Invention and characterization of a systemically administered, attenuated and killed bacteria-based multiple immune receptor agonist for anti-tumor immunotherapy.

Activation of immune receptors, such as Toll-like (TLR), NOD-like (NLR) and Stimulator of Interferon Genes (STING) is critical for efficient innate and adaptive immunity. Gram-negative bacteria (G-NB) contain multiple TLR, NOD and STING agonists. Potential utility of G-NB for cancer immunotherapy is supported by observations of tumor regression in the setting of infection and Coley's Toxins.

First evidence of a functional spiracle in stem chondrichthyan acanthodians, with the oldest known elastic cartilage.

Spiracles are a general character of gnathostomes (jawed fishes), being present in antiarch placoderms, commonly regarded as the most basal gnathostome group. The presence of spiracular tubes in acanthodians has been deduced from grooves on the neurocranium of the derived acanthodiform Acanthodes bronni from the Permian of Germany, but until now these tubes were presumed to lack an external opening, rendering them non-functional. Here we describe the external spiracular elements in specimens of the Middle Devonian acanthodiforms Cheiracanthus murchisoni, Cheiracanthus latus and Mesacanthus pusillus from northern Scotland, and the internal structure of these elements in C.

Photo-stability study of a solution-processed small molecule solar cell system: correlation between molecular conformation and degradation.

Solution-processed organic small molecule solar cells (SMSCs) have achieved efficiency over 11%. However, very few studies have focused on their stability under illumination and the origin of the degradation during the so-called burn-in period. Here, we studied the burn-in period of a solution-processed SMSC using benzodithiophene terthiophene rhodamine:[6,6]-phenyl C butyric acid methyl ester (BTR:PCBM) with increasing solvent vapour annealing time applied to the active layer, controlling the crystallisation of the BTR phase.

Glomus tumour: a rare differential for subungual lesions.

A 21-year-old, usually fit and well man, presented with a 10-year history of intermittent, paroxysmal pain and temperature sensitivity to his right thumb. He felt this was associated with a subungual lesion present on the same digit. He was diagnosed as having a glomus tumour and was referred to the hand surgeons for surgical excision.

A mistaken case of tension pneumothorax.

The patient was an otherwise usually fit and well 25-year-old man who presented to A&E department in extremis. The initial working diagnosis was a tension pneumothorax, and he was subsequently treated with needle thoracocentesis causing a release of air. A chest radiograph was taken, after which a chest drain was inserted.

Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity.

Purpose: Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor of the benzamide class currently under clinical development in cancer indications. This study reports the in vitro and in vivo antitumor characteristics of the compound.

Methods: Selectivity and potency of chidamide in inhibition of HDAC isotypes were analyzed by using a panel of human recombinant HDAC proteins.

Kinase-mediated trapping of bi-functional conjugates of paclitaxel or vinblastine with thymidine in cancer cells.

In the present work, we explore the possibility of introducing selectivity to existing chemotherapeutics via the design of non-pro-drug, bi-functional molecules comprising a microtubule-binding agent and a substrate for a disease-associated kinase. The design, synthesis, and in vitro biological evaluation of paclitaxel-thymidine and vinblastine-thymidine bi-functional conjugates are reported here. This work provides the first account of 'kinase-mediated trapping' of cancer therapeutics.

A phase I pharmacokinetic study of the P-glycoprotein inhibitor, ONT-093, in combination with paclitaxel in patients with advanced cancer.

Background: ONT-093 is an orally bioavailable inhibitor of P-glycoprotein (P-gp). In pre-clinical studies, ONT-093 could inhibit P-gp and reverse multidrug resistance at nM concentrations with no effect on paclitaxel pharmacokinetics. Phase I trials of ONT-093 in normal human volunteers showed no dose-limiting toxicities at serum concentrations associated with biologic activity achieved with doses ranging from 300 to 500 mg.

Structure-based design of selective and potent inhibitors of protein-tyrosine phosphatase beta.

Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors.

Inhibition of fructose-1,6-bisphosphatase by a new class of allosteric effectors.

A highly constrained pseudo-tetrapeptide (OC252-324) further defines a new allosteric binding site located near the center of fructose-1,6-bisphosphatase. In a crystal structure, pairs of inhibitory molecules bind to opposite faces of the enzyme tetramer. Each ligand molecule is in contact with three of four subunits of the tetramer, hydrogen bonding with the side chain of Asp187 and the backbone carbonyl of residue 71, and electrostatically interacting with the backbone carbonyl of residue 51.

Pyrrolopyrazinedione-based inhibitors of human hormone-sensitive lipase.

The regulation of lipid metabolism and it's effect on glucose control and diabetes has received intense interest. Hormone-sensitive lipase (HSL) is a vital enzyme in lipid metabolism. A series of novel pyrrolopyrazinediones has been discovered that demonstrate submicromolar activity both in the enzyme assay and in a (14)C-emulsion assay employing cholesteryl oleate as a substrate as a secondary measure of HSL activity.

Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B.

Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors.

OC144-093, a novel P glycoprotein inhibitor for the enhancement of anti-epileptic therapy.

Inhibitors of P gLycoprotein (Pgp) may be useful for the enhancement of blood-brain barrier penetration of anti-epileptic drugs (AEDs). Due to polypharmacy and the need for chronic treatment, Pgp inhibitors used in epilepsy should be highly specific and non-toxic. In particular, it may be essential to use compounds that produce minimal inhibition of enzymes involved in metabolism of AEDs and other drugs used by epilepsy patients.