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Neerup T.S.R.,Zealand Pharma A S | Stahlhut M.,Zealand Pharma A S | Petersen J.S.,Zealand Pharma A S | Petersen J.S.,Merck Serono International SA | And 5 more authors.
Bone | Year: 2011

Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac5c1, Aib3, Leu8, Gln10, Har11, Ala12, Trp14, Asp17]PTH(1-17)-NH2), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K13-D17 side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40-320nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical testing of rat femora confirmed that ZP2307 dramatically increased bone strength. Over a broad maximally effective dose range (40-160nmol/kg) ZP2307 did not increase serum concentrations of ionized free calcium above normal levels. Only at the highest dose (320nmol/kg) ZP2307 induced hypercalcemic calcium levels in the ovariectomized rats.To our knowledge ZP2307 is the smallest PTH peptide analog known to exert augmentation of bone. Our findings suggest that ZP2307 has the potential to effectively augment bone mass over a broad dose range without a concomitant increase in the serum concentration of ionized free calcium above the normal range. © 2011 Elsevier Inc.

Yip Y.L.,Merck Serono International SA
Yearbook of medical informatics | Year: 2011

To summarize current excellent research in the field of bioinformatics, with an emphasis on those that have direct application in the medical domain. Synopsis of the articles selected for the IMIA Yearbook 2011. The selection process for this yearbook's section on Bioinformatics results in six excellent articles highlighting the continuous progress towards a better understanding of human phenotype. Compared to the selection in Yearbook 2010, several key advancements can be noted. First, year 2010 marked the inaugural use of a complete human genome in a clinical context. This proof-of-principle study represents a large step towards personalized medicine. Second, there is a clear trend to understand diseases beyond the genome level, namely to include environmental and epigenetic information. Third, an innovative framework making use of the web to harness participant-driven genotype-phenotype information sets a new scene for conducting research in an era where social media plays an increasingly important role. The current literature showed that all pieces are now present to enable a much more comprehensive understanding of human diseases and traits, beyond the highly focused genetic or genomic studies seen previously.

Reutershan J.,University of Virginia | Reutershan J.,University of Tubingen | Saprito M.S.,University of Virginia | Wu D.,Yale University | And 3 more authors.
European Respiratory Journal | Year: 2010

Phosphoinositide 3-kinase γ(PI3Kγ) is a critical mediator of directional cell movement. Here, we sought to characterise the role of PI3Kγ in mediating the different steps of polymorphonuclear leukocyte (PMN) trafficking in the lung. In a murine model of lipopolysaccharide (LPS)-induced lung injury, PMN migration into the different lung compartments was determined in PI3Kγ gene-deficient (PI3Kγ-/-) and wild-type mice. Bone marrow chimeras were created to characterise the role of PI3Kγ on haematopoietic versus nonhaematopoietic cells. A small-molecule PI3Kγ inhibitor was tested in vitro and in vivo. PMN adhesion to the pulmonary endothelium and transendothelial migration into the lung interstitium was enhanced in PI3Kγ-/-mice. However, transepithelial migration into the alveolar space was reduced in these mice. When irradiated PI3Kγ-/- mice were reconstituted with bone marrow from wild-type mice, migratory activity into the alveolar space was restored partially. A small-molecule PI3Kγ inhibitor reduced chemokine-induced PMN migration in vitro when PMNs or epithelial cells, but not when endothelial cells, were treated. The inhibitor also reduced LPS-induced PMN migration in vivo. We conclude that PI3Kγ is required for transepithelial but not for transendothelial migration in LPS-induced lung injury. Inhibition of PI3Kγ activity may be effective at curbing excessive PMN infiltration in lung injury. Copyright©ERS Journals Ltd 201.

Smith D.A.,Compass Oncology | Smith D.A.,Us Oncology Research | Conkling P.,Us Oncology Research | Richards D.A.,Us Oncology Research | And 9 more authors.
Cancer Immunology, Immunotherapy | Year: 2014

Background: IMO-2055 is a Toll-like receptor 9 (TLR9) agonist that potentially enhances the efficacy of antitumor agents through immune stimulation. The objective of this phase Ib dose-escalation trial (3 + 3 design) was to determine the recommended phase II dose (RP2D) of IMO-2055 when combined with erlotinib and bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients with stage 3/4 NSCLC and progressive disease (PD) following chemotherapy received IMO-2055 0.08, 0.16, 0.32, or 0.48 mg/kg once weekly plus erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients could receive treatment until PD or unacceptable toxicity. Results: Thirty-six patients were enrolled; 35 received at least one treatment dose. Two dose-limiting toxicities were observed across the dose range (Grade 3 dehydration and fatigue) with neither suggestive of a consistent toxicity pattern. IMO-2055 0.32 mg/kg was adopted as RP2D based on clinical and pharmacodynamic data. The most common treatment-emergent adverse events (TEAEs) were diarrhea (74 %), nausea (51 %), fatigue (51 %), rash (51 %), and injection-site reactions (49 %). Four patients experienced serious TEAEs considered to be study drug related. Five patients died, all due to PD. High-grade neutropenia and electrolyte disturbances previously reported with TLR9 agonists combined with platinum-based therapy were not observed in this study. Five of 33 patients evaluable for response (15 %) achieved partial response; another 20 (61 %) had stable disease, including 13 with stable disease ≥4 months. Conclusions: IMO-2055 demonstrated good tolerability and possible antitumor activity in combination with erlotinib and bevacizumab in heavily pretreated patients with advanced NSCLC. © 2014 Springer-Verlag.

Tanino Y.,Veterans Affairs Puget Sound Medical Center | Tanino Y.,University of Washington | Coombe D.R.,Curtin University Australia | Gill S.E.,University of Washington | And 11 more authors.
Journal of Immunology | Year: 2010

Chemokine-glycosaminoglycan (GAG) interactions are thought to result in the formation of tissue-bound chemokine gradients. We hypothesized that the binding of chemokines to GAGs would increase neutrophil migration toward CXC chemokines instilled into lungs of mice. To test this hypothesis we compared neutrophil migration toward recombinant human CXCL8 (rhCXCL8) and two mutant forms of CXCL8, which do not bind to heparin immobilized on a sensor chip. Unexpectedly, when instilled into the lungs of mice the CXCL8 mutants recruited more neutrophils than rhCXCL8. The CXCL8 mutants appeared in plasma at significantly higher concentrations and diffused more rapidly across an extracellular matrix in vitro. A comparison of the murine CXC chemokines, KC and MIP-2, revealed that KC was more effective in recruiting neutrophils into the lungs than MIP-2. KC appeared in plasma at significantly higher concentrations and diffused more rapidly across an extracellular matrix in vitro than MIP-2. In kinetic binding studies, KC, MIP-2, and rhCXCL8 bound heparin differently, with KC associating and dissociating more rapidly from immobilized heparin than the other chemokines. These data suggest that the kinetics of chemokine-GAG interactions contributes to chemokine function in tissues. In the lungs, it appears that chemokines, such as CXCL8 or MIP-2, which associate and disassociate slowly from GAGs, form gradients relatively slowly compared with chemokines that either bind GAGs poorly or interact with rapid kinetics. Thus, different types of chemokine gradients may form during an inflammatory response. This suggests a new model, whereby GAGs control the spatiotemporal formation of chemokine gradients and neutrophil migration in tissue.

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