Camelid-derived Tcell engagers harnessing human γδ T cells as promising antitumor immunotherapeutic agents.

In the last decade, there has been a surge in developing immunotherapies to enhance the immune system's ability to eliminate tumor cells. Bispecific antibodies known as T cell engagers (TCEs) present an attractive strategy in this pursuit. TCEs aim to guide cytotoxic T cells toward tumor cells, thereby inducing a strong activation and subsequent tumor cell lysis.

Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening.

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression.

Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce -MYC Protein Levels in Cells.

Elevated expression of the -MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous -MYC protein levels in a amplified cell line led to the discovery of a compound series that phenocopies -MYC knockdown by siRNA.

Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells .

Epithelial ovarian cancer (EOC) represents 5% of human gynecologic cancers in the world, is heterogeneous and highly invasive with a dismal prognosis (5 year-survival rate <35%). Diagnosis of EOC is frequently made at advanced stages and, despite aggressive treatments combining surgery and chemotherapy, fatal relapse rapidly occurs and is accompanied by a peritoneal carcinosis. In this context, novel therapeutical advances are urgently required.

NKG2D Controls Natural Reactivity of Vγ9Vδ2 T Lymphocytes against Mesenchymal Glioblastoma Cells.

Purpose: Cellular immunotherapies are currently being explored to eliminate highly invasive and chemoradioresistant glioblastoma (GBM) cells involved in rapid relapse. We recently showed that concomitant stereotactic injections of nonalloreactive allogeneic Vγ9Vδ2 T lymphocytes eradicate zoledronate-primed human GBM cells. In the present study, we investigated the spontaneous reactivity of allogeneic human Vγ9Vδ2 T lymphocytes toward primary human GBM cells, and , in the absence of any prior sensitization.

Dentistry and nursing working together to improve oral health care in a long-term care facility.

Inadequate oral care in long-term care (LTC) facilities compromises the quality of life of residents. This study assessed oral care knowledge of, and challenges experienced by, nurses and allied nursing staff (ANS) in a LTC facility in Canada. Dentists and nursing staff used the findings to implement strategies for improved care.

Research- and Practice-Based Nutrition Education and Cooking Workshops in Pediatric Oncology: Protocol for Implementation and Development of Curriculum.

Background: Progresses in childhood cancer treatment, diagnosis, and management have resulted in childhood cancer survival rates of over 80%. However, this therapeutic success comes with a heavy price: two-thirds of childhood cancer survivors will be affected by further complications, including cardiovascular and metabolic diseases. Adequate nutrition during cancer treatment is essential to ensure the child's optimal development, improve tolerance to treatments, and can contribute to lower the risk of developing cardiometabolic diseases.

Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2.

The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.

EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.

In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types.

Development and validation of reagents and assays for EZH2 peptide and nucleosome high-throughput screens.

Histone methyltransferases (HMT) catalyze the methylation of histone tail lysines, resulting in changes in gene transcription. Misregulation of these enzymes has been associated with various forms of cancer, making this target class a potential new area for the development of novel chemotherapeutics. EZH2 is the catalytic component of the polycomb group repressive complex (PRC2), which selectively methylates histone H3 lysine 27 (H3K27).

Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines.

The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.

Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.

Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693).

Substituted 1,4-benzodiazepine-2,5-diones as alpha-helix mimetic antagonists of the HDM2-p53 protein-protein interaction.

Small molecule antagonists of protein-protein interactions represent a particular challenge for pharmaceutical discovery. One approach to finding molecules that can disrupt these interactions is to seek mimics of common protein structure motifs. We present an analysis of how molecules based on the 1,4-benzodiazepine-2,5-dione scaffold serve to mimic the side-chains presented by the hydrophobic face of two turns of an alpha-helix derived from the tumor suppressor protein p53, and thus antagonize the HDM2-p53 protein-protein binding interaction.

Enhanced pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione antagonists of the HDM2-p53 protein-protein interaction through structure-based drug design.

Guided by structure-based drug design, modification of the 1,4-benzodiazepin-2,5-dione lead compound 1 resulted in the discovery of 19, a potent and orally bioavailable antagonist of the HDM2-p53 protein-protein interaction (FP IC50 = 0.7 microM, F approximately 100%).

Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo.

The activity and stability of the p53 tumor suppressor are regulated by the human homologue of the mouse double minute 2 (Hdm2) oncoprotein. It has been hypothesized that small molecules disrupting the Hdm2:p53 complex would allow for the activation of p53 and result in growth suppression. We have identified small-molecule inhibitors of the Hdm2:p53 interaction using our proprietary ThermoFluor microcalorimetry technology.

Design, synthesis, and biological evaluation of novel potent and selective alphavbeta3/alphavbeta5 integrin dual inhibitors with improved bioavailability. Selection of the molecular core.

A novel series of potent and selective alpha(v)beta(3)/alpha(v)beta(5) dual( )()inhibitors was designed, synthesized, and evaluated against several integrins. These compounds were synthesized through a Mitsunobu reaction between the guanidinium mimetics and the corresponding central templates. Guanidinium mimetics with enhaced rigidity (i.

Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells.

HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties.

1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR.

A library of 1,4-benzodiazepine-2,5-diones was screened for binding to the p53-binding domain of HDM2 using Thermofluor, a miniaturized thermal denaturation assay. The hits obtained were shown to bind to HDM2 in the p53-binding pocket using a fluorescence polarization (FP) peptide displacement assay. The potency of the series was optimized, leading to sub-micromolar antagonists of the p53-HDM2 interaction.

Effects of different glycaemic index foods and dietary fibre intake on glycaemic control in type 1 diabetic patients on intensive insulin therapy.

To evaluate the influence of a low glycaemic index (GI), high GI and high fibre diet on glycaemic control and insulin requirement in Type 1 diabetic patients on intensive insulin therapy, nine well-controlled, highly-motivated Type 1 diabetic patients were put on a control diet for 12 days and then randomized in a consecutive manner to 12 days of each diet, in a crossover design. During each experimental diet, the study subjects adjusted their premeal insulin (soluble) dose to maintain their 1-h postprandial capillary glucose at or below 10 mmol l(-1). At the end of each experimental diet, they were submitted to a standardized breakfast of the diet under study, using the same premeal insulin dose as that required for the control diet.

Advisory Committee: A Powerful Tool for Helping Decision Makers inEnvironmental Issues.

/ It has been suggested that the general public should be moreinvolved in environmental policy and decision making. It is important forthem to realize that they will have to live with the consequences ofenvironmental policies and decisions. Consequently, policy makers shouldconsider the concerns and opinions of the general public before makingdecisions on environmental issues.

End point attached heparin affinity matrix.

Heparin is a highly sulfated long-chain glycosaminoglycan utilized extensively for its anticoagulation properties, which has found widespread use as a general affinity ligand. The polysaccharide is composed of repeating units of uronic acid and glucosamine with great variability in sequence within the chain. The high degree of sulfation imparts strong acidity to the molecule and it may bond with many compounds simply by ionic interaction.

Dissociation of anorectic and affective responses to epinephrine and glucose in rats.

The purpose of this study was to determine whether the anorexia following epinephrine and glucose IP injections is due to the activation of mechanisms of satiety. Epinephrine (100 micrograms.kg-1) and glucose (4 g.

Ingestive response shows absence of taste aversion after bovine satietin in rats.

Six adult male rats (409 +/- 16 g) were equipped with chronically implanted oral catheters. Facial consummatory responses to gustatory stimuli, of 50 microliters 2.0 mol.

Duodenal preabsorptive origin of gustatory alliesthesia in rats.

Facial consummatory responses reflecting ingestive and aversive perceptions were studied and quantified in rats chronically implanted with gastric, duodenal, and oral catheters. A gustatory stimulus of 50 microliters of 1.75 mol/l sucrose was injected into the mouth every 5 min for 65 min.