Morbidity and mortality due to Plasmodium falciparum and Plasmodium vivax, the two predominant human malaria parasites, result during the asexual development and replication of these protozoan parasites within erythrocytes (RBCs) (44). To reduce this burden on nearly half of the world's population, several malaria vaccine strategies are being pursued (28,40,53). Blood-stage vaccines are being developed to reduce parasite load and/or prevent life-threatening complications of malaria once parasites are replicating within RBCs. The single most feasible strategy for blood-stage malaria is to immunize with subunit vaccines that induce high titers of antibodies that neutralize extracellular merozoites and prevent the invasion of erythrocytes (2,25,31,40). The multiple receptor-ligand interactions and alternate redundant pathways involved in the merozoite invasion of RBCs combined with the polymorphism of vaccine candidate antigens present a challenge for vaccine design (2,25,26).P. falciparum merozoite surface protein 1 (MSP-1)
Background/Aims: Acute myeloid leukemia (AML) is an aggressive cancer with limited treatment options outside of chemotherapy. Improved therapies with novel mechanisms of action are desperately needed to fill this need. Both hTERT, the catalytic subunit of telomerase, and BCL-2, an apoptotic regulator, are overexpressed in AML, correlating with disease severity and poor prognosis respectively. Imetelstat is a novel, first-in-class competitive inhibitor of telomerase with clinical activity in hematologic malignancies. Venetoclax, an approved BCL-2 inhibitor for CLL, has shown a promising clinical benefit in AML patients. Preclinical evidence shows that downregulation of hTERT induces apoptosis via disruptions of hTERT and BCL-2 interaction; we hypothesize that inhibiting both targets would yield greater anti-tumor activity in AML compared to treatment with either agent alone. Methods: AML cell lines and AML patient’s PBMC samples were treated with imetelstat or venetoclax alone, or in combination, and viable and apoptotic populations of cells were evaluated by flow cytometry. Telomerase activity, hTERT expression and mitochondrial dysfunction were investigated for mechanism of action. Furthermore, an in vivo study in the MOLM-13 AML disseminated model was conducted to assess efficacy and survival. Results: A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax. In the MOLM-13 cell line, single-agent imetelstat and venetoclax had modest apoptotic activity after 48 hours (22% and 30% respectively), but the combination achieved 88% at 48 hours and nearly 100% at 96 hours. Similarly enhanced apoptotic activity was also observed in PBMCs purified from 4 AML patient whole blood samples. Molecular analyses showed combining imetelstat with venetoclax reduced hTERT expression and telomerase activity much more strongly than either agent alone. Furthermore, in vivo studies showed all mice tolerated the combination of imetelstat with ABT-199 well, with increased life span as compared to the vehicle control (68.1%, p=0.0001), to imetelstat (39.6%, p=0.0011) alone, or to venetoclax (23.3%, p=0.0001) alone. In the combination group, 40% of treated mice were alive 77-days after treatment discontinued whereas all mice of the other single agent arms died within two weeks, demonstrating a significant survival benefit. Conclusions: To our knowledge, this is the first investigation combining imetelstat with venetoclax in AML, and the results demonstrated a synergistic effect on induction of apoptosis in cell lines and patient samples in vitro, which translated into prolonged survival in xenograft models, thus providing a strong rationale for clinical exploration of this combination. Citation Format: Joshua J. Rusbuldt, Leopoldo Luistro, Diana Chin, Melissa Smith, Amy Wong, Margarita Romero, Aleksandra Rizo, Jacqueline Bussolari, Fei Huang, Amy (Kate) Sasser. Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1101. doi:10.1158/1538-7445.AM2017-1101
S e realizó un experimento con el objeto d e investigar la capacidad del mosquito Psorophora confinnis para transmitir por picadura a ratones blanco-suizos d e 21 días una cepa d e virus d e encefalitis equina venezolana, subgrupo ID.Cuando los mosquitos se alimentaron sobre hamster con altas viremias (7.5, 6.5 y 6.3 dex en 0.1 ml. d e suero), los porcentajes d e infección d e los mosquitos y los d e transmisión fueron altos.Sin embargo, cuando los mosquitos se alimentaron sobre Proechimys hendei con viremias bajas (1,4 y 2.6 dex en 0.1 ml. d e suero) el porcentaje d e infección d e los mosquitos f u e muy bajo y no hubo transmisión. Cuando la viremia en el Proechimys f u e d e 4.4 dex en 0.1 ml. d e suero, el porcentaje d e infección d e los mosquitos aumentó y hubo transmisión baja (9%).Los resultados sugieren que Psorophora confinnis es un mosquito que tiene un alto umbral d e infección para EEV subgrupo ID. INTRODUCCIONEn un trabajo anterior demostramos que casi la totalidad de las hembras d e Psorophoro confinnis que se alimentaron en el laboratorio sobre bamsters con concentraciones altas d e virus de la encefalitis equina venezolana, subgrupo ID, muestran el virus en la hemolinfa. En dicho trabajo. que se realizó como parte del estudio para apreciar la capacidad vectorial del Ps.confinnis, se examin6 la hemolinfa d e mosquitos con períodos v a r i a b l e s d e incubación extrínseca; en el trabajo aludido se mostraron los resultados del intento de aislamiento d e virus a partir de la hemolinfa de estos mosquitos. (1).Los mosquitos a los cuales se les extrajo la hemolinfa habían picado inmediatamente antes a ratones blancos con el propósito d e ver si a estos roedores les transmitían el virus. Ahora presentamos los resultados del intento d e transmisión del virus por la picadura d e los mosquitos a dichos ratones.
CD3 bispecific antibodies target both CD3 on T cells, and a tumor-specific antigen on cancer cells to harness the ability of cytotoxic T cells to eradicate solid tumors. Preclinical modeling of potential clinical leads in animal models can be challenging due to the need to have both a human immune system and a tumor model to study. Here we describe using various humanized mouse models in immune-compromised NSG mice as well as the use of surrogate antibodies in syngeneic models in mice with a competent immune system. To reconstitute the human immune system, female NSG mice were inoculated either intravenously with PBMCs or intraperitoneally with T cells that were expanded and activated in vitro. Engraftment of human T cells was evaluated in PBMC and T-cell humanized NSG mice in peripheral blood. In the absence of treatment, PBMC humanized mice had a greater reconstitution of T cells in the peripheral blood (~10-40%) compared to T-cell humanized mice (~3-10%). An antibody-specific expansion of T cells was observed in the T-cell humanized model in response to CD3 bispecific treatment. The slower engraftment of effector T cells in the T-cell humanized model correlated with slower onset to GVHD (graft versus host disease), allowing for extended evaluation of antitumor responses. Bispecific CD3 redirection antibodies elicited antitumor efficacy and T-cell infiltration in various human xenografts in both T-cell and PBMC-humanized mouse models. Additionally, mouse surrogate bispecific antibodies were generated that bind CD3 on mouse T cells. CT26 murine mouse colon carcinoma syngeneic tumors were transfected with a human cancer antigen for use in immune-competent Balb/c mice. Treatment with a surrogate bispecific molecule resulted in significant tumor growth inhibition (greater than 60%) and significant increase in life span. To confirm the mechanism of action, histologic analyses of T-cell infiltration into tumors was performed as well as T-cell cytokine analysis. These data showed that the level of T-cell infiltration and cytokine production correlated well with in vivo efficacy, demonstrating a T cell-mediated elimination of antigen-presenting tumor cells. In summary, both humanized mouse models and syngeneic mouse models using surrogate antibodies were successfully employed to study antitumor effects of CD3 bispecific antibodies. Citation Format: Bethany Mattson, Krista Menard, Damon Hamon, Darlene Pizutti, Emily Chen, Margarita Romero, Kristen Chevalier, Karla Wiehagen, Mark Richter, Gerald Chu, Brenda Hertzog, Anna Hughes, John Alvarez, Raluca Verona, Colleen Kane, Sheri Moores, Sylvie Laquerre, Joseph Erhardt, Kathryn Packman. Preclinical assessment of CD3 bispecific antibody efficacy: A comparison of humanized mouse models bearing xenografts and syngeneic mouse models using surrogate antibodies [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A11.
CONCENTRACION DEL VIRUS DENGUE 2 EN LA HEMOLIMFA DE MOSQUITOS AEDES AEGYPTI INOCULADOS IMTRATORACICAMEMTESe realizó u n estudio para determinar si ere posible demostrar replicaciones del virus Dengue 2 en la hemolinfa de mosquitos Aedes aegyptiinoculados intratorácicamente.Los resultados mostraron que el virus pudo ser detectado en la hemolinfa circulante de los mosquitos por varios dias despubs de la inoculación.En los mosquitos Aedes aegyptiinoculados por vla intratorhcica con 50 PFU de virus dengue 2 fue posible demostrar el virus en la hemolinfa en el 98% de los casos (89/911 entre los días 3O y lo0 post-inoculación.En el primero y segundo dia post-inoculación. la proporción de mosquitos con virus en la hemolinfa fue respectivamente de 1 entre 5 y de 4 entre 5. Entre el undbcimo y el decimocuarto dla la positividad fue del 36% (9125).En '18 mosquitos probados 28 días post-inoculación se logró aislar el virus D 2 en la hemolinfa de un poco m&s del 88% de los mosquitos inoculados.U n rnbtodosimple para obtención de hemolinfa de mosquitos es descrito.
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