidates diverse pathomechanisms and risks of malignancies in patients with PIDs in light of current tumor immune therapies.
The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes. Several FFA1 agonists containing the para-substituted dihydrocinnamic acid moiety are known. We here present a structure-activity relationship study of this compound family suggesting that the central methyleneoxy linker is preferable for the smaller compounds, whereas the central methyleneamine linker gives higher potency to the larger compounds. The study resulted in the discovery of the potent and selective full FFA1 agonist TUG-469 (29).
Free
fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated
insulin secretion from pancreatic β-cells and currently attracts
high interest as a new target for the treatment of type 2 diabetes.
We here report the discovery of a highly potent FFA1 agonist with
favorable physicochemical and pharmacokinetic properties. The compound
efficiently normalizes glucose tolerance in diet-induced obese mice,
an effect that is fully sustained after 29 days of chronic dosing.
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