SUELY KAZUE NAGAHASHI MARIE
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina - Docente
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina - Líder
20 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 20
- Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies(2014) BETTEGOWDA, Chetan; SAUSEN, Mark; LEARY, Rebecca J.; KINDE, Isaac; WANG, Yuxuan; AGRAWAL, Nishant; BARTLETT, Bjarne R.; WANG, Hao; LUBER, Brandon; ALANI, Rhoda M.; ANTONARAKIS, Emmanuel S.; AZAD, Nilofer S.; BARDELLI, Alberto; BREM, Henry; CAMERON, John L.; LEE, Clarence C.; FECHER, Leslie A.; GALLIA, Gary L.; GIBBS, Peter; LE, Dung; GIUNTOLI, Robert L.; GOGGINS, Michael; HOGARTY, Michael D.; HOLDHOFF, Matthias; HONG, Seung-Mo; JIAO, Yuchen; JUHL, Hartmut H.; KIM, Jenny J.; SIRAVEGNA, Giulia; LAHERU, Daniel A.; LAURICELLA, Calogero; LIM, Michael; LIPSON, Evan J.; MARIE, Suely Kazue Nagahashi; NETTO, George J.; OLINER, Kelly S.; OLIVI, Alessandro; OLSSON, Louise; RIGGINS, Gregory J.; SARTORE-BIANCHI, Andrea; SCHMIDT, Kerstin; SHIH, Ie-Ming; OBA-SHINJO, Sueli Mieko; SIENA, Salvatore; THEODORESCU, Dan; TIE, Jeanne; HARKINS, Timothy T.; VERONESE, Silvio; WANG, Tian-Li; WEINGART, Jon D.; WOLFGANG, Christopher L.; WOOD, Laura D.; XING, Dongmei; HRUBAN, Ralph H.; WU, Jian; ALLEN, Peter J.; SCHMIDT, C. Max; CHOTI, Michael A.; VELCULESCU, Victor E.; KINZLER, Kenneth W.; VOGELSTEIN, Bert; PAPADOPOULOS, Nickolas; DIAZ JR., Luis A.The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in > 75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
- Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness(2021) FRANCO, Yollanda E. Moreira; ALVES, Maria Jose; UNO, Miyuki; MORETTI, Isabele Fattori; TROMBETTA-LIMA, Marina; SANTOS, Suzana de Siqueira; SANTOS, Ancely Ferreira dos; ARINI, Gabriel Santos; BAPTISTA, Mauricio S.; LERARIO, Antonio Marcondes; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue NagahashiBackground Glioblastoma is the most frequent and high-grade adult malignant central nervous system tumor. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. Metabolic reprogramming currently is recognized as one of the hallmarks of cancer. Glutamine metabolism through glutaminolysis has been associated with tumor cell maintenance and survival, and with antioxidative stress through glutathione (GSH) synthesis. Methods In the present study, we analyzed the glutaminolysis-related gene expression levels in our cohort of 153 astrocytomas of different malignant grades and 22 non-neoplastic brain samples through qRT-PCR. Additionally, we investigated the protein expression profile of the key regulator of glutaminolysis (GLS), glutamate dehydrogenase (GLUD1), and glutamate pyruvate transaminase (GPT2) in these samples. We also investigated the glutathione synthase (GS) protein profile and the GSH levels in different grades of astrocytomas. The differential gene expressions were validated in silico on the TCGA database. Results We found an increase of glutaminase isoform 2 gene (GLSiso2) expression in all grades of astrocytoma compared to non-neoplastic brain tissue, with a gradual expression increment in parallel to malignancy. Genes coding for GLUD1 and GPT2 expression levels varied according to the grade of malignancy, being downregulated in glioblastoma, and upregulated in lower grades of astrocytoma (AGII-AGIII). Significant low GLUD1 and GPT2 protein levels were observed in the mesenchymal subtype of GBM. Conclusions In glioblastoma, particularly in the mesenchymal subtype, the downregulation of both genes and proteins (GLUD1 and GPT2) increases the source of glutamate for GSH synthesis and enhances tumor cell fitness due to increased antioxidative capacity. In contrast, in lower-grade astrocytoma, mainly in those harboring the IDH1 mutation, the gene expression profile indicates that tumor cells might be sensitized to oxidative stress due to reduced GSH synthesis. The measurement of GLUD1 and GPT2 metabolic substrates, ammonia, and alanine, by noninvasive MR spectroscopy, may potentially allow the identification of IDH1(mut) AGII and AGIII progression towards secondary GBM.
- Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation(2023) YONAMINE, Caio Yogi; PASSARELLI, Marisa; SUEMOTO, Claudia Kimie; PASQUALUCCI, Carlos Augusto; JACOB-FILHO, Wilson; ALVES, Venancio Avancini Ferreira; MARIE, Suely Kazue Nagahashi; CORREA-GIANNELLA, Maria Lucia; BRITTO, Luiz Roberto; MACHADO, Ubiratan FabresDiabetes mellitus (DM) is an important risk factor for dementia, which is a common neurodegenerative disorder. DM is known to activate inflammation, oxidative stress, and advanced glycation end products (AGEs) generation, all capable of inducing neuronal dysfunctions, thus participating in the neurodegeneration progress. In that process, disturbed neuronal glucose supply plays a key role, which in hippocampal neurons is controlled by the insulin-sensitive glucose transporter type 4 (GLUT4). We investigated the expression of GLUT4, nuclear factor NF-kappa B subunit p65 [NFKB (p65)], carboxymethyllysine and synapsin1 (immunohistochemistry), and soma area in human postmortem hippocampal samples from control, obese, and obese+DM subjects (41 subjects). Moreover, in human SH-SY5Y neurons, tumor necrosis factor (TNF) and glycated albumin (GA) effects were investigated in GLUT4, synapsin-1 (SYN1), tyrosine hydroxylase (TH), synaptophysin (SYP) proteins, and respective genes; NFKB binding activity in the SLC2A4 promoter; effects of increased histone acetylation grade by histone deacetylase 3 (HDAC3) inhibition. Hippocampal neurons (CA4 area) of obese+DM subjects displayed reduced GLUT4 expression and neuronal soma area, associated with increased expression of NFKB (p65). Challenges with TNF and GA decreased the SLC2A4/GLUT4 expression in SH-SY5Y neurons. TNF decreased SYN1, TH, and SYP mRNAs and respective proteins, and increased NFKB binding activity in the SLC2A4 promoter. Inhibition of HDAC3 increased the SLC2A4 expression and the total neuronal content of CRE-binding proteins (CREB/ICER), and also counterbalanced the repressor effect of TNF upon these parameters. This study revealed reduced postmortem human hippocampal GLUT4 content and neuronal soma area accompanied by increased proinflammatory activity in the brains of DM subjects. In isolated human neurons, inflammatory activation by TNF reduced not only the SLC2A4/GLUT4 expression but also the expression of some genes related to neuronal function (SYN1, TH, SYP). These effects may be related to epigenetic regulations (H3Kac and H4Kac status) since they can be counterbalanced by inhibiting HDAC3. These results uncover the improvement in GLUT4 expression and/or the inhibition of HDAC3 as promising therapeutic targets to fight DM-related neurodegeneration.
article 60 Citação(ões) na Scopus Exomic Sequencing of Four Rare Central Nervous System Tumor Types(2013) BETTEGOWDA, Chetan; AGRAWAL, Nishant; JIAO, Yuchen; WANG, Yuxuan; WOOD, Laura D.; RODRIGUEZ, Fausto J.; HRUBAN, Ralph H.; GALLIA, Gary L.; BINDER, Zev A.; RIGGINS, Callen J.; SALMASI, Vafi; RIGGINS, Gregory J.; REITMAN, Zachary J.; RASHEED, Ahmed; KEIR, Stephen; SHINJO, Sueli; MARIE, Suely; MCLENDON, Roger; JALLO, George; VOGELSTEIN, Bert; BIGNER, Darell; YAN, Hai; KINZLER, Kenneth W.; PAPADOPOULOS, NickolasA heterogeneous population of uncommon neoplasms of the central nervous system (CNS) cause significant morbidity and mortality. To explore their genetic origins, we sequenced the exomes of 12 pleomorphic xanthoastrocytomas (PXA), 17 non-brainstem pediatric glioblastomas (PGBM), 8 intracranial ependymomas (IEP) and 8 spinal cord ependymomas (SCEP). Analysis of the mutational spectra revealed that the predominant single base pair substitution was a C: G>T: A transition in each of the four tumor types. Our data confirm the critical roles of several known driver genes within CNS neoplasms, including TP53 and ATRX in PGBM, and NF2 in SCEPs. Additionally, we show that activating BRAF mutations play a central role in both low and high grade glial tumors. Furthermore, alterations in genes coding for members of the mammalian target of rapamycin (mTOR) pathway were observed in 33% of PXA. Our study supports the hypothesis that pathologically similar tumors arising in different age groups and from different compartments may represent distinct disease processes with varied genetic composition.- Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival(2015) LOPES, M. H.; SANTOS, T. G.; RODRIGUES, B. R.; QUEIROZ-HAZARBASSANOV, N.; CUNHA, I. W.; WASILEWSKA-SAMPAIO, A. P.; COSTA-SILVA, B.; MARCHI, F. A.; BLEGGI-TORRES, L. F.; SANEMATSU, P. I.; SUZUKI, S. H.; OBA-SHINJO, S. M.; MARIE, S. K. N.; TOULMIN, E.; HILL, A. F.; MARTINS, V. R.Glioblastomas (GBMs) are resistant to current therapy protocols and identification of molecules that target these tumors is crucial. Interaction of secreted heat-shock protein 70 (Hsp70)-Hsp90-organizing protein (HOP) with cellular prion protein (PrPC) triggers a large number of trophic effects in the nervous system. We found that both PrPC and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I-III. High levels of PrPC and HOP were associated with greater GBM proliferation and lower patient survival. HOP-PrPC binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrPC binding site (HOP230-245) abrogates this effect. PrPC knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP230-245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP230-245 peptide inhibited tumor growth, maintained cognitive performance and improved survival. Thus, together, the present results indicate that interfering with PrPC-HOP engagement is a promising approach for GBM therapy.
- Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer(2019) Tu Nguyen; KIRSCH, Brian James; ASAKA, Ryoichi; NABI, Karim; QUINONES, Addison; TAN, Jessica; ANTONIO, Marjorie Justine; CAMELO, Felipe; LI, Ting; NGUYEN, Stephanie; Giang Hoang; Kiet Nguyen; UDUPA, Sunag; SAZEIDES, Christos; SHEN, Yao-An; ELGOGARY, Amira; REYES, Juvenal; ZHAO, Liang; KLEENSANG, Andre; CHAICHANA, Kaisorn Lee; HARTUNG, Thomas; BETENBAUGH, Michael J.; MARIE, Suely K.; JUNG, Jin G.; WANG, Tian-Li; GABRIELSON, Edward; LE, AnneN-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetylaspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest thatNAAGserves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.
- ATRX-DAXX Complex Expression Levels and Telomere Length in Normal Young and Elder Autopsy Human Brains(2019) CAVALCANTE, Stella G.; SILVA, Clarisse P. N.; SOLA, Paula R.; TANAKA, Leonardo Y.; OBA-SHINJO, Sueli M.; MARIE, Suely K. N.The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.
- Adult stem cells in neural repair: Current options, limitations and perspectives(2015) MARIANO, Eric Domingos; TEIXEIRA, Manoel Jacobsen; MARIE, Suely Kazue Nagahashi; LEPSKI, GuilhermeStem cells represent a promising step for the future of regenerative medicine. As they are able to differentiate into any cell type, tissue or organ, these cells are great candidates for treatments against the worst diseases that defy doctors and researchers around the world. Stem cells can be divided into three main groups: (1) embryonic stem cells; (2) fetal stem cells; and (3) adult stem cells. In terms of their capacity for proliferation, stem cells are also classified as totipotent, pluripotent or multipotent. Adult stem cells, also known as somatic cells, are found in various regions of the adult organism, such as bone marrow, skin, eyes, viscera and brain. They can differentiate into unipotent cells of the residing tissue, generally for the purpose of repair. These cells represent an excellent choice in regenerative medicine, every patient can be a donor of adult stem cells to provide a more customized and efficient therapy against various diseases, in other words, they allow the opportunity of autologous transplantation. But in order to start clinical trials and achieve great results, we need to understand how these cells interact with the host tissue, how they can manipulate or be manipulated by the microenvironment where they will be transplanted and for how long they can maintain their multipotent state to provide a full regeneration.
article 14 Citação(ões) na Scopus Morphometric analyses of normal pediatric brachial biceps and quadriceps muscle tissue(2013) SALLUM, Adriana M. E.; VARSANI, Hemlata; HOLTON, Janice L.; MARIE, Suely K. N.; WEDDERBURN, Lucy R.Pediatric normal brachial biceps (14 specimens) and quadriceps muscles (14 specimens) were studied by immunohistochemistry to quantify fiber-type, diameter and distribution, capillary density, presence of inflammatory cells (CD3, CD20, CD68) and expression of neonatal myosin and MHC class 1 proteins. Brachial biceps showed more fast-twitch fibers and lower capillary/fiber ratio than quadriceps. The mean diameter of both fiber types was smaller in biceps than quadriceps. Fast-fibers were smaller than slow-fibers, and capillary/fiber ratio was <1.0 in both muscles. Fiber size and capillary / fiber ratio increased with age. Normal limits for infiltrating haematopoietic cells were <4 T lymphocytes, or CD68+ cells, very few B cells, <6 neonatal myosin positive fibers, and no fibers MHC class 1 positive in one x20 field, for both muscles. The present comparison of quantitative findings between brachial biceps and quadriceps may allow standardization of the assessment of pathological changes in both pediatric muscles.conferenceObject Engagement of cellular prion and heat shock organizing protein as a novel therapeutic target for glioblastoma.(2012) LOPES, M. H.; QUEIROZ-HAZARBASSANOV, N. T.; RODRIGUES, B. R.; SANTOS, T. G.; CUNHA, I. W.; OBA-SHINJO, M.; MARIE, S. K.; MARTINS, V. R.