Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

EVALUATING SOFTWARE OUTSOURCING OPTIONS Do Your Software Operations Add Value ?

If you don't know the current productivity rates, usage volumes, and other quantitative baseline data for your software operations, then software might not be a key component of the company's core business. The evaluation criteria in this article can help the IS executive determine the outsourcing options for software operations.     

The rationale for cementless total hip replacement

Current cementing techniques of distal plugging, pulsatile water cleaning of the canal, and retrograde filling with PMMA in a low-viscous state prepared using porosity reduction techniques and then pressurized have been shown to give excellent results at 10 or more years after operation. However, physical and aging characteristics of PMMA do not guarantee that those results will hold up in the 20- to 30-year time frame. Fifteen-year experience with bony ingrowth systems indicate the development of a durable interface without PMMA, although the interface does appear more vulnerable to attack by the biologic reaction to HMWPE debris. Bone remodeling appears more favorable around proximally fixed bone ingrowth prostheses than around distally fixed prostheses. Softening of the physical characteristics of the stem tip may reduce the incidence of thigh pain. Patients with high activity potential and a life expectancy of greater than 25 years should be strongly considered for a proximally fixed bone ingrowth or ongrowth prosthesis.     

Facial myokymia and spastic paretic facial contracture as the result of anaplastic pontocerebellar glioma

The case of a 36-year-old man who sought treatment of right facial myokymia and spastic paretic facial contracture is reported. Computed tomography and magnetic resonance imaging revealed a tumor located in the right cerebellar peduncle and the right dorsal pons bulging into the fourth ventricle. After microsurgical partial resection of the mass, which was verified histologically as an anaplastic glioma, facial myokymia initially ceased. The vermicular rippling movements were less intense upon recurrence and could be controlled by low-dose dexamethasone in the further course, when magnetic resonance imaging showed an interstitial pontine edema after percutaneous radiation therapy. It is assumed that facial myokymia and spastic paretic facial contracture were generated by ectopic activity due to alterations in the microenvironment at the intrapontine portion of the axons of the seventh nerve caused by the compressive effect of the tumor and later by edema.     

Biodegradation of chlorpyrifos by either single or combined cultures of some soilborne plant pathogenic fungi

Biodegradation of chlorpyrifos was studied in liquid culture media amended with either single or combined eight different plant pathogenic fungi isolated from the continuous cropping wheat fields. The average recovery of chlorpyrifos from the liquid media was found to be 86.1%. The detection limit of chlorpyrifos by the analytical method used was 19 ppb. Data showed that the growth of mixed fungi at concentrations up to 200 ppm of chlorpyrifos was higher than in the control treatment. Chlorpyrifos concentrations declined in the medium of combined fungi more than it did in the medium of any single fungus with increase in the incubation period. The amount of chlorpyrifos recovered was 79.8 ppm (39.9%) in the combined fungal cultures after 21 days. However, those recovered from the media of Fusarium graminearum, F. oxysporum, Rhizoctonia solani, Cladosporium cladosporiodes, Cephalosporium sp., Trichoderma viridi, Alternaria alternata, and Cladorrhinum brunnescens, ranged from 48.0 to 74.8%. The half-life value (T1/2) for chlorpyrifos was 15.8 day in the medium amended with mixed fungi. However, for the single cultures it ranged from 19.3 to 33.0 day.