Doll Therapy Intervention Reduces Challenging Behaviours of Women with Dementia Living in Nursing Homes: Results from a Randomized Single-Blind Controlled Trial.

Background: Doll therapy (DT) is a non-pharmacological intervention for the treatment of the behavioural and psychological symptoms of dementia (BPSD). We designed a single-blind randomized controlled trial of the 30-day efficacy of DT in reducing the BPSD, professional caregivers’ distress and patients’ biomarkers of stress, and in improving the exploration and caregiving behaviours. Methods: We randomly assigned 134 women with moderate-to-severe dementia living in nursing homes (NHs) to a DT intervention (DTI, 67) or a sham intervention with a cube (SI, 67).

Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-]pyrimidine RET Inhibitors.

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-]pyrimidine scaffold. The optimization of this pyrrolo[2,3-]pyrimidine core resulted in compound , which demonstrated potent RET kinase inhibition and robust efficacy in RET-driven tumor xenografts upon multiday dosing in mice.

Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis.

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877.

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control.

Efficacy and Tolerability of Pyrazolo[1,5-]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma.

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse studies, compound demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd).