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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bookPart Fundamentos da terapia celular(2013) JANZ, Felipe de Lara; DEBES, Adriana de Aguiar; SEKIYA, Elíseo Joji; ALVES, Adelson; BYDLOWSKI, Sérgio PauloconferenceObject 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 MESENCHYMAL STEM CELLS FROM ADIPOSE TISSUE IN THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS - A CASE REPORT(2013) SEKIYA, E. J.; JORDY, S. S.; KUHN, T. I.; FORTE, A.; BRUNIERA, G.; ALVES, A.; BYDLOWSKI, S. P.Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that selectively affects motor neurons in the brain and spinal cord leading to bulbar and respiratory muscle weakness. Currently there is no treatment proven effective and the disease is considered incurable. Mesenchymal Stem Cells (MSCs) derived from adipose tissue have immunomodulatory properties, inducing suppression and differentiation into neural cell types in vitro. Here we describe a compassionate intervention in a 66 years old male patient with Amyotrophic Lateral Sclerosis. The patient is suffering from Amyotrophic Lateral Sclerosis diagnosed 4 years ago, unsuccessfully treated with Riluzole. It was observed atrophy of the shoulder girdle, upper limbs and thenar and hypothenar regions, fasciculations, tetra-pyramidal release (Hoffmann and Babinsky bilateral and global hyperre flexia) and inexhaustible clonus in the lower limbs. ALSFRS (ALS Functional Rating Scale) and its revised version ALSFRS-R were ALSFRS18 and ALSFRS-R26, respectively. After approval by the Ethics Committee, adipose tissue was collected from abdominal region by liposuction. Adipose tissue-derived MSCs were expanded under GMP conditions and administered intrathecaly. Five days after the first infusion of 1 10 7 cells, patient showed improvement of overall muscle strength and speech, exhaustible clonus in limbs, absence of Babinsky in lower left limb, and ALSFRS25 and ALSFRS-R33. One month later clinical condition worsened, with ALSFRS18 and ALSFRS-R26. The patient received other two higher dose infusions (5 10 7 and 10 10 7 cells) during the next 6 months and clinical data improved (ALSFRS25 and ALSFRS-R33) for a longer period. Moreover, no adverse effects were observed by MSC administration. In conclusion, although the study was performed in a single patient, intra-thecal administration of autologous adipose tissue-derived MSC is potentially safe. It is tempting to speculate that administration of these cells could be beneficial for ALS patients, mainly using higher doses.- 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.
bookPart Bases da farmacogenética(2013) SOUZA, Pamela Oliveira de; MASELLI, Luciana Morganti Ferreira; LEVY, Débora; BYDLOWSKI, Sérgio PauloconferenceObject STARVATION PROMOTES DECREASE OF SURVIVIN GENE EXPRESSION IN HUMAN LYMPHOMA CELLS LINES(2013) STERN, Ana Carolina; LEVY, Debora; RUIZ, Jorge Luis; BYDLOWSKI, SergioBackground: The survivin gene is a member of the IAP family, which is commonly overexpressed in lymphoma cell lines. This phenomenon has been correlated with resistance to radiotherapy-induced apoptosis and chemotherapy. Recently survivin gene expression was identified as an independent prognostic factor of poor clinical outcome. Objective: In vitro evaluation of survivin gene expression from four different human lymphoma cell lines cultured in the absence of FBS for up to 72 h. Methods: Molt-4 (acute lymphoblastic leukemia, ATCC CRL-1582), K562 (chronic myelogenous leukemia, ATCC CCL-243), Raji (Burkitt's lymphoma, ATCC CCL-86) and Jurkat (T-cell leukemia, ATCC TIB-154) were cultivated in triplicate in the absence of FBS for up to 72h. RNA was extracted by Trizol method. cDNA was synthesized using a High Capacity cDNA Reverse Transcription kit and qPCR was performed using TaqMan system. Gusb expression was used as reference control. For quantification of the gene expression a relative curve was performed using cDNA from Lucena cell line (K562/VCR). Data were evaluated by ANOVA using the Prism 5.0 software (GraphPad, San Diego, CA) Results: The basal expression of the survivin was: 181.88 relative units (UR) in Raji cell line; 176.47UR in Molt-4 cell line; 136.92UR in Jurkat cell line and 85.33UR in K562 cell line. The absence of FBS decreased survivin expression in the Raji, Jukart and K562 cells in a time-dependent way while expression in Molt-4 was not affected. However, decreased expression was different among cells. In the Jukart cells the decrease was detected after 48h and remained low after 72h. In the Raji and K562 cells the expression reduction was observed after 24h with a further decrease after 72h. Conclusion: Starvation promotes decrease of survivin gene expression in human lymphoma cells lines.- Anti-Angiogenic and Anti-Metastatic Activity of Synthetic Phosphoethanolamine(2013) FERREIRA, Adilson Kleber; FREITAS, Vanessa Morais; LEVY, Debora; RUIZ, Jorge Luiz Maria; BYDLOWSKI, Sergio Paulo; RICI, Rose Eli Grassi; FILHO, Otaviano Mendonca R.; CHIERICE, Gilberto Orivaldo; MARIA, Durvanei AugustoBackground: Renal cell carcinoma (RCC) is the most common type of kidney cancer, and represents the third most common urological malignancy. Despite the advent of targeted therapies for RCC and the improvement of the lifespan of patients, its cost-effectiveness restricted the therapeutic efficacy. In a recent report, we showed that synthetic phosphoethanolamine (Pho-s) has a broad antitumor activity on a variety of tumor cells and showed potent inhibitor effects on tumor progress in vivo. Methodology/Principal Findings: We show that murine renal carcinoma (Renca) is more sensitive to Pho-s when compared to normal immortalized rat proximal tubule cells (IRPTC) and human umbilical vein endothelial cells (HUVEC). In vitro anti-angiogenic activity assays show that Pho-s inhibits endothelial cell proliferation, migration and tube formation. In addition, Pho-s has anti-proliferative effects on HUVEC by inducing a cell cycle arrest at the G2/M phase. It causes a decrease in cyclin D1 mRNA, VEGFR1 gene transcription and VEGFR1 receptor expression. Pho-s also induces nuclear fragmentation and affects the organization of the cytoskeleton through the disruption of actin filaments. Additionally, Pho-s induces apoptosis through the mitochondrial pathway. The putative therapeutic potential of Pho-s was validated in a renal carcinoma model, on which our remarkable in vivo results show that Pho-s potentially inhibits lung metastasis in nude mice, with a superior efficacy when compared to Sunitinib. Conclusions/Significance: Taken together, our findings provide evidence that Pho-s is a compound that potently inhibits lung metastasis, suggesting that it is a promising novel candidate drug for future developments.
bookPart Princípios da terapia gênica(2013) RUIZ, Jorge Luís Maria; LEVY, Débora; BYDLOWSKI, Sérgio PaulobookPart 0 Citação(ões) na Scopus Nutraceuticals to prevent thrombogenesis and its application to women's health(2013) SUBBIAH, M. T. R.; BYDLOWSKI, S. P.; MASELLI, L.Thrombosis plays an important role in diseases affecting the arterial and venous vascular systems and substantially contributes to morbidity and mortality in Western countries. The etiology of both arterial and venous thrombosis is complex and involves environmental and genetic factors. Atherothrombosis represents an advanced stage of atherosclerosis in which plaque rupture or erosion trigger increased clotting activity, leading to the formation of an arterial thrombus. Platelets play a pivotal role in the development of atherosclerosis. This important contribution of platelets is strengthened by the observed benefits of antiplatelet agents like aspirin and clopidogrel in primary and secondary therapy of atherothrombotic disorders. Advances in human genome project have enabled scientific investigators to identify a number of mutations in genes that increase the risk of thrombosis. These genetic tests are routinely carried out in the laboratory to identify individuals that may have increased risk for thrombosis and they come under the 'thrombophilic panel' of tests. There are some issues unique to women' health that deserves increased attention for the risk of thrombosis. Oral contraceptive use in women is associated with increased risk of deep vein thrombosis and stroke and risk is even greater for those women with prothrombin and factor V Leiden mutations. Similarly, hormone replacement therapy (HRT) in postmenopausal has also indicated the negative effects on the risk of stroke and venous thrombosis. Women's Health Initiative (WHI) trial using estrogen plus progestin reported a doubling of the risk of stroke and venous thrombosis. These observations provide opportunities to develop nutraceuticals to reduce the activity of platelets and the risk of thrombosis. Antioxidants, procyanidins from guarana (paulinnia cupana), polyphenols from grape and other berries, green tea and garlic phytochemicals are being explored to as nutraceuticals to combat thrombosis. Such nutraceuticals may play a preventive role as dietary supplements, especially in women taking oral contraceptives in reproductive years or hormone replacement therapy in menopause. © 2013 by Nova Science Publishers, Inc. All rights reserved.