SERGIO PAULO BYDLOWSKI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder
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conferenceObject FREQUENCY OF LYMPHOMAS IN A COHORT OF PATIENTS WITH COMMON VARIABLE IMMUNODEFICIENCY(2013) SINI, B. C.; KOKRON, C. M.; LEVY, D.; PEREIRA, Juliana; OLIVEIRA, Ana Karolina Barreto; COHON, Andrea; KALIL, Jorge; BYDLOWSKI, S. P.; BARROS, Myrthes ToledoIntroduction: Common variable immunodeficiency (CVID) is characterized by recurrent infections and in-creased susceptibility to autoimmunity and malignancies. Objective: To evaluate the frequency of lymphoma in a cohort of patients with CVID. Methods: Analysis of data obtained from medical records. Results: We analyzed 144 patients, 80 men and 64 women, aged 15-72 years. Seven (0.5 %) lymphoma cases were diagnosed (1 Hodgkin lymphoma and 6 non-Hodgkin lymphomas), affecting 5 men and 2 women aged 1953 years at lymphoma diagnosis. The time period between the onset of symptoms of CVID and lymphoma diagnosis ranged from 7 to 24 years in 4 patients and in 3 of them the diagnosis of both diseases were nearly overlapped preceding the CVID diagnosis in only 1, 3 and 6 months. Fever, splenomegaly and lymphadenopathy occurred in all patients. Lymphocytosis with inversion of the CD4/CD8 ratio at the expense of increased CD8+ T cells was detected in 2 patients and lymphopenia in one. B lymphocytes were undetectable in 3 patients in whom the diagnosis of lymphoma and CVID were established simultaneously and in one B cells were present at the beginning of CVID but undetectable at diagnosis of lymphoma. Conclusions: Patients with absence of B cells in recently diagnosed CVID or absence of B cells in long term followed CVID with previously detectable B cells demands a screening for the presence of lymphomas.conferenceObject PARAOXONASE 3 POLYMORPHISMS ARE NOT ASSOCIATED WITH PROGRESSION FREE SURVIVAL AND OVERALL SURVIVAL IN DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS(2012) BYDLOWSKI, Sergio; SINI, Bruno; FLORES, Milagros; CHAVES, Denise; MASELLI, Luciana; PEREIRA, Juliana; LEVY, DeboraBackground: Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. It is a heterogeneous disease. Approximately 40% of the patients respond well to chemotherapy based on rituximab-CHOP (R-CHOP). The prognosis for the other 60% is poor and only half of the patients survive 5 years after the onset of the disease. The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3). All the three proteins have been shown to exhibit antioxidant and anti-inflammatory properties. Evidences exist indicating that the PON family plays an important role in a variety of human illnesses such as cardiovascular disease, diabetes mellitus, metabolic syndrome, obesity, non-alcoloholic steatohepatitis and several mental disorders. However, their role inDLBCL is still unknown. Methods: 106 DLBCL patients treated with R-CHOP or CHOP were studied. Control group included 130 healthy blood donors. Blood was drawn and DNA extracted by conventional methods. Polymorphisms of PON3 were performed by real time polymerase chain reaction using TaqMan system. Results: Forty-six (43.4%) patients were in stage III-IV and 42 (39.6%) had more than 2 factors established by the International Prognostic Index (IPI). Seventy-nine (74.5%) achieved complete response (IC95%: 77-93%); 6 (5.6%) had partial response (RD) and 21 (19.9%) patients had refractory disease. Eighteen (16.9%) patients died in a follow up median of 29.6 months (5.5 to 72.7). Polymorphisms frequencies in control group were:76% and 24%, respectively, for the alleles PON3-10340T and PON3-10340G; 8% and 92%, respectively, for the alleles PON3-2115A and PON3-2115T; and 4% and 96%, respectively, for the alleles PON3-45486A and PON3-45486C. The frequencies in the group of patients were: 76% and 24% for the alleles PON3-10340T and PON3-10340G, respectively; 9% and 91% for the alleles PON3-2115A and PON3-2115T, respectively; and 1% and 99% for the alleles PON3-45486A and PON3-45486C, respectively. Fisher exact test showed no significant difference between groups. The overall response and progression-free survival of patients with DLBCL were not related to PON3 polymorphisms. Conclusion: The present data shows that PON3 polymorphisms do not play a role in diffuse large B-cell lymphoma.- Azidothymidine is Effective Against Human Multiple Myeloma: A New Use for an Old Drug?(2013) PEREIRA, Juliana; LEVY, Debora; RUIZ, Jorge L. M.; BROCARDO, Graciela A.; FERREIRA, Kleber A.; COSTA, Renata O.; QUEIROZ, Rodrigo G.; MARIA, Durvanei A.; HALLACK NETO, Abrahao E.; CHAMONE, Dalton A. F.; BYDLOWSKI, Sergio P.Azidothymidine (AZT) is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-kappa B pathway. As multiple myeloma (MM) presents with constitutive activation of NF-kappa B, we analyzed the effect of AZT on human MM cell lines. We evaluated the cytotoxic effect of AZT in human MM cell lines sensitive (8226/S) or resistant to doxorubicin (8226/DX5) and human T cell lymphoblast-like cells, uterine sarcoma cells, and HUVEC using MTT assay. Cytotoxicity was also evaluated in vivo in nude mice xenografted with 8226/S tumor. The effect of AZT on the expression of genes involved in cell proliferation, apoptosis, angiogenesis, and the NF-kappa B pathway was analyzed in the xenografts using real-time polymerase chain reaction. AZT was effective against both 8226/S and 8226/DX5 cells in a dose and time-dependent manner (p = 0.02) in vitro and promoted cell cycle arrest in S phase in these cells. The tumor volume was lower in mice treated with AZT compared to untreated mice (p = 0.0003). AZT down-regulated the pro-proliferative genes encoding AKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3, and cyclin D2; pro-angiogenenic genes encoding VEGF and IL8; and genes involved in cell adhesion (ICAM1 and FN1) and the NF-kappa B pathway. AZT up-regulated the expression of tumor suppressor gene FOXP1 and the pro-apoptotic genes encoding BID, Bcl-10, and caspase-8. Thus, we demonstrated the cytotoxic effect of AZT in human MM cell lines for the first time. Our data may provide the rationale for future clinical trials of AZT for treating MM.
- 7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia(2019) PAZ, Jessica Liliane; LEVY, Debora; OLIVEIRA, Beatriz Araujo; MELO, Thatiana Correia de; FREITAS, Fabio Alessandro de; REICHERT, Cadiele Oliana; RODRIGUES, Alessandro; PEREIRA, Juliana; BYDLOWSKI, Sergio Paulo7-Ketocholesterol (7-KC) is a cholesterol oxidation product with several biological functions. 7-KC has the capacity to cause cell death depending on the concentration and specific cell type. Mesenchymal stem cells (MSCs) are multipotent cells with the ability to differentiate into various types of cells, such as osteoblasts and adipocytes, among others. MSCs contribute to the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases, such as leukemia, to a yet unknown extent. Here, we describe the effect of 7-KC on the death of bone marrow MSCs from patients with acute myeloid leukemia (LMSCs). LMSCs were less susceptible to the death-promoting effect of 7-KC than other cell types. 7-KC exposure triggered the extrinsic pathway of apoptosis with an increase in activated caspase-8 and caspase-3 activity. Mechanisms other than caspase-dependent pathways were involved. 7-KC increased ROS generation by LMSCs, which was related to decreased cell viability. 7-KC also led to disruption of the cytoskeleton of LMSCs, increased the number of cells in S phase, and decreased the number of cells in the G1/S transition. Autophagosome accumulation was also observed. 7-KC downregulated the SHh protein in LMSCs but did not change the expression of SMO. In conclusion, oxiapoptophagy (OXIdative stress + APOPTOsis + autophagy) seems to be activated by 7-KC in LMSCs. More studies are needed to better understand the role of 7-KC in the death of LMSCs and the possible effects on the SHh pathway.
conferenceObject IN VITRO AND IN VIVO ANTITUMOR EFFECTS OF AZIDOTHYMIDINE IN A HUMAN MULTIPLE MYELOMA CELL LINE(2012) LEVY, Debora; RUIZ, Jorge Luis; BROCARDO, Graciela; FERREIRA, Adilson; QUEIROZ, Rodrigo; MARIA, Durvanei; BYDLOWSKI, Sergio; PEREIRA, JulianaBackground: Azidothymidine (AZT) is an antiretroviral nucleoside analogous inhibitor ofreverse transcriptase with known effects on cell proliferation, apoptosis, and angiogenesis Multiple myeloma is a severe disease and one of the steps involved in the malignant transformation of plasma cells is the activation of the nuclear factor kappa B (NF-κB) pathway. Objective: Evaluate the in vitro cytotoxic activity of AZT in human myeloma cell lines (RPMI 8226/S and RPMI 8226/Dx5) as well as in other cell lines: human T cell lymphoblast-like, T cell leukemia, uterine sarcoma and HUVEC. The in vivo effect was also evaluated in tumor xenograft model of human multiple myeloma in nude mice. Methods: Cells were treated with increasing concentrations of AZT (32.2 to 500μM) for 24 to 72 hours. Cytotoxicity was measured by MTT. Cell cycle and proteins Bcl-2 and p53 were evaluated by flow cytometry. For the in vivo experiments, 1x107 RPMI 8226/S cells were injected SC in the right flank of nude mice. After 7 days, animals were treated or not with AZT 12.5 μM IV every other day for 5 weeks. Thirty five genes were then investigated in the grafted tumor cells by real time polymerase chain reaction. Results: AZT showed in vitro antitumor activity in cell lines 8226/S and 8226/Dx5 in a dose and time dependent way (p = 0.02), but not in the other studied cells. Histological signs of apoptosis were seen, such as cytoplasmic blebs, nuclear condensation. A significant decrease of Bcl-2 (p<0.001) and p53 (p = 0.0139) proteins was observed in cells treated with AZT. A cell cycle arrest in Sphase was also seen after 72 hours of treatment with AZT 62.5 μM. Tumor volume in nude mice reated with AZT was reduced (p = 0.0003). In these tumors, AZT decreased the expression of genes associated with cell proliferation (AKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3 and Cyclin D2), angiogenesis (VEGF, IL8), cell adhesion (ICAM1 and FN1) and NF-κB. Moreover, also in tumors, AZT induced expression of the tumor suppressor gene FOXP1, pro-apoptotic genes BID, Bcl-10 and caspase-8. Conclusion: Azidothymidine promotes a cytotoxic effect in human multiple myeloma cells both in vitro and in vivo. This action involves the cell cycle arrest in S phase, inhibition of expression of genes that activate cell proliferation, as well as proangiogenic genes and NF- κB, and activation of apoptosis genes. Therefore, AZT could be potentially promising in the treatment of multiple myeloma.- Cell Cycle Changes, DNA Ploidy, and PTTG1 Gene Expression in HTLV-1 Patients(2020) LEVY, Debora; FERREIRA, Mari Cleia M. R.; REICHERT, Cadiele O.; ALMEIDA, Lis Vilela de; BROCARDO, Graciela; LAGE, Luis Alberto P. C.; CULLER, Hebert F.; NUKUI, Youko; BYDLOWSKI, Sergio P.; PEREIRA, JulianaHuman T-cell lymphotropic virus type-1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). Genetic instability is the hallmark of ATL. Cell cycle progression is needed for virus particle reproduction. HTLV-1 encoded Tax protein ultimately disrupts the mitotic spindle checkpoint, leading to incorrect chromosome segregation, resulting in aneuploidy. Cell cycle abnormalities have been described in T cells transfected with HTLV-1 virusin vitro, but not in HTLV-1 asymptomatic carriers. PTTG1 and HTLV-1 viral protein Tax exhibit a cooperative transforming activity. Overexpressed PTTG1 results in chromosome instability and aneuploidy, which has been suggested as a mechanism underlying PTTG1 transforming activity. Here we aimed to investigate cell cycle, DNA ploidy and PTTG1 mRNA expression in CD4(+)and CD8(+)T cells in healthy subjects (HS), HTLV-1 asymptomatic carriers and ATL patients. We have identified that HTLV-1 asymptomatic carriers have shown DNA aneuploidy and cell cycle arrest at cell cycle phase G(0)/G(1)in CD4(+)T cells. CD8(+)T cells of HTLV-1 asymptomatic carriers also demonstrated DNA aneuploidy but without alteration in cell cycle. In ATL, CD4(+)and CD8(+)T cells present a higher number of cells in cell cycle S-phase and PTTG1 overexpression. These studies provide insight into malignant transformation of HTLV-1 asymptomatic carriers to ATL patients.
- New genetic prognostic biomarkers in primary central nervous system lymphoma (PCNSL)(2021) REIS, Diego Gomes Candido; LEVY, Debora; LAGE, Luis Alberto de Padua Covas; CULLER, Hebert Fabricio; ROCHA, Vanderson; BYDLOWSKI, Sergio Paulo; ZERBINI, Maria Claudia Nogueira; PEREIRA, JulianaBackground PCNSL is a rare extranodal NHL with poor prognosis. Tumorigenesis has been associated with hyperactivation of BCR downstream and NFkB pathways. We studied the prognosis of the relative expression profile of target genes of NFkB pathway (MYC, BCL2), the essential transcriptional regulator in hematopoiesis LMO2, the checkpoint regulation pathway MGMT, the transcription factor POU2F1, the immune checkpoint gene PDCD1, and the proto-oncogene and transcriptional repressor gene BCL6 and its proteins in PCNSL. Methods This study is a retrospective cohort study; 35 immunocompetent PCNSL-DLBCL patients had their gene expression (RT-qPCR) normalized to internal control gene GUSB. Results Median patient age was 62 years, median OS was 42.6 months (95% CI: 26.6-58.6), PFS was 41 months (95% CI: 19.7-62.4), and DFS was 59.2 months (95% CI 31.9-86.6). A moderate correlation was found between the gene/protein expressions of MYC (kappa = 0.596, p = .022) and of BCL2 (kappa = 0.426, p = .042). Relative gene expression of MYC >= 0.201 (HR 6.117; p = .003) was associated with worse 5-year OS. Relative gene expression of MYC >= 0.201 (HR 3.96; p = .016) and MGMT >= 0.335 (HR 3.749; p = .056) was associated with worse PFS. Age > 60 years and IELSG score moderate/high were also associated with worse prognosis. Conclusions Overexpression of MYC and overexpression of MGMT were prognostic markers associated with unfavorable clinical outcomes in PCNSL.
- Protocol for qRT-PCR analysis from formalin fixed paraffin embedded tissue sections from diffuse large b-cell lymphoma: Validation of the six-gene predictor score(2016) TEKIN, Nilgun; OMIDVAR, Nader; MORRIS, Tim Peter; CONGET, Paulette; BRUNA, Flavia; TIMAR, Botond; GAGYI, Eva; BASAK, Ranjan; NAIK, Omkar; AUEWARKUL, Chirayu; SRITANA, Narongrit; LEVY, Debora; CERCI, Juliano Julio; BYDLOWSKI, Sergio Paulo; PEREIRA, Juliana; DIMAMAY, Mark Pierre; NATIVIDAD, Filipinas; CHUNG, June-Key; BELDER, Nevin; KUZU, Isinsu; PAEZ, Diana; DONDI, Maurizio; CARR, Robert; OZDAG, Hilal; PADUA, Rose AnnAs a part of an international study on the molecular analysis of Diffuse Large B-cell Lymphoma (DLBCL), a robust protocol for gene expression analysis from RNA extraction to qRT-PCR using Formalin Fixed Paraffin Embedded tissues was developed. Here a study was conducted to define a strategy to validate the previously reported 6-gene (LMO2, BCL6, FN1, CCND2, SCYA3 and BCL2) model as predictor of prognosis in DLBCL. To avoid variation, all samples were tested in a single centre and single platform. This study comprised 8 countries (Brazil, Chile, Hungary, India, Philippines, S. Korea, Thailand and Turkey). Using the Kaplan-Meier and log rank test on patients (n=162) and two mortality risk groups (with those above and below the mean representing high and low risk groups) confirmed that the 6-gene predictor score correlates significantly with overall survival (OS, p< 0.01) but not with event free survival (EFS, p= 0.18). Adding the International Prognostic Index (IPI) shows that the 6-gene predictor score correlates significantly with high IPI scores for OS (p< 0.05), whereas those with low IPI scores show a trend not reaching significance (p= 0.08). This study defined an effective and economical qRT-PCR strategy and validated the 6-gene score as a predictor of OS in an international setting.
conferenceObject Paraoxonases 1 and 2 (PON1 and 2) Polymorphisms in Diffuse Large B-Cell Lymphoma (DLBCL): Correlation with Clinical Outcomes(2017) LEVY, Debora; REIS, Diego; SILVA, Karolline Santana da; LAGE, Luis A. P. C.; SINI, Bruno; MASELI, Luciana M. F.; ROCHA, Vanderson; PEREIRA, Juliana; BYDLOWSKI, Sergio P.- The H/R Fc gamma RIIA-131 polymorphism and survival in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP: a study in a genetically mixed population(2011) LEVY, Debora; BELLESSO, Marcelo; OLIVEIRA-SOUZA, Pamela; MACIEL, Felipe V.; PEREIRA, Juliana; BYDLOWSKI, Sergio P.