The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.

During persistent antigen stimulation, exhausted CD8 T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8 T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway.

Rapid Affinity and Microsomal Stability Ranking of Crude Mixture Libraries of Histone Deacetylase Inhibitors.

The science of drug discovery involves multiparameter optimization of molecular structures through iterative design-make-test cycles. For medicinal chemistry library synthesis, traditional workflows involve the isolation of each individual compound, gravimetric quantitation, and preparation of a standard concentration solution for biological assays. In this work, we explore ways to expedite this process by testing unpurified library mixtures using a combination of mass spectrometry-based assays for affinity selection and microsomal metabolic stability.

A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C-H oxidation of carbocyclic -heterocycles.

An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles (-heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes are capable of direct site- and chemo-selective oxidation of a broad range of substrates but are not preparative.

The role of patient inexperience in medication discontinuation: a retrospective analysis of medication nonpersistence in seven chronic illnesses.

Background: Previous studies have reported that patients who are medication naive in some medication classes have a higher risk of medication discontinuation during the first 30 days of treatment and shorter median times to discontinuation than do medication-experienced patients.

Objectives: This study compared the risk of discontinuation during the first 30 days after the index fill and the median time to discontinuation for medication-naive and medication-experienced patients who were prescribed drugs for asthma, diabetes mellitus, high cholesterol, cardiovascular disease, breast cancer, glaucoma, or osteoporosis.

Methods: Deidentified outpatient pharmacy records from 4 large US retail chains were searched for patients who had obtained a prescription for one of the index medications between January 1, 2007, and January 31, 2007.

Effect of copayments on drug use in the presence of annual payment limits.

Objective: To test the hypothesis that deductibles (copayment combined with annual limits on out-of-pocket payments) may reduce the effect of copayments on drug use for patients who expect to reach the annual limit, using as a natural experiment the introduction of copayments with an annual maximum to the seniors' drug plan in Nova Scotia.

Study Design: An interrupted time-series design estimated effects of the introduction of and subsequent increase in drug copayments on the use (vs nonuse) of medications and on the mean daily quantity of use among users by patients' likelihood of exceeding the annual maximum copayment. Effects on the use of less essential medications (histamine(2)-receptor antagonists) and more essential medications (oral antihyperglycemic agents) were examined.

A prospective multicenter clinical investigation of a bone quality-based dental implant system.

This article reports the 5-year interim results of an independently monitored, prospective, multicenter clinical trial of a bone quality-based implant design. At six study centers, 495 implants were placed in 151 cases with an average follow-up period of 1.6 years (range: 1.

A bone quality-based implant system: first year of prosthetic loading.

This interim report presents the data from a prospective study of BioHorizons, a bone quality-based implant system, with four implant designs. The surgical survival of 975 implants was 99.4%, with the survival 100% for D4 bone.

A bone quality-based implant system: a preliminary report of stage I & stage II.

A system is introduced in which dental implants are specifically designed for containment within four different categories of bone densities. The sizes and the textured surfaces that accompany the gradations of lengths and diameters are standardized for each bone type. A modified thread design focuses on compression of bone rather than on shear, and the geometry of the entire implant body reflects features that are concurrent with a "platform effect.