Handbook of Combinatorial Chemistry. Vols. 1 and 2 Edited by K. C. Nicolaou (Scripps Research Institute and University of California, San Diego), R. Hanko (Bayer AG, Leverkusen), and W. Hartwig (Bayer AG, Wuppertal). Wiley-VCH Publishers, Weinheim. xxxi + 609 pp (Vol. 1), xxxi + 503 pp (Vol. 2). 17 × 24 cm. $345.00. ISBN 3-527-30509-2.

2002 ◽  
Vol 65 (11) ◽  
pp. 1746-1747
Author(s):  
Derek Hudson
Keyword(s):  
Combinatorial Chemistry ◽  
San Diego ◽  
University Of California ◽  
Scripps Research Institute ◽  
Research Institute

Reversal of Novel Oral Anticoagulant (NOAC)-Induced Bleeding in Mice By Engineered superfactor Va

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 695-695 ◽  
Author(s):  
Vikas Bhat ◽  
Andrew J. Gale ◽  
John H. Griffin ◽  
Laurent O. Mosnier ◽  
Annette von Drygalski
Keyword(s):  
Blood Loss ◽  
San Diego ◽  
Thrombin Generation ◽  
Direct Thrombin Inhibitor ◽  
University Of California ◽  
Thrombin Inhibitor ◽  
Scripps Research Institute ◽  
Research Institute

Abstract Introduction and Objectives: Novel oral anticoagulants (NOACs), such as Factor (F) Xa inhibitors (Rivaroxaban and Apixaban) or the direct thrombin inhibitor (Dabigatran), are used for prevention of venous thromboembolism and ischemic strokes. However, conventional hemostatic reversal strategies in case of bleeding or surgery are ineffective, posing a major unmet clinical need. We recently demonstrated that superFVa, a novel FVa variant engineered with mutations of 3 activated protein C (APC) cleavage sites and a disulfide bond between the A2 and A3 domains, has enhanced biological activity and APC resistance. SuperFVa provided efficient normalization of hemostasis in hemophilia A mice and in animal models of APC-induced bleeding. Moreover, superFVa synergistically reduced bleeding in combination with recombinant human (rh) FVIIa in hemophilia mice. Thus, superFVa fits the criteria for a prohemostatic biologic. Therefore, the in vitro and in vivo effects of superFVa alone and in combination with other prohemostatic agents such as rhFVIIa or 4-Factor prothrombin complex concentrates (4F-PCC) as a novel hemostatic reversal strategy for NOAC-induced bleeding were determined. Materials and Methods: In vitro procoagulant properties of superFVa alone and in combination with rhFVIIa or 4F-PCC were studied using thrombin generation assays in normal human plasma (NHP) in the presence of FXa inhibitors (Rivaroxaban, Apixaban) or the direct thrombin inhibitor (Dabigatran, active form). In vivo prevention of blood loss by superFVa after intravenous injection of Rivaroxaban, Apixaban, or Dabigatran was studied using the tail clip model in BalbC mice. Results: Rivaroxaban and Apixaban each dose-dependently reduced thrombin generation in NHP and reduced the Endogenous Thrombin Potential (ETP) by ~60% at therapeutic concentrations (200 nM). Addition of either superFVa (50 nM) or rhFVIIa (40 nM, equivalent to a 90 µg/kg therapeutic dose in hemophilia patients), increased thrombin generation to some extent. However, ETP and thrombin peak height increased dose-dependently when increasing concentrations of superFVa (6.25 to 400 nM) were added with rhFVIIa (40 nM). superFVa effects appeared synergistic, with a plateau reached at 25-50 nM superFVa and ETP restored to ~93% of normal. Synergistic effects of superFVa were also present and even more pronounced in combination with 4F-PCC (1.35 U/ml; therapeutic plasma concentration). In the presence of Dabigatran (1 µM), superFVa (0.1 nM-100 nM) in combination with rhFVIIa (40 nM) or 4F-PCC (1.35 U/ml) showed a concentration dependent reduction of the lag time of thrombin generation. However, in contrast to the FXa inhibitors, in the presence of Dabigatran, no effects on ETP and thrombin peak height were observed for the addition of superFVa or combinations of superFVa and rhFVIIa or 4F-PCC. The in vivo efficacy of superFVa to reduce NOAC-induced bleeding was determined by blood loss after tail transection in BalbC mice injected i.v. with Rivaroxaban (40 mg/kg), Apixaban (20 mg/kg), or Dabigatran (0.4 mg/kg). Mean blood loss in mice injected with Rivaroxaban (16 µL/g), Apixaban (16.5 µL/g) or Dabigatran (14.5 µL/g) was significantly higher than baseline bleeding (4 µL/g, p<0.001). superFVa reduced blood loss after Rivaroxaban or Apixaban administration significantly in a dose dependent manner, e.g., superFVa at 40 U/kg significantly reduced bleeding to the baseline control level (5 µL/g). RhFVIIa (1 mg/kg) was able to reduce bleeding caused by Rivaroxaban but not by Apixaban. Neither superFVa nor rhFVIIa was able to reduce bleeding caused by Dabigatran. Conclusion: superFVa alone or in combination with rhFVIIa significantly improved in vitro thrombin generation in the presence of FXa inhibitors and to some extent in the presence of a direct thrombin inhibitor. SuperFVa alone consistently reduced bleeding in mice treated with FXa inhibitors, whereas a mixed response dependent on the type of FXa inhibitor was obtained with rhFVIIa. None of the agents was able to decrease bleeding in mice induced by Dabigatran. Because superFVa exerts a potent class effect as a hemostatic reversal strategy for FXa inhibitor-induced bleeding, it deserves further consideration for potential development as a hemostatic agent. Disclosures Gale: University of California, San Diego: University of California, San Diego Patents & Royalties. Griffin:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties. Mosnier:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties. von Drygalski:University of California, San Diego: University of California, San Diego Patents & Royalties.

scholarly journals Synergistic Effect in Bleed Reduction By superfva and Recombinant Human FVIIa in Vivo Suggests a Novel Bypassing Strategy for Hemophilia Patients with Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 692-692
Author(s):  
Vikas Bhat ◽  
Annette von Drygalski ◽  
Andrew J. Gale ◽  
John H. Griffin ◽  
Laurent O. Mosnier
Keyword(s):  
San Diego ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
University Of California ◽  
Clot Lysis ◽  
Scripps Research Institute ◽  
Normal Plasma ◽  
Deficient Mice ◽  
Research Institute

Abstract Introduction: In Hemophilia patients with inhibitors, recombinant human (rh)FVIIa-based bypassing strategy does not always achieve hemostasis indicating a clinical need for improved treatment strategies. We engineered an activated FVa variant (superFVa) with mutations at 3 activated protein C cleavage sites (R506, R306 and R679) and an engineered interdomain disulfide bond (H609C-E1691C) connecting the A2 and A3 domains. SuperFVa resisted inactivation and showed superior hemostatic properties in FVIII-deficient plasma and in mouse models of Hemophilia A compared to wild type rhFVa. Therefore, the hemostatic effects of superFVa alone and in combination with rhFVIIa in hemophilia with inhibitors were determined in more detail. Materials and Methods: Procoagulant and clot stabilizing properties of superFVa, rhFVIIa, and combinations thereof were studied in thrombin generation (endogenous thrombin potential (ETP) and peak height) and clot lysis assays in hemophilia A and normal plasma with or without high titer inhibitors. In vivo efficacy of superFVa alone and in combination with rhFVIIa for bleed reduction in hemophilia was tested in FVIII-deficient mice using a tail clip model. Results: Extensive dose-response titrations of superFVa, rhFVIIa, and combinations thereof in hemophilic or normal plasma with inhibitors indicated synergistic responses for normalization of thrombin generation or clot stabilization. For instance, at 0.4 nM rhFVIIa (1/100 of the therapeutic plasma level), the concentration of superFVa required to normalize thrombin generation was reduced 10-fold. Vice versa, rhFVIIa tested up to 40 nM only marginally improved thrombin generation, however, rhFVIIa in the presence of a low concentration of superFVa (3 nM) normalized thrombin generation at concentrations 50-fold below the therapeutic plasma level. Saturation of the synergistic effect between superFVa and rhFVIIa was evident as thrombin generation reached a plateau at ~110% of normal plasma at higher concentrations of superFVa and rhFVIIa. Similar synergistic normalization of clot lysis time was observed when superFVa and rhFVIIa were used together at low concentration. Beneficial effects of superFVa and rhFVIIa combinations were also observed in 5 individual plasma samples of hemophilia A patients with inhibitors (41-280 BU/ml). ETP and peak height improved ~1.5-3 fold when both superFVa (3 nM) and rhFVIIa (2 nM) were present compared to the individual 10 to 20-fold higher concentrations of superFVa (30 nM) or rhFVIIa (40 nM). Also, a therapeutic dose of rhFVIIa administered to 2 hemophilia patients with inhibitors (32 & 64 BU/ml) provided unremarkable improvements of thrombin generation in plasma taken before and 10 minutes post-infusion, whereas thrombin generation was fully restored upon titration of superFVa ex-vivo. In-vivo tail bleed analysis of FVIII-deficient mice showed a dose dependent reduction of bleeding by superFVa (mean blood loss was 25.9 µL/g at 10 U/kg; 9.7 µL/g at 40 U/kg and 2.5 µL/g at 200 U/kg of superFVa compared to 26.3 µL/g for saline). At the highest dose of superFVa (200 U/kg), bleed reduction was indistinguishable from the bleed reduction by rhFVIII (200 U/kg; 2.9 µL/g). Injection of 1 or 3 mg/kg rhFVIIa, reduced mean blood loss from 25.9 µL/g (saline control) to 16.8 (p=0.1) or 7.2 µL/g (p=0.003), respectively, but rhFVIIa’s effects did not reach the blood loss reduction achieved with rhFVIII (2.9 µL/g, p=0.03). However, combination of rhFVIIa (1 mg/kg) with 10 U/kg superFVa, a concentration that did not reduce bleeding by itself, significantly reduced bleeding from 16.7 to 10.2 µL/g (p=0.05). Combination of rhFVIIa (3 mg/kg) with superFVa (40 U/kg) decreased bleeding even further (1.6 µL/g; p=0.01), similar to what was observed with rhFVIII. Conclusion: The engineered superFVa variant showed synergistic procoagulant effects with rhFVIIa in vitro in hemophilic and normal plasma with inhibitors in thrombin generation and clot lysis assays. Notably, in vivo, superFVa reduced bleeding similar to rhFVIII in FVIII-deficient mice in a dose-dependent fashion, and it was able to enhance further bleed reduction when administered in combination with rhFVIIa. These results warrant further characterization of the potential therapeutic benefits of superFVa as a novel bypassing strategy either alone or in combination with rhFVIIa-based therapy in hemophilia patients with inhibitors. Disclosures von Drygalski: University of California, San Diego: University of California, San Diego Patents & Royalties. Gale:University of California, San Diego: University of California, San Diego Patents & Royalties. Griffin:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties. Mosnier:The Scripps Research Institute: The Scripps Research Institute Patents & Royalties.

scholarly journals Estudio serológico del virus de la Enfermedad de Borna en pacientes esquizofrénicos de Yucatán, México

2004 ◽  
Vol 15 (3) ◽  
pp. 141-147 ◽  
Author(s):  
Fernando I Puerto ◽  
Jorge E Zavala ◽  
Arsenio Rosado-Franco ◽  
Luis Jorge Gamboa-Albornoz
Keyword(s):  
Western Blot ◽  
San Diego ◽  
Scripps Research Institute ◽  
Icd 10 ◽  
Research Institute

Antecedentes. El Virus de la Enfermedad de Borna (VEB) es un virus envuelto, con una cadena de RNA simple de polaridad negativa. VEB causa enfermedad a nivel del Sistema Nervioso Central en muchos animales vertebrados, que frecuentemente se manifiesta como anormalidades en la conducta. La infección silvestre con el VEB ocurre de manera natural. De hecho fue detectada primero en caballos y en ovejas en algunas regiones de Europa Central. Los resultados serológicos obtenidos de diferentes laboratorios en los últimos 15 años y recientemente con la biología molecular, muestran que el VEB puede infectar a los seres humanos y que también puede estar asociado a ciertos trastornos psiquiátricos. Reportamos el primer estudio de seroprevalencia del VEB en humanos de Latinoamérica. Metodología. Muestras de suero fueron obtenidas de 70 pacientes con diagnóstico de esquizofrenia y otras 70 muestras de suero se tomaron de personas sanas que participaron de manera voluntaria al estudio y que fueron pareados por edad, sexo y nivel socioeconómico. Las muestras de ambos grupos fueron procesadas para analizar por Western-blot en nuestro laboratorio y en The Scripps Research Institute en San Diego, CA USA. Como antígeno se utilizó a la fosfoproteína (P) obtenida de la expresión con GSTP. Resultados. El grupo de pacientes esquizofrénicos, fueron 47 hombres y 23 mujeres con un promedio de edad de 40 años (rango de 17 a 73 años). Todos ellos nacieron en la Península de Yucatán. Para su clasificación el diagnóstico se basó en el ICD-10. El estudio mostró una prevalencia de anticuerpos en los sueros contra la proteína GST-P de 21.43% (15/70), mientras que no se encontraron anticuerpos en el suero de las personas sanas. No se encontró relación entre el género, la edad y tipo de esquizofrenia y la presencia de anticuerpos contra VEB. Conclusiones. Hasta donde sabemos, éste es el primer estudio en Latinoamérica que se lleva a cabo para detectar anticuerpos contra el VEB en seres humanos. Nuestros resultados son semejantes a lo reportado en la literatura y apoyan la posible asociación entre la presencia de anticuerpos contra el VEB y los trastornos psiquiátricos. Sin embargo, se necesita continuar con más estudios para conocer si es realmente un problema de salud y cual podría ser su magnitud.

University of California San Diego Performance-based Skills Assessment--Korean Version

2017 ◽  
Author(s):  
Sung-Jin Kim ◽  
Jung-Min Kim ◽  
Joo-Cheol Shim ◽  
Beom-Joo Seo ◽  
Sung-Soo Jung ◽  
...  
Keyword(s):  
San Diego ◽  
University Of California ◽  
Skills Assessment ◽  
Korean Version

Appraising Newness: Whiteness, Neoliberalism & the Building of the Archive for New Poetry

2017 ◽  
Vol 1 (2) ◽  
Author(s):  
Eunsong Kim
Keyword(s):  
San Diego ◽  
University Of California ◽  
Collection Development ◽  
Literary Scholarship ◽  
Avant Garde ◽  
Archival Practice ◽  
Small Press ◽  
The University

The Archive for New Poetry (ANP) at the University of California San Diego was founded with the specific intention of collecting alternative, small press publications and acquiring the manuscripts of contemporary new poets. The ANP’s stated collection development priority was to acquire alternative, non-mainstream, emerging, “experimental” poets as they were writing and alive, and to provide a space in which their papers could live, along with recordings of their poetry readings. In this article, I argue that through racialized understandings of innovation and new, whiteness positions the ANP’s collection development priority. I interrogate two main points in this article: 1) How does whiteness—though visible and open—remain unquestioned as an archival practice? and 2) How are white archives financed and managed? Utilizing the ANP’s financial proposals, internal administrative correspondences, and its manuscript appraisals and collections, I argue that the ANP’s collection development priority is racialized, and this prioritization is institutionally processed by literary scholarship that linked innovation to whiteness. Until very recently, US Experimental and “avant-garde” poetry has been indexed to whiteness. The indexing of whiteness to experimentation, or the “new” can be witnessed in the ANP’s collection development priorities, appraisals, and acquisitions. I argue that the structure of the manuscripts acquired by the ANP reflect literary scholarship that theorized new poetry as being written solely by white poets and conclude by examining the absences in the Archive for New Poetry.

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