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We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and the corresponding antibody-drug conjugate (ADC). Payload 6 was designed for rapid hepatic inactivation to minimize systemic exposure of nonconjugated GRM. Mouse PK indicated that 6 is cleared 10-fold more rapidly than a first-generation GRM payload, resulting in 10-fold lower exposure and 3-fold decrease in Cmax. The anti-mTNF conjugate ADC5 fully inhibited inflammation in mouse contact hypersensitivity with minimal effects on corticosterone, a biomarker for systemic GRM effects, at doses up to and including 100 mg/kg. Concomitant inhibition of P1NP suggests potential delivery to cells involved in the remodeling of bone, which may be a consequence of TNF-targeting or bystander payload effects. Furthermore, ADC5 fully suppressed inflammation in collagen-induced arthritis mouse model after one 10 mg/kg dose for 21 days. The properties of the anti-hTNF conjugate were suitable for liquid formulation and may enable subcutaneous dosing.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro . Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

Background: Clinical and functional impairment after nonoperative treatment of distal biceps ruptures is not well understood. The goal of this study was to measure patients' perceived disability, kinematic adjustment, and forearm supination power after nonoperative treatment of distal biceps ruptures., Methods: Fourteen individuals after nonoperative treatment of distal biceps ruptures were matched to a control group of 18 uninjured volunteers. Both groups prospectively completed the Disabilities of the Arm, Shoulder and Hand (DASH), Single Assessment Numerical Evaluation (SANE), and Biceps Disability Questionnaire. Both performed a new timed isotonic supination test that was designed to simulate activities of daily life. The isotonic torque dynamometer measures the supination arc, center of supination arc, torque, angular velocity, and power. Motion analysis quantifies forearm and shoulder contributions to the arc of supination., Results: The nonoperative treated group's DASH (23.2 ± 10.3) and SANE (59.6 ± 16.2) scores demonstrated a clinical meaningful impairment. The control group showed no significant differences in kinematic values between dominant and nondominant arms (P = .854). The nonoperative biceps ruptured arms, compared with their uninjured arms, changed supination motion by decreasing the supination arc (P ≤ .036), shifting the center of supination arc to a more pronated position (P ≤ .030), and increasing the shoulder contribution to rotation (P ≤ .001); despite this adaptation, their average corrected power of supination decreased by 47% (P = .001)., Conclusion: Patients should understand that nonoperative treatment for distal biceps ruptures will result in varying degrees of functional loss as measured by the DASH, SANE, and Biceps Disability Questionnaire, change their supination kinematics during repetitive tasks, and that they will lose 47% of their supination power., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

GLUT4 is necessary for acute insulin- and contraction-induced skeletal muscle glucose uptake, but its role in chronic muscle loading (overload)-induced glucose uptake is unknown. Our goal was to determine whether GLUT4 is required for overload-induced glucose uptake. Overload was induced in mouse plantaris muscle by unilateral synergist ablation. After 5 days, muscle weights and ex vivo [ 3 H]-2-deoxy-d-glucose uptake were assessed. Overload-induced muscle glucose uptake and hypertrophic growth were not impaired in muscle-specific GLUT4 knockout mice, demonstrating that GLUT4 is not necessary for these processes. To assess which transporters mediate overload-induced glucose uptake, chemical inhibitors were used. The facilitative GLUT inhibitor cytochalasin B, but not the sodium-dependent glucose cotransport inhibitor phloridzin, prevented overload-induced uptake demonstrating that GLUTs mediate this effect. To assess which GLUT, hexose competition experiments were performed. Overload-induced [ 3 H]-2-deoxy-d-glucose uptake was not inhibited by d-fructose, demonstrating that the fructose-transporting GLUT2, GLUT5, GLUT8, and GLUT12 do not mediate this effect. To assess additional GLUTs, immunoblots were performed. Overload increased GLUT1, GLUT3, GLUT6, and GLUT10 protein levels twofold to fivefold. Collectively, these results demonstrate that GLUT4 is not necessary for overload-induced muscle glucose uptake or hypertrophic growth and suggest that GLUT1, GLUT3, GLUT6, and/or GLUT10 mediate overload-induced glucose uptake., (© 2017 by the American Diabetes Association.)

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.

Background: The radial tuberosity contributes to the biceps supination moment arm and the elbow flexion moment. The purpose of our study was to compare the impact of a cortical bone trough versus an anatomic repair on measurements of the forearm supination moment arm and elbow flexion force efficiency. Our hypothesis was that a trough repair would decrease the tuberosity height, the native biceps supination moment arm, and elbow flexion force efficiency compared with an anatomic repair., Methods: The isometric supination moment arm and elbow flexion force efficiency were measured in ten matched pairs of cadaveric upper limbs. After testing, the geometry of the proximal aspect of the radius was reconstructed with use of stereophotogrammetry. All of the repair sites were three-dimensionally reconstructed to quantify the disturbance of the trough on native anatomy. The tuberosity distance was defined as the distance between the central axis of the radius and the centroid of the respective repair site., Results: Specimens with a trough repair had a 27% lower supination moment arm at 60° of supination (p = 0.036). There were no differences found for pronation or neutral forearm positioning (p > 0.235). Flexion force efficiency was not significantly different between the trough and anatomic repair groups. The average tuberosity distance was 11.0 ± 2.1 mm for the anatomic repairs and 8.3 ± 1.4 mm for the trough repairs (p = 0.003). The percentage of distance lost due to the trough was 25%. Furthermore, the supination moment arm in the supinated position was significantly correlated with the tuberosity distance., Conclusions: The trough technique resulted in a significant decrease (p = 0.036) in the moment arm of a 60° supinated forearm and a significant reduction (p = 0.003) in radial tuberosity height. The loss of the supination moment arm was correlated with the decrease in tuberosity height, providing evidence that the radial protuberance acts as a mechanical cam., Clinical Relevance: The anterior protuberance of the radial tuberosity functions as a supination cam; therefore, consideration should be given to preserve its topographical anatomy during a distal biceps repair., (Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.)

We introduce a controlled ionic coacervation (CIC) process that rapidly forms uniform, gel-like latex films with significant mechanical integrity without loss of water from the film. This process uses latex particles that contain both strong cationic charges and weak protonated acid groups. An increase in pH ionizes the weak acid and triggers the rapid setting of the latex films. The necessary increase in pH can be achieved by coating the latex onto an alkaline surface (such as concrete) or by controlled release of a fugitive acid (such as carbon dioxide). We explore the effect of latex composition and concentration on this process. We show that the CIC process does not require a water-soluble polymer to obtain the rapid-set film properties. Our proposed mechanism for CIC process is consistent with models for rapid, irreversible, particle-particle aggregation.

Adhesive and marine biofouling release properties of coatings containing surface-oriented perfluoroalkyl groups were investigated. These coatings were prepared by cross-linking a copolymer of 1H,1H,2H,2H-heptadecafluorodecyl acrylate and acrylic acid with a copolymer of poly(2-isopropenyl-2-oxazoline) and methyl methacrylate at different molar ratios. The relationships between contact angle, contact angle hysteresis, adhesion, and marine biofouling were studied. Adhesion was determined by peel tests using pressure-sensitive adhesives. The chemical nature of the surfaces was studied by using X-ray photoelectron spectroscopy. Resistance to marine biofouling of an optimized coating was studied by immersion in seawater and compared to previous, less optimized coatings. The adhesive release properties of the coatings did not correlate well with the surface energies of the coatings estimated from the static and advancing contact angles nor with the amount of fluorine present on the surface. The adhesive properties of the surfaces, however, show a correlation with water receding contact angles and contact angle hysteresis (or wetting hysteresis) resulting from surface penetration and surface reconstruction. Coatings having the best release properties had both the highest cross-link density and the lowest contact angle hysteresis. An optimized coating exhibited unprecedented resistance to marine biofouling. Water contact angle hysteresis appears to correlate with marine biofouling resistance.

A modular infrared spectrometer with microsampling and cryosampling capabilities has been designed, constructed, and tested. The main design features and preliminary results are discussed, and some strengths of the final instrument, when used in the optical characterization of superconducting materials, are presented.

The dependence of the optical attenuation on the fiber coating has been measured for a sensor fiber subjected to periodic microbending. The dependence on the spectral characteristics of the selected light sources is also addressed and the proper source/coating combination is discussed. Results indicate that the proper selection of this combination is of crucial importance in the design, development, and performance of fiber optic sensors in which intensity modulated microbending transducers are considered. A combination of a short wavelength for the light source and a fiber coated with a hard, elastomeric material seems to be the optimal selection for enhancing the sensitivity in controlled microbending experiments with applications to fiber optic sensors. The highest sensitivity to microbending was obtained for a nylon coated fiber and using a He-Ne laser at 632.8 nm.

The functional effects of three types of therapy for subjects with long-term incomplete cervical spinal cord injuries were investigated. Men and women, aged 18 to 45 years, were assigned to one of four groups using a restricted randomization process. The training period was divided into two consecutive eight-week time blocks where subjects received either (1) supervised physical exercise therapy (PET), (2) neuromuscular stimulation (NMS), or (3) electromyographic (EMG) biofeedback. Group 1 received EMG biofeedback followed by PET; Group 2 received EMG biofeedback followed by NMS; Group 3 received NMS followed by PET; and Group 4 received 16 weeks of PET. Dependent measures (manual muscle tests, self-care scores, mobility measures, and voluntary EMG activity) were assessed before training, at eight weeks, and after 16 weeks of training. A significant improvement (p less than .05) across time was found on all dependent measures except voluntary EMG. No difference was found on comparisons between groups.