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.     

Segmented polymer networks containing amino‐dendrimers

Polymer networks in which poly(propylene imine) dendrimers (Astramol?) are connected to each other by linear polytetrahydrofuran (polyTHF) segments, were prepared by two methods. The first method was a one‐step procedure in which bifunctionally living polyTHF, obtained by initiation of the THF polymerization with trifluoromethane sulfonic anhydride (triflic anhydride), was reacted with an amino‐dendrimer. This reaction was very fast but did not allow formation of the end products. The second method was a two‐step procedure. In a first step, living polyTHF, prepared with acryloyloxybutyl triflate as initiator, was grafted on an amino‐dendrimer, to form a star‐like, acrylate‐terminated polyTHF multi‐macromonomer with the dendrimer as core. In a second step, networks were obtained by Michael addition between the acrylate end‐groups and unreacted amino‐groups of the dendrimer. This cross‐linking reaction occurred spontaneously upon heating of the solution of the multi‐macromonomer with gelation times varying from a few minutes to a few hours, depending on the temperature and the composition of the prepolymers. With this method it was possible to prepare networks in the form of coatings or films. © 2003 Society of Chemical Industry     

Verbal Representation and Therapeutic Change in Anaclitic and Introjective Inpatients.

This study examined the relation between changes in clinical functioning and changes in verbal expression in 81 seriously disturbed and treatment-resistant young adults seen in a comprehensive, psychoanalytically oriented inpatient treatment. Clinical functioning was evaluated with a battery of clinical and social measures. Verbal representations were assessed using computer-assisted scoring of Thematic Apperception Test responses. Changes in the frequency of verbal content and style in the narratives of these patients covaried with changes in clinical functioning. Significantly different covariations of verbal and clinical change, particularly differences in covariates of referential activity, were found for patients with anaclitic versus introjective personality configurations. The implications of these findings for understanding and treating severe psychopathology are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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