BRYAN ERIC STRAUSS
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
51 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 51
- TP53 Regulated Inhibitor of Apoptosis 1 (TRIAP1) stable silencing increases late apoptosis by upregulation of caspase 9 and APAF1 in RPMI8226 multiple myeloma cell line(2016) FOOK-ALVES, Veruska L.; OLIVEIRA, Mariana Bleker de; ZANATTA, Daniela B.; STRAUSS, Bryan E.; COLLEONI, Gisele W. B.Background: TP53 Regulated Inhibitor of Apoptosis 1 (TRIAP1) modulates apoptotic pathways preventing the formation of the apoptosome complex. Our group previous study showed that 90% of patients' multiple myeloma (MM) marrow-derived plasma cells present TRIAP1 overexpression as compared to normal plasma cells. Due to high prevalence and lack of information on TRIAP1's role in MM biology, we decided to explore the impact of TRAIP1 through stable gene silencing in MM cell lines and its effect on cell cycle and apoptosis. Methods: TRIAP1 expression was examined in MM cell lines by quantitative real time PCR. Cell lines were submitted to transduction with lentiviral vector encoding a TRIAP1-specific short hairpin RNA (shRNA) and, as control, encoding a non-targeting shRNA (scramble). Apoptosis was assessed by flow cytometry with annexin V and propidium iodide staining (the later also used for cell cycle), APAF1 and Caspase 9 apoptosome related genes expression and Caspase 9 and Caspase 3/7 activity. Results: RPMI8226 and U266 cell lines were chosen for transduction experiments since they present higher levels of TRIAP1 expression. Inhibition of TRIAP1 in RPMI8226 cells increased the percentage of apoptotic cells, accompanied by increased expression of APAF1 and Caspase 9, and Caspase 9 and Caspase 3/7 activity. Transduced U266 cell line did not show sustained inhibition of TRIAP1 expression nor apoptosis induction. Conclusion: Stable silencing of TRIAP1 induces late apoptosis through APAF1/Caspase 9 pathway at least in RPMI8226 cell line, suggesting that it could be exploited as a potential target at least for a subgroup of MM patients. General significance: In the present study, we demonstrated effects of TRIAP1 silencing on RPMI8226 MM cell line and established its mechanism mediated through APAF1 and Caspase 9. No relevant effect was found after gene silencing in U266 cell line.
- Consensus guidelines for the definition, detection and interpretation of immunogenic cell death(2020) GALLUZZI, Lorenzo; VITALE, Ilio; WARREN, Sarah; ADJEMIAN, Sandy; AGOSTINIS, Patrizia; MARTINEZ, Aitziber Buque; CHAN, Timothy A.; COUKOS, George; DEMARIA, Sandra; DEUTSCH, Eric; DRAGANOV, Dobrin; EDELSON, Richard L.; FORMENTI, Silvia C.; FUCIKOVA, Jitka; GABRIELE, Lucia; GAIPL, Udo S.; GAMEIRO, Sofia R.; GARG, Abhishek D.; GOLDEN, Encouse; HAN, Jian; HARRINGTON, Kevin J.; HEMMINKI, Akseli; HODGE, James W.; HOSSAIN, Dewan Md Sakib; ILLIDGE, Tim; KARIN, Michael; KAUFMAN, Howard L.; KEPP, Oliver; KROEMER, Guido; LASARTE, Juan Jose; LOI, Sherene; LOTZE, Michael T.; MANIC, Gwenola; MERGHOUB, Taha; MELCHER, Alan A.; MOSSMAN, Karen L.; PROSPER, Felipe; REKDAL, Oystein; RESCIGNO, Maria; RIGANTI, Chiara; SISTIGU, Antonella; SMYTH, Mark J.; SPISEK, Radek; STAGG, John; STRAUSS, Bryan E.; TANG, Daolin; TATSUNO, Kazuki; GOOL, Stefaan W. van; VANDENABEELE, Peter; YAMAZAKI, Takahiro; ZAMARIN, Dmitriy; ZITVOGEL, Laurence; CESANO, Alessandra; MARINCOLA, Francesco M.Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
- Overhauling CAR T Cells to Improve Efficacy, Safety and Cost(2020) CHICAYBAM, Leonardo; BONAMINO, Martin H.; INVITTI, Adriana Luckow; ROZENCHAN, Patricia Bortman; VIEIRA, Igor de Luna; STRAUSS, Bryan E.Gene therapy is now surpassing 30 years of clinical experience and in that time a variety of approaches has been applied for the treatment of a wide range of pathologies. While the promise of gene therapy was over-stated in the 1990's, the following decades were met with polar extremes between demonstrable success and devastating setbacks. Currently, the field of gene therapy is enjoying the rewards of overcoming the hurdles that come with turning new ideas into safe and reliable treatments, including for cancer. Among these modalities, the modification of T cells with chimeric antigen receptors (CAR-T cells) has met with clear success and holds great promise for the future treatment of cancer. We detail a series of considerations for the improvement of the CAR-T cell approach, including the design of the CAR, routes of gene transfer, introduction of CARs in natural killer and other cell types, combining the CAR approach with checkpoint blockade or oncolytic viruses, improving pre-clinical models as well as means for reducing cost and, thus, making this technology more widely available. While CAR-T cells serve as a prime example of translating novel ideas into effective treatments, certainly the lessons learned will serve to accelerate the current and future development of gene therapy drugs.
- Combined p19Arf and interferon-beta gene transfer enhances cell death of B16 melanoma in vitro and in vivo(2013) MERKEL, C. A.; MEDRANO, R. F. V.; BARAUNA, V. G.; STRAUSS, B. E.Approximately 90% of melanomas retain wild-type p53, a characteristic that may help shape the development of novel treatment strategies. Here, we employed an adenoviral vector where transgene expression is,controlled by p53 to deliver the p19 alternate reading frame (An) and interferon-beta (IFN beta) complementary DNAs in the B16 mouse model of melanoma. In vitro, cell death was enhanced by combined gene transfer (63.82 +/- 15.30% sub-GO cells); yet introduction of a single gene resulted in significantly fewer hypoploid cells (37.73 +/- 7.3% or 36.96 +/- 11.58%, p19Arf or IFN beta, respectively, P < 0.05). Annexin V staining and caspase-3 cleavage indicate a cell death mechanism consistent with apoptosis. Using reverse transcriptase quantitative PCR, we show that key transcriptional targets of p53 were upregulated in the presence of p19Arf, although treatment with IFN beta did not alter expression of the genes studied. In situ gene therapy revealed significant inhibition of subcutaneous tumors by IFN beta (571 +/- 25 mm(3)) or the combination of p19Arf and IFN beta (489 +/- 124 mm(3)) as compared with the LacZ control (1875 +/- 33 mm(3), P < 0.001); whereas p19Arf yielded an intermediate result (1053 +/- 169 mm(3), P < 0.01 vs control). However, only the combination was associated with increased cell death and prolonged survival (P < 0.01). As shown here, the combined transfer of p19Arf and IFN beta using p53-responsive vectors enhanced cell death both in vitro and in vivo.
- Distinct Roles of Direct Transduction Versus Exposure to the Tumor Secretome on Murine Endothelial Cells After Melanoma Gene Therapy with Interferon-beta and p19Arf(2019) VIEIRA, Igor de Luna; TAMURA, Rodrigo Esaki; HUNGER, Aline; STRAUSS, Bryan E.Tumor vasculature plays a central role in tumor progression, making it an attractive therapeutic target. In this study, we explore the antiangiogenic potential of our melanoma gene therapy approach combining interferon beta (IFN beta) and p19Arf gene transfer. Since these proteins are modulators of tumor vasculature, we explore the impact of IFN beta and p19Arf gene transfer on murine endothelial cells (tEnd). Adenovirus-mediated gene transfer of p19Arf to tEnd cells inhibited proliferation, tube formation, migration, and led to increased expression of genes related to the p53 cell death pathway, yet IFN beta gene transfer had no significant impact on tEnd viability. Alternatively, tEnd cells were exposed to the factors generated by transduced B16 (mouse melanoma) cells using either coculture or conditioned medium. In either case, transduction of B16 cells with the IFN beta vector, whether alone or in combination with p19Arf, resulted in endothelial cell death. Strikingly, treatment of tEnd cells with recombinant IFN beta did not induce death, demonstrating that additional factors produced by B16 cells contributed to the demise of tEnd cells. In this work, we have shown that our melanoma gene therapy strategy produces desirable negative effects on endothelial cells, possibly correlating with antiangiogenic activity.
- AAVPG: A vigilant vector where transgene expression is induced by p53(2013) BAJGELMAN, Marcio C.; MEDRANO, Ruan F. V.; CARVALHO, Anna Carolina P. V.; STRAUSS, Bryan E.Using p53 to drive transgene expression from viral vectors may provide on demand expression in response to physiologic stress, such as hypoxia or DNA damage. Here we introduce AAVPG, an adeno-associated viral (AAV) vector where a p53-responsive promoter, termed PG, is used to control transgene expression. In vitro assays show that expression from the AAVPG-luc vector was induced specifically in the presence of functional p53 (1038 +/- 202 fold increase, p < 0.001). The AAVPG-Iuc vector was an effective biosensor of p53 activation in response to hypoxia (4.48 +/- 0.6 fold increase in the presence of 250 mu M CoCl2, p < 0.001) and biomechanical stress (253 +/- 0.4 fold increase with stretching, p < 0.05). In vivo, the vigilant nature of the AAVPG-luc vector was revealed after treatment of tumor-bearing mice with doxorubicin (pretreatment, 3.4 x 10(5) +/- 0.43 x 10(5) photons/s; post-treatment, 6.6 x 10(5) +/- 2.1 x 10(5) photons/s, p < 0.05). These results indicate that the AAVPG vector is an interesting option for detecting p53 activity both in vitro and in vivo.
- Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy(2017) MEDRANO, Ruan F. V.; HUNGER, Aline; MENDONCA, Samir Andrade; BARBUTO, Jose Alexandre M.; STRAUSS, Bryan E.During the last decades, the pleiotropic antitumor functions exerted by type I interferons (IFNs) have become universally acknowledged, especially their role in mediating interactions between the tumor and the immune system. Indeed, type I IFNs are now appreciated as a critical component of dendritic cell (DC) driven T cell responses to cancer. Here we focus on IFN-alpha and IFN-beta, and their antitumor effects, impact on immune responses and their use as therapeutic agents. IFN-alpha/beta share many properties, including activation of the JAK-STAT signaling pathway and induction of a variety of cellular phenotypes. For example, type I IFNs drive not only the high maturation status of DCs, but also have a direct impact in cytotoxic T lymphocytes, NK cell activation, induction of tumor cell death and inhibition of angiogenesis. A variety of stimuli, including some standard cancer treatments, promote the expression of endogenous IFN-alpha/beta, which then participates as a fundamental component of immunogenic cell death. Systemic treatment with recombinant protein has been used for the treatment of melanoma. The induction of endogenous IFN-alpha/beta has been tested, including stimulation through pattern recognition receptors. Gene therapies involving IFN-alpha/beta have also been described. Thus, harnessing type I IFNs as an effective tool for cancer therapy continues to be studied.
- Interferons: key modulators of the immune system in cancer(2023) YUSUF, Nabiha; ALLIE, S. Rameeza; STRAUSS, Bryan E.
- Cochlea cell-specific marker expression upon in vitro Hes1 knockdown(2021) BATISSOCO, A. C.; LEZIROVITZ, K.; ZANATTA, D. B.; HEMZA, C. R. M. L.; VASQUES, L. R.; STRAUSS, B. E.; MINGRONI-NETTO, R. C.; HADDAD, L. A.; BENTO, R. F.; OITICICA, J.NOTCH pathway proteins, including the transcriptional factor HES1, play crucial roles in the development of the inner ear by means of the lateral inhibition mechanism, in which supporting cells have their phenotype preserved while they are prevented from becoming hair cells. Genetic manipulation of this pathway has been demonstrated to increase hair cell number. The present study aimed to investigate gene expression effects in hair cells and supporting cells after Hes1-shRNA lentivirus transduction in organotypic cultures of the organ of Corti from postnatal-day-3 mice. Forty-eight hours after in vitro knockdown, Hes1 gene expression was reduced at both mRNA and protein levels. Myo7a (hair cell marker) and Sox2 (progenitor cell marker) mRNA levels also significantly increased. The modulation of gene expression in the organ of Corti upon Hes1 knockdown is consistent with cell phenotypes related to lateral inhibition mechanism interference in the inner ear. The lentivirus-based expression of Hes1-sh RNA is a valuable strategy for genetic interference in the organ of Corti and for future evaluation of its efficacy in protocols aiming at the regeneration of hair cells in vivo.
- Near future of tumor immunology: Anticipating resistance mechanisms to immunotherapies, a big challenge for clinical trials(2017) CATANI, Joao Paulo Portela; RIECHELMANN, Rachel P.; ADJEMIAN, Sandy; STRAUSS, Bryan E.The success of immunotherapies brings hope for the future of cancer treatment. Even so, we are faced with a new challenge, that of understanding which patients will respond initially and, possibly, develop resistance. The examination of the immune profile, especially approaches related to the immunoscore, may foretell which tumors will have a positive initial response. Ideally, the mutation load would also be analyzed, helping to reveal tumor associated antigens that are predictive of an effective cytolytic attack. However, the response may be hindered by changes induced in the tumor and its microenvironment during treatment, perhaps stemming from the therapy itself. To monitor such alterations, we suggest that minimally invasive approaches should be explored, such as the analysis of circulating tumor DNA. When testing new drugs, the data collected from each patient would initially represent an N of 1 clinical trial that could then be deposited in large databases and mined retrospectively for trends and correlations between genetic alterations and response to therapy. We expect that the investment in personalized approaches that couple molecular analysis during clinical trials will yield critical data that, in the future, may be used to predict the outcome of novel immunotherapies.