The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer.

The heterogeneity and severity of certain autoimmune diseases and B-cell malignancies warrant simultaneous targeting of multiple disease-relevant signaling pathways. Dual inhibition of spleen tyrosine kinase (SYK) and Janus kinase (JAK) represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity. To this end, we provide data on the discovery and preclinical development of PRT062070 [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide hydrochloride], an orally active kinase inhibitor that demonstrates activity against SYK and JAK.

The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia.

B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies. SYK is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and SYK inhibition results in abrogation of downstream kinase activity and apoptosis. P505-15 (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule SYK inhibitor (SYK IC(50) = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases.

Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis.

Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency.

Review of continuing education course on hemostasis.

The continuing education course "Hemostasis" provided a comprehensive review of hemostasis and selected perturbations of the underlying processes as well as an assessment of hemostasis in animal models and preclinical testing environments. The session began with a review of the current state of understanding of hemostasis and how the waterfall or cascade of activation has transformed to the current cell-based, membrane-associated sequence of highly regulated events. The specific mechanisms of drug-induced thrombocytopenia were then presented, followed by a discussion of the relationships of coagulation and platelets in inflammation and cancer metastasis and platelet activity.

Decreased dislocation after revision total hip arthroplasty using larger femoral head size and posterior capsular repair.

The purpose of this study was to determine if the use of both a larger femoral head size and a posterior capsular repair would lead to a decreased incidence of dislocation following revision total hip arthroplasty (THA). Two hundred forty-two consecutive revision THAs with posterolateral approach were performed between 2000 and 2005. Group 1 had 132 revision THAs with posterolateral approach and 28-mm head size without posterior capsule repair.

Ceramic-on-ceramic total hip arthroplasty.

Ceramic bearing surfaces have been introduced to prevent bone loss after osteolysis seen with conventional polyethylene bearing surfaces. One hundred three ceramic-on-ceramic total hip arthroplasties in 97 patients were retrospectively reviewed. Average follow-up was 50.

Sites of modification of hemospan, a poly(ethylene glycol)-modified human hemoglobin for use as an oxygen therapeutic.

Hemospan is an acellular hemoglobin-based oxygen therapeutic in clinical trials in Europe and the United States. The product is prepared by site-specific conjugation of maleimide-activated poly(ethylene) glycol (PEG, MW approximately 5500) to human oxyhemoglobin through maleimidation reactions either (1) directly to reactive Cys thiols or (2) at surface Lys groups following thiolation using 2-iminothiolane. The thiolation/maleimidation reactions lead to the addition of approximately 8 PEGs per hemoglobin tetramer.

Acetabular component revision using a porous tantalum biomaterial: a case series.

Biologic ingrowth can be difficult to achieve in acetabular component revision, especially in cases with significant bone loss. The purpose of this study was to review our clinical results of acetabular component revisions in patients with significant bone loss using a porous tantalum biomaterial. This is a retrospective review of 25 patients.

Fulkerson procedure for chronic patella component dislocation after total knee arthroplasty.

Chronic patella component dislocation after primary knee arthroplasty can be a challenging problem. The purpose of this case series was to review our results of a chronic patella dislocation after total knee arthroplasty treated with a Fulkerson procedure (anteromedialization of the tibial tubercle). Five patients with an average age of 68.

Solution structure of poly(ethylene) glycol-conjugated hemoglobin revealed by small-angle X-ray scattering: implications for a new oxygen therapeutic.

Developing protein therapeutics has posed challenges due to short circulating times and toxicities. Recent advances using poly(ethylene) glycol (PEG) conjugation have improved their performance. A PEG-conjugated hemoglobin (Hb), Hemospan, is in clinical trials as an oxygen therapeutic.

A quantitative framework for the design of acellular hemoglobins as blood substitutes: implications of dynamic flow conditions.

The delivery of oxygen to tissue by cell-free carriers eliminates intraluminal barriers associated with red blood cells. This is important in arterioles, since arteriolar tone controls capillary perfusion. We describe a mathematical model for O(2) transport by hemoglobin solutions and red blood cells flowing through arteriolar-sized tubes to optimize values of p50, Hill number, hemoglobin molecular diffusivity and concentration.

Venezuelan equine encephalitis virus vaccine candidate (V3526) safety, immunogenicity and efficacy in horses.

A new vaccine, V3526, is a live-attenuated virus derived by site-directed mutagenesis from a virulent clone of the Venezuelan equine encephalitis virus (VEEV) IA/B Trinidad donkey (TrD) strain, intended for human use in protection against Venezuelan equine encephalitis (VEE). Two studies were conducted in horses to evaluate the safety, immunogenicity, ability to boost and protective efficacy of V3526 against challenges of TrD and VEEV IE 64A99. Horses were vaccinated subcutaneously (SC) with 10(7), 10(5), 10(3) or 10(2) plaque-forming units (pfu) of V3526.

Impaction grafting for femoral component revision using a non-polished bead-blasted chrome cobalt stem-average 8 1/2-year follow-up.

Impaction grafting for femoral component revision in patients with significant bone loss has been reported using a tapered polished femoral component that is meant to subside. This study reports our results of femoral component revision using impaction grafting with a bead-blasted chrome cobalt stem designed not to subside. Forty-eight femoral component revisions using impaction grafting were retrospectively reviewed with a minimum 6 1/2-year follow-up.

Transfer of the long head of the triceps tendon for irreparable rotator cuff tears.

This study presents the clinical and anatomic findings of the use of the long head of the triceps tendon for treatment of massive, irreparable rotator cuff tears. The clinical study included 19 shoulders in 18 patients with a minimum followup of 2 years who were prospectively reviewed. All patients had preoperative and postoperative functional evaluations using the UCLA scoring system.

Femoral component revision using an extensively hydroxyapatite-coated stem.

Femoral component revisions with extensively coated stems have shown promising clinical results, although concerns over stress shielding still exist. We retrospectively reviewed 59 patients undergoing femoral component revision with an extensively hydroxyapatite (HA)-coated stem. The average length of follow-up was 3.

Intravenous mouse infection model for studying the pathology of Enterococcus faecalis infections.

An intravenous mouse infection model was used to compare the virulence of Enterococcus faecalis strains, to study bacterial localization and organ histopathology, and to examine the effects of Nramp1 and gamma interferon (IFN-gamma) on the course of infection. Infection of BALB/c mice with 5 x 10(8) CFU of E. faecalis JH2-2, MGH-2, 418, DS16C2, or OG1X revealed the following virulence ranking (from highest to lowest): MGH-2, 418, DS16C2, JH2-2, and OG1X.

Experimental infection of horses with West Nile virus.

A total of 12 horses of different breeds and ages were infected with West Nile virus (WNV) via the bites of infected Aedes albopictus mosquitoes. Half the horses were infected with a viral isolate from the brain of a horse (BC787), and half were infected with an isolate from crow brain (NY99-6625); both were NY99 isolates. Postinfection, uninfected female Ae.