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.     

Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection

Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus.     

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