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)

No abstract

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.

No abstract