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.     

Efficient computation of time-varying and adaptive filters

Two techniques for efficient computation of filters that support time-varying coefficients are developed. These methods are forms of distributed arithmetic that encode the data, rather than the filter coefficients. The first approach efficiently computes scalar-vector products, with which a digital filter is easily implemented in a transpose-form structure. This method, based on digital coding, supports time-varying coefficients with no additional overhead. Alternatively, distributed-arithmetic schemes that encode the data stream in sliding blocks support efficient direct-form filter computation with time-varying coefficients. A combination of both of these techniques greatly reduces the computation required to implement LMS adaptive filters     

Ratings of the performances of practicing internists by hospital-based registered nurses

PURPOSE: To examine the feasibility and reliability of ratings completed by hospital-based registered nurses of the humanistic qualities, communication skills, and selected aspects of the clinical skills of practicing internists. METHOD: In 1988-1989, registered nurses who worked in the same 175 hospitals as 232 internists with admitting privileges at these hospitals rated the internists' performances. The nurses were selected from medicine floors, specialty floors, and intensive care units and/or critical care units, using lists provided by head nurses. A total of 1,877 rating questionnaires with 13 performance categories were collected (with a mean of 8.01 nurses per internist). The ratings were analyzed to determine measurement characteristics and the relationships of the nurses' demographic characteristics to the ratings. In addition, for each of ten performance categories for 152 of the internists, the average rating each internist received from nurses was compared with the average rating each internist received from peer physicians. Statistical analysis used Pearson correlations, canonical correlations, factor analyses, Student's t-tests, analysis of variance, and stepwise multiple regression. Finally, the internists themselves, including physicians who were not actually rated by the nurses, were asked to complete a brief questionnaire that included questions about their opinions of the use of nurses' ratings. RESULTS: The nurses' ratings correlated moderately strongly with the peer physicians' ratings and had a common structure. However, the nurses' ratings were lower for several humanistic qualities, including respect, integrity, and responsibility, and their ratings were higher for medical knowledge and verbal communications. Across the 13 performance categories, approximately 10-15 ratings from nurses were needed to obtain a reliable assessment of an internist's humanistic qualities and communication skills. Many internists felt that nurses' ratings should be used equally with, or at least as a lesser contribution to, ratings by peer physicians of humanistic qualities and communication skills. CONCLUSION: Nurses' ratings appear to provide a feasible and reliable method of evaluating the internists' communication skills and humanistic qualities, when used in conjunction with ratings by peer physicians.