Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma

We describe the clinical course of a recurrent case of congenital fibrosarcoma diagnosed in a 9-mo-old boy with a history of hemimelia. Following complete surgical resection of the primary tumor, the patient subsequently presented with bulky bilateral pulmonary metastases 6 mo following surgery. Molecular characterization of the tumor revealed the absence of the prototypical ETV6-NTRK3 translocation. However, tumor characterization incorporating cytogenetic, array comparative genomic hybridization, and RNA sequencing analyses, revealed a somatic t(2;15)(2p21;15q25) translocation resulting in the novel fusion of EML4 with NTRK3. Cloning and expression of EML4-NTRK3 in murine fibroblast NIH 3T3 cells revealed a potent tumorigenic phenotype as assessed in vitro and in vivo. These results demonstrate that multiple fusion partners targeting NTRK3 can contribute to the development of congenital fibrosarcoma

RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition

High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Exploring the positive self and virtual relationship experience of emering Filipino Facebook users

Facebook is considered as one of the most popular social networking sites in the world and it is apparent that Filipinos are one of its top users. Despite the popularity of the site, empirical evidence has implicated Facebook use with a wide variety of negative outcomes but with less knowledge on the positive effects of its use. The present investigation seeks to understand the positive experiences of Facebook use among Filipinos to capture a deeper understanding of the positive influences of the social networking site on the self and social relationships. Six individuals were asked to share two Facebook posts that they believe had a positive influence on them. Semi-structured interviews were conducted which focused on the two shared posts. The results of thematic analysis using Giorgi’s (1975) phenomenological analysis show four themes: Facebook makes families closer; Facebook facilitates connection with people; Facebook contributes to identity formation and; Facebook facilitates positive emotions. The findings of the study provide insights on positive Facebook experiences, family dynamics, and Filipino virtual identity

Plasmodium yoelii nigeriensis (N67) Is a Robust Animal Model to Study Malaria Transmission by South American Anopheline Mosquitoes

Submitted by Nuzia Santos ([email protected]) on 2017-02-23T18:24:28Z No. of bitstreams: 1 ve_Orfano_Alessandra_ Plasmodium yoelii_CPqRR_2016.pdf: 6369959 bytes, checksum: d459b9a02443550b0378396bc879eedd (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2017-02-23T18:27:19Z (GMT) No. of bitstreams: 1 ve_Orfano_Alessandra_ Plasmodium yoelii_CPqRR_2016.pdf: 6369959 bytes, checksum: d459b9a02443550b0378396bc879eedd (MD5)Made available in DSpace on 2017-02-23T18:27:19Z (GMT). No. of bitstreams: 1 ve_Orfano_Alessandra_ Plasmodium yoelii_CPqRR_2016.pdf: 6369959 bytes, checksum: d459b9a02443550b0378396bc879eedd (MD5) Previous issue date: 2016National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MA, United States of America/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Entomologia Médica. Belo Horizonte, MG, BrasilNational Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MA, United States of America/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Entomologia Médica. Belo Horizonte, MG, Brasil/Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, BrasilNational Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MA, United States of America.Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Entomologia Médica. Belo Horizonte, MG, Brasil/Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MA, United States of America.Malaria is endemic in the American continent and the Amazonian rainforest is the region with the highest risk of transmission. However, the lack of suitable experimental models to infect malaria vectors from the Americas has limited the progress to understand the biology of transmission in this region. Anopheles aquasalis, a major vector in coastal areas of South America, was found to be highly refractory to infection with two strains of Plasmodium falciparum (NF54 and 7G8) and with Plasmodium berghei (mouse malaria), even when the microbiota was eliminated with antibiotics and oxidative stress was reduced with uric acid. In contrast, An. aquasalis females treated with antibiotics and uric acid are susceptible to infection with a second murine parasite, Plasmodium yoelii nigeriensis N67 (PyN67). Anopheles albimanus, one of the main malaria vectors in Central America, Southern Mexico and the Caribbean, was more susceptible to infection with PyN67 than An. aquasalis, even in the absence of any pre-treatment, but was still less susceptible than Anopheles stephensi. Disruption of the complement-like system in An. albimanus significantly enhanced PyN67 infection, indicating that the mosquito immune system is mounting effective antiplasmodial responses. PyN67 has the ability to infect a broad range of anophelines and is an excellent model to study malaria transmission by South American vectors