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1.
Extremophiles ; 25(5-6): 483-492, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34533626

RESUMO

Two extremely halophilic archaea, isolates SYSU A00711T and SYSU A00630, were isolated from a sediment soil sample collected from the Aiding lake, China. Cells of these isolates were cocci, non-motile and stained Gram-negative. They grew optimally at 37 °C, with 20-22% NaCl (w/v) and at pH 7.5-8.0. Cells lysed in distilled water. Major polar lipids were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, mannosyl glucosyl diether, sulfated mannosyl glucosyl diether, and two unidentified glycolipids. Pairwise sequence comparison revealed that isolates SYSU A00711T and SYSU A00630 were closely related to Halegenticoccus soli SYSU A9-0T (94.1 and 94.0% 16S rRNA gene sequence similarities; 94.0 and 94.2% rpoB' gene similarities, respectively). The overall genomic relatedness indices values between the two isolates and Halegenticocus soli SYSU A9-0 T were: AAI, both 79.6%; ANI, 84.6 and 84.5%; dDDH, 32.5 and 26.3%, respectively. Phylogenetic trees based on the 16S rRNA gene, rpoB' gene, and genome sequences demonstrated a robust clade of these two isolates with Halegenticoccus soli SYSU A9-0T. The DNA G + C contents of these two isolates are both 64.7% (genome method). Based on the differences in phenotypic, chemotaxonomic, and phylogenetic properties, isolates SYSU A00711T and SYSU A00630 are characterized to represent a novel species in the genus Halegenticoccus, for which the name Halegenticoccus tardaugens sp. nov. is proposed. The type strain of the species Halegenticoccus tardaugens is SYSU A00711T (= KCTC 4245T = CGMCC 1.15768T).


Assuntos
Halobacteriaceae , Solo , China , DNA Arqueal , Halobacteriaceae/genética , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
2.
Acta Pharmacol Sin ; 42(11): 1860-1874, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34363007

RESUMO

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and 95% of patients die within 2 years after diagnosis. In this study, aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ), we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy. To accelerate the drug's clinical application, we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors. After screening a set of 93 FDA-approved drugs with simple structures, we identified pimavanserin tartrate (PIM), an effective 5-HT2A receptor inverse agonist used for the treatment of Parkinson's disease-associated psychiatric symptoms, as having the most potent inhibitory activity against the NFAT signaling pathway. Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity. In cellula, PIM significantly suppressed the proliferation, migration, division, and motility of U87 glioblastoma cells, induced G1/S phase arrest and promoted apoptosis. In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM's antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM's side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.


Assuntos
Neoplasias Encefálicas/metabolismo , Inibidores de Calcineurina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Glioblastoma/metabolismo , Fatores de Transcrição NFATC/metabolismo , Piperidinas/farmacologia , Ureia/análogos & derivados , Animais , Neoplasias Encefálicas/tratamento farmacológico , Calcineurina/metabolismo , Inibidores de Calcineurina/uso terapêutico , Sinalização do Cálcio/fisiologia , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Glioblastoma/tratamento farmacológico , Células HeLa , Humanos , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fatores de Transcrição NFATC/antagonistas & inibidores , Piperidinas/uso terapêutico , Ureia/farmacologia , Ureia/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(4): 1018-1025, 2024 Aug.
Artigo em Zh | MEDLINE | ID: mdl-39192392

RESUMO

OBJECTIVE: To investigate the expression level, clinical significance and function of circular RNAs (circRNAs) circ_0073585 in the bone marrow of patients with acute myeloid leukemia (AML). METHODS: The expression levels of circ_0073585 in bone marrow samples of 106 newly diagnosed AML patients and 38 controls were detected by real-time quantitative PCR (RQ-PCR). The differences were compared between the two groups and their clinical significance was analyzed. The diagnostic value of circ_0073585 expression for AML was evaluated by receiver operating characteristic curve(ROC). THP-1 cells with lentivirus overexpressing circ_0073585 vector and empty vector were divided into two groups: circ_0073585-THP-1 and NC-THP-1 group. CCK-8 assay and flow cytometry were used to study the effects of circ_0073585 on THP-1 cell proliferation, survival, apoptosis and drug sensitivity. RESULTS: Compared with the controls, the expression level of circ_0073585 in the bone marrow of AML patients was significantly reduced (P < 0.001). There was a statistically significant difference between the high and low expression groups of circ_0073585 in the white blood cell count, platelet count (P < 0.01) and chromosome risk (P < 0.05). Compared with NC-THP-1 cells, the proliferation and viability of circ_0073585-THP-1 cells were weakened (P < 0.01), the apoptosis rate was increased (P < 0.01), and the sensitivity to homoharringtonine (P < 0.05) and daunorubicin hydrochloride (P < 0.001) was increased. CONCLUSION: The expression level of circ_0073585 is decreased in AML patients. Overexpression of circ_0073585 can inhibit the proliferation and viability of leukemic cells, promote apoptosis, and increase sensitivity of leukemia cells to chemotherapy drugs.


Assuntos
Apoptose , Proliferação de Células , Leucemia Mieloide Aguda , RNA Circular , Humanos , Leucemia Mieloide Aguda/genética , RNA Circular/genética , Medula Óssea/metabolismo , Células THP-1
5.
Acta Neurochir (Wien) ; 155(2): 335-41, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23238942

RESUMO

BACKGROUND: The occurrence of a contralateral acute epidural hematoma (AEDH) following removal of an acute subdural hematoma (ASDH) is a rare but nearly devastating postoperative complication. Here, we describe a series of five patients with contralateral AEDH and provide a review of the literature to elucidate the characteristics and improve management of these patients. METHODS: A total of 386 patients underwent ASDH evacuations in our hospital between August 2008 and July 2011. Five of these patients (1.3 %) developed AEDH that required surgery. Thirty-two additional patients were identified by a search of the PubMed database. Clinical features, surgical treatment, and outcomes (scored by Glasgow outcome scale, GOS) of the collective 37 AEDH cases were analyzed retrospectively. RESULTS: Contralateral AEDH after ASDH evacuation occurred in 27 males (73 %) and 10 females (27 %) (mean age: 35.9 ± 14.2 years). Twenty-six patients (70 %) had unfavorable outcomes (GOS 1-3), and 11 patients (30 %) had favorable outcomes (GOS 4-5). Contralateral skull fractures and intraoperative acute brain swelling occurred in 30 (81 %) and 28 (76 %) patients, respectively. The preoperative Glasgow coma score (GCS) was significantly associated with outcome (p < 0.05). CONCLUSIONS: Lower preoperative GCS score is an independent risk factor for prognosis of contralateral AEDH after ASDH. Postoperative management should include assessment of AEDH in patients treated for contralateral skull fractures and who experienced intraoperative acute brain swelling. We recommend early decompression with a burr-hole craniotomy, immediately followed by a decompressive craniectomy. This strategy provides gradual decompression, while advancing the initial surgical time and preventing the suddle decreased tamponade effect. As such, it may help decrease the risk of contralateral AEDH associated with decompression.


Assuntos
Craniectomia Descompressiva , Hematoma Epidural Craniano/cirurgia , Hematoma Subdural Agudo/cirurgia , Complicações Pós-Operatórias , Adulto , Feminino , Escala de Coma de Glasgow , Escala de Resultado de Glasgow , Hematoma Epidural Craniano/diagnóstico , Hematoma Epidural Craniano/etiologia , Hematoma Subdural Agudo/complicações , Hematoma Subdural Agudo/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Mol Cancer ; 10: 82, 2011 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-21749705

RESUMO

BACKGROUND: Overexpression of the RON receptor tyrosine kinase contributes to epithelial cell transformation, malignant progression, and acquired drug resistance. RON also has been considered as a potential target for therapeutic intervention. This study determines biochemical features and inhibitory activity of a mouse monoclonal antibody (mAb) Zt/f2 in experimental cancer therapy. RESULTS: Zt/f2 is a mouse IgG2a mAb that is highly specific and sensitive to human RON and its oncogenic variants such as RON160 (ED(50) = 2.3 nmol/L). Receptor binding studies revealed that Zt/f2 interacts with an epitope(s) located in a 49 amino acid sequence coded by exon 11 in the RON ß-chain extracellular sequences. This sequence is critical in regulating RON maturation and phosphorylation. Zt/f2 did not compete with ligand macrophage-stimulating protein for binding to RON; however, its engagement effectively induced RON internalization, which diminishes RON expression and impairs downstream signaling activation. These biochemical features provide the cellular basis for the use of Zt/f2 to inhibit tumor growth in animal model. Repeated administration of Zt/f2 as a single agent into Balb/c mice results in partial inhibition of tumor growth caused by transformed NIH-3T3 cells expressing oncogenic RON160. Colon cancer HT-29 cell-mediated tumor growth in athymic nude mice also was attenuated following Zt/f2 treatment. In both cases, ~50% inhibition of tumor growth as measured by tumor volume was achieved. Moreover, Zt/f2 in combination with 5-fluorouracil showed an enhanced inhibition effect of ~80% on HT-29 cell-mediated tumor growth in vivo. CONCLUSIONS: Zt/f2 is a potential therapeutic mAb capable of inhibiting RON-mediated oncogenesis by colon cancer cells in animal models. The inhibitory effect of Zt/f2 in vivo in combination with chemoagent 5-fluorouracil could represent a novel strategy for future colon cancer therapy.


Assuntos
Adenocarcinoma/patologia , Anticorpos Monoclonais/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/imunologia , Células 3T3 , Adenocarcinoma/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos , Terapia de Alvo Molecular , Células NIH 3T3 , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mol Cancer ; 10: 66, 2011 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-21619683

RESUMO

BACKGROUND: Epithelial to mesenchymal transition (EMT) occurs during cancer cell invasion and malignant metastasis. Features of EMT include spindle-like cell morphology, loss of epithelial cellular markers and gain of mesenchymal phenotype. Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein (MSP) has been implicated in cellular EMT program; however, the major signaling determinant(s) responsible for MSP-induced EMT is unknown. RESULTS: The study presented here demonstrates that RSK2, a downstream signaling protein of the Ras-Erk1/2 pathway, is the principal molecule that links MSP-activated RON signaling to complete EMT. Using MDCK cells expressing RON as a model, a spindle-shape based screen was conducted, which identifies RSK2 among various intracellular proteins as a potential signaling molecule responsible for MSP-induced EMT. MSP stimulation dissociated RSK2 with Erk1/2 and promoted RSK2 nuclear translocation. MSP strongly induced RSK2 phosphorylation in a dose-dependent manner. These effects relied on RON and Erk1/2 phosphorylation, which is significantly potentiated by transforming growth factor (TGF)-ß1, an EMT-inducing cytokine. Specific RSK inhibitor SL0101 completely prevented MSP-induced RSK phosphorylation, which results in inhibition of MSP-induced spindle-like morphology and suppression of cell migration associated with EMT. In HT-29 cancer cells that barely express RSK2, forced RSK2 expression results in EMT-like phenotype upon MSP stimulation. Moreover, specific siRNA-mediated silencing of RSK2 but not RSK1 in L3.6pl pancreatic cancer cells significantly inhibited MSP-induced EMT-like phenotype and cell migration. CONCLUSIONS: MSP-induced RSK2 activation is a critical determinant linking RON signaling to cellular EMT program. Inhibition of RSK2 activity may provide a therapeutic opportunity for blocking RON-mediated cancer cell migration and subsequent invasion.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Cães , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HT29 , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Fator de Crescimento Transformador beta1/farmacologia
8.
Mol Pharm ; 8(6): 2310-9, 2011 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-22014215

RESUMO

Cancer stem cells (CSCs) contribute to pancreatic cancer tumorigenesis through tumor initiation, drug resistance, and metastasis. Currently, therapeutics targeting pancreatic CSCs are under intensive investigation. This study tested a novel strategy that utilizes the RON receptor as a drug delivery moiety for increased therapeutic activity against pancreatic CSCs. CD24(+)CD44(+)ESA(+) triple-positive pancreatic CSCs (CSCs(+24/44/ESA)) were obtained from spheroids of pancreatic L3.6pl cancer cells by sequential magnetic cell sorting methods. These cells displayed a spherical growth pattern, expressed the unique self-renewal marker Bmi-1, redifferentiated into an epithelial phenotype, acquired an epithelial to mesenchymal phenotype, and caused tumor formation in animal models. Among several receptor tyrosine kinases examined, RON was highly expressed and sustained by CSCs(+24/44/ESA). This feature provided the cellular basis for validating the therapeutic effectiveness of anti-RON antibody Zt/c9-directing doxorubicin-immunoliposomes (Zt/c9-Dox-IL). Zt/c9-Dox-IL specifically interacted with CSCs(+24/44/ESA) and rapidly caused RON internalization, which led to the uptake of liposome-coated Dox. Moreover, Zt/c9-Dox-IL was effective in reducing viability of L3.6pl cells and CSCs(+24/44/ESA). The IC(50) values between free Dox (62.0 ± 3.1 µM) and Zt/c9-Dox-IL (95.0 ± 6.1 µM) treated CSCs(+24/44/ESA) were at relatively comparable levels. In addition, Zt/c9-Dox-IL in combination with small molecule inhibitors lapatinib, sunitinib, or dasatinib further reduced the viability of CSCs(+24/44/ESA). In conclusion, RON expression by CSCs(+24/44/ESA) is a suitable molecule for the targeted delivery of chemoagents. The anti-RON antibody-directed delivery of chemotherapeutics is effective in reducing viability of pancreatic CSCs.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/enzimologia , Receptores Proteína Tirosina Quinases/metabolismo , Anticorpos Monoclonais , Diferenciação Celular , Linhagem Celular Tumoral , Imunofluorescência , Humanos
9.
Mol Cancer ; 9: 307, 2010 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-21114864

RESUMO

BACKGROUND: Activation of the RON receptor tyrosine kinase, a member of the c-MET family, regulates tumorigenic phenotypes. The RON extracellular domains are critical in regulating these activities. The objective of this study was to determine the role of the first IPT domain in regulating RON-mediated tumorigenic activities and the underlying mechanisms. RESULTS: Two RON variants, RON160 and RONE5/6in with deletion and insertion in the first IPT domain, respectively, were molecularly cloned. RON160 was a splicing variant generated by deletion of 109 amino acids encoded by exons 5 and 6. In contrast, RONE5/6in was derived from a transcript with an insertion of 20 amino acids between exons 5 and 6. Both RON160 and RONE5/6in were proteolytically matured into two-chain receptor and expressed on the cell surface. RON160 was constitutively active with tyrosine phosphorylation. However, activation of RONE5/6in required ligand stimulation. Deletion resulted in the resistance of RON160 to proteolytic digestion by cell associated trypsin-like enzymes. RON160 also resisted anti-RON antibody-induced receptor internalization. These features contributed to sustained intracellular signaling cascades. On the other hand, RONE5/6in was highly susceptible to protease digestion, which led to formation of a truncated variant known as RONp110. RONE5/6in also underwent rapid internalization upon anti-RON antibody treatment, which led to signaling attenuation. Although ligand-induced activation of RONE5/6in partially caused epithelial to mesenchymal transition (EMT), it was RON160 that showed cell-transforming activities in cell focus formation and anchorage-independent growth. RON160-mediated EMT is also associated with increased motile/invasive activity. CONCLUSIONS: Alterations in the first IPT domain in extracellular region differentially regulate RON mediated tumorigenic activities. Deletion of the first IPT results in formation of oncogenic variant RON160. Enhanced degradation and internalization with attenuated signaling cascades could be the mechanisms underlying non-tumorigenic features of RONE5/6in.


Assuntos
Mutagênese Insercional/métodos , Receptores Proteína Tirosina Quinases/metabolismo , Deleção de Sequência/genética , Animais , Western Blotting , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Neoplasias do Colo/enzimologia , Cães , Humanos , Imunoprecipitação , Camundongos , Células NIH 3T3 , Neoplasias Pancreáticas/enzimologia , Fosforilação , RNA Mensageiro , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
10.
Acta Pharmacol Sin ; 31(9): 1181-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20694025

RESUMO

Products of proto-oncogenes c-MET and RON belong to a subfamily of receptor tyrosine kinases that contribute significantly to tumorigenic progression. In primary tumors, altered c-MET/RON expression transduces signals regulating invasive growth that is characterized by cell migration and matrix invasion. These pathogenic features provide the basis for targeting c-MET/RON in cancer therapy. In the last decade, various approaches have been investigated to suppress c-MET/RON-transduced oncogenesis. Among the therapeutics developed, monoclonal antibodies (mAbs) and small-molecule inhibitors (SMIs) have emerged as promising candidates. The mechanism of these therapeutic candidates is the disruption of tumor dependency on c-MET/RON signals for survival. The mAbs specific to hepatocyte growth factor (AMG102) and c-MET (MetMAb) are both humanized and able to block c-MET signaling, leading to inhibition of tumor cell proliferation in vitro and inhibition of tumor growth in xenograft models. The mAb AMG102 neutralizes hepatocyte growth factor and enhances the cytotoxicity of various chemotherapeutics to tumors in vivo. AMG102 is currently in phase II clinical trials for patients with advanced solid tumors. IMC-41A40 and Zt/f2 are RON-specific mAbs that down-regulate RON expression and inhibit ligand-induced phosphorylation. Both mAbs inhibit tumor growth in mice mediated by colon and pancreatic cancer cells. SMIs specific to c-MET (ARQ107 and PF-02341066) are in various phases of clinical trials. Therapeutic efficacy has also been observed with dual inhibitors such as Compound I, which is specific to c-MET/RON. However, a potential issue is the emergence of acquired resistance to these inhibitors. Clearly, development of c-MET/RON therapeutics provides opportunities and challenges for combating cancer in the future.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Anticorpos Monoclonais/imunologia , Humanos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/imunologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/imunologia , Transdução de Sinais/efeitos dos fármacos
11.
Int J Neurosci ; 119(9): 1494-506, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19922369

RESUMO

Perhaps the most difficult practical decision for neurosurgeons these days is whether to secure aneurysms during the intermediate period (4-10 days) after aneurysmal subarachnoid hemorrhage (SAH). We reviewed retrospectively a series of 115 patients with a Hunt-Hess grade I-III upon admission who were admitted 4-10 days after initial supratentorial aneurysmal SAH. Patients who underwent active treatment in the intermediate period were assigned to the intermediate group (n = 49), while those who accepted delayed obliteration of a ruptured aneurysm (11-30 days) were assigned to the late group (n = 66). The demographic characteristics, size and site of aneurysms, and clinical conditions were well balanced in the two groups. There was no difference in outcome between the two groups according to the Glasgow Outcome Scale (GOS) at discharge or a 6-month follow-up. Rebleeding before aneurysms obliteration was the leading factor resulting in poor outcome. In conclusion, for patients with supratentorial aneurysmal SAH who were in good clinical condition upon admission, active treatment during the intermediate period offered a good chance for a favorable outcome. An even larger number of patients from randomized clinical trials might be necessary to draw more reliable conclusions.


Assuntos
Hemorragia Subaracnóidea/cirurgia , Idoso , Aneurisma Roto/cirurgia , Angiografia Digital , Isquemia Encefálica/cirurgia , Isquemia Encefálica/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
Int J Neurosci ; 119(10): 1956-67, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19922395

RESUMO

Perhaps the most difficult practical decision for neurosurgeons these days is whether to secure aneurysms during the intermediate period (4-10 days) after aneurysmal subarachnoid hemorrhage (SAH). We retrospectively reviewed a series of 115 patients with a Hunt-Hess grade I-III upon admission who were admitted 4-10 days after initial supratentorial aneurysmal SAH. Patients who underwent active treatment in the intermediate period were assigned to the intermediate group (n = 49) while those who accepted delayed obliteration of a ruptured aneurysm (11-30 days) were assigned to the late group (n = 66). The demographic characteristics, size and site of aneurysms, and clinical conditions were well balanced in the two groups. There was no difference in outcome between the two groups according to the Glasgow Outcome Scale (GOS) at discharge or a six-month follow-up. Rebleeding before aneurysms obliteration was the leading factor resulting in poor outcome. In conclusion, for patients with supratentorial aneurysmal SAH who were in good clinical condition upon admission, active treatment during the intermediate period offered a good chance of a favorable outcome. An even larger number of patients from randomized clinical trials might be necessary to draw more reliable conclusions.


Assuntos
Aneurisma Roto/etiologia , Revascularização Cerebral/métodos , Complicações Pós-Operatórias/fisiopatologia , Hemorragia Subaracnóidea/cirurgia , Adulto , Idoso , Aneurisma Roto/fisiopatologia , Angiografia Digital , Feminino , Seguimentos , Escala de Resultado de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/patologia , Fatores de Tempo , Tomografia , Resultado do Tratamento
13.
Hepatobiliary Pancreat Dis Int ; 7(5): 551-4, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18842507

RESUMO

BACKGROUND: Posttransplantation lymphoproliferative disorder (PTLD) involving the central nervous system (CNS) is a rare and serious complication associated with solid organ transplantation. We treated a case of PTLD with CNS involvement in a liver transplant recipient and reviewed the literature. METHOD: The clinicopathological features of a 53-year-old man were retrospectively analyzed. RESULTS: Metastasis of the hepatoma was preoperatively considered on the basis of clinical findings. Craniotomy was performed and PTLD was diagnosed pathologically. The patient was treated with antiviral agents, radiation therapy, and chemotherapy; the immunosuppressive medication was reduced. The patient is still alive after follow-up for 14 months. CONCLUSIONS: Definitive diagnosis of PTLD is only established on the basis of histopathologic evaluation of the tissue. Although there are several ways to manage PTLD with CNS involvement, the prognosis is still poor.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Imunossupressores/efeitos adversos , Transplante de Fígado/efeitos adversos , Linfoma Difuso de Grandes Células B/patologia , Antivirais/uso terapêutico , Biópsia , Carcinoma Hepatocelular/cirurgia , Neoplasias do Sistema Nervoso Central/etiologia , Neoplasias do Sistema Nervoso Central/terapia , Quimioterapia Adjuvante , Cefaleia/etiologia , Cefaleia/patologia , Humanos , Neoplasias Hepáticas/cirurgia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/terapia , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Radioterapia Adjuvante , Resultado do Tratamento
14.
World J Gastroenterol ; 12(42): 6884-8, 2006 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-17106942

RESUMO

AIM: To study the effect of albumin administration on lung injury in trauma/hemorrhagic shock (T/HS). METHODS: Sixty experimental animals were randomly divided into three groups: rats undergoing laparotomy without shock (T/SS); rats with T/HS and resuscitation with blood plus twice the volume of shed blood as Ringer's lactate (RL), and rats with T/HS and resuscitation with blood plus additional 3 mL of 50 g/L human albumin. Expression of polymorphonuclear neutrophil (PMN) CD11b/CD18, intercellular adhesion molecule-1 (ICAM-1) of jugular vein blood and the severity of lung injuries [determined mainly by measuring activity of lung tissue myeloperoxidase (MPO) and lung injury score (LIS)] were measured after a 3-h recovery period. RESULTS: All three groups showed a significant difference in the expressions of CD11b/CD18, ICAM-1, and severity of lung injury. The expressions of CD11b/CD18 in T/SS group, T/HS + RL group, T/HS + albumin group were 17.76% +/- 2.11%, 31.25% +/- 3.48%, 20.36% +/- 3.21%, respectively (F = 6.25, P < 0.05). The expressions of ICAM-1 (U/mL) in T/SS group, T/HS + RL group, T/HS + albumin group were 258.76 +/- 98.23, 356.23 +/- 65.6, 301.01 +/- 63.21, respectively (F = 5.86, P < 0.05). The expressions of MPO (U/g) in T/SS group, T/HS + RL group, T/HS + albumin group were 2.53 +/- 0.11, 4.63 +/- 1.31, 4.26 +/- 1.12, respectively (F = 6.26, P < 0.05). Moreover, LIS in T/HS + RL group, T/HS + albumin group was 2.62 +/- 0.23, 1.25 +/- 0.24, respectively. The expressions of CD11b/CD18, ICAM-1 and MPO in T/HS + RL group were significantly increased compared to T/SS group (P = 0.025, P = 0.036, P = 0.028, respectively). However, administration of 3 mL of 50 g/L albumin significantly down-regulated the expressions of CD11b/CD18, ICAM-1 and lung injury index (MPO and LIS) when compared with the T/HS + RL rats (P = 0.035, P = 0.046, P = 0.038, P = 0.012, respectively). CONCLUSION: The infusion of albumin during resuscitation period can protect lung from injury and decrease the expressions of CD11b/CD18, ICAM-1 in T/HS rats.


Assuntos
Albuminas/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/etiologia , Choque Hemorrágico/complicações , Ferimentos e Lesões/complicações , Albuminas/farmacologia , Animais , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Antígenos CD18/genética , Antígenos CD18/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Lesão Pulmonar , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Peroxidase/genética , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório/prevenção & controle
15.
J Exp Clin Cancer Res ; 35: 70, 2016 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-27102688

RESUMO

BACKGROUND: Aberrant expression of the RON receptor tyrosine kinase, a member of the MET proto-oncogene family, in breast cancer and non-small cell lung cancer (NSCLC) has therapeutic implication. Here we evaluated the efficacy of a novel anti-RON antibody-drug maytansinoid conjugate Zt/g4-DM1 for treatment of breast and NSCLC xenograft tumors in mouse models and explored a treatment strategy by combination of Zt/g4-DM1 with chemotherapeutics to achieve the maximal therapeutic activity. METHODS: Mouse monoclonal antibody Zt/g4 (IgG1a/κ) specific to human RON was conjugated to DM1 via thioether linkage to form Zt/g4-DM1 with a drug-antibody ratio of 4:1. Several breast cancer and NSCLC cell lines, expressing different levels of RON, were used as the model. Immunofluorescence was used to determine Zt/g4-induced RON internalization. Flow cytometric analysis and cell viability assay were used to determine the effect of Zt-g4-DM1 on cell cycle and death. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of Zt/g4-DM1 alone or in combination with chemotherapeutics. RESULTS: In vitro, Zt/g4 treatment of breast cancer and NSCLC cells rapidly induced cell surface RON internalization, which results in intracellular delivery of DM1 sufficient to arrest cell cycle at G2/M phase, reduce cell viability, and cause massive cell death. In mouse tumor xenograft models, Zt/g4-DM1 at 20 mg/kg in a Q12 × 2 regimen effectively blocked breast cancer and NSCLC cell- mediated tumor growth. More than 95% inhibition of tumor growth among three tumor xenograft models tested was achieved according to the measured tumor volume. The minimal dose to balance the tumor growth and inhibition (tumoristatic concentration) was established at 2.02 mg/kg for H2228, 1.94 mg/kg for H358 cell, and 6.25 mg/kg for T-47D cell-mediated xenograft tumors. CONCLUSION: Zt/g4 is highly effective in RON-directed drug delivery for targeted inhibition of NSCLC cell-derived tumor growth in mouse xenograft models. This work provides the basis for clinical development of humanized Zt/g4-DM1 for potential cancer therapy in the future.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Maitansina/análogos & derivados , Terapia de Alvo Molecular/métodos , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Maitansina/administração & dosagem , Maitansina/farmacologia , Camundongos , Proto-Oncogene Mas , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Oncogene ; 21(41): 6382-6, 2002 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-12214279

RESUMO

RON, a member of the MET proto-oncogene family, has been implicated in the progression of certain epithelial cancers. The purpose of this study was to determine the oncogenic potential of RON in vivo in lung epithelial cells. Transgenic mice were established using surfactant protein C promoter to express human RON in the distal lung epithelial cells. These mice were born normal but developed multiple lung tumors with distinct morphology and growth patterns. Tumors appeared as a single mass in the lung around 2 months of age and gradually developed into multiple nodules located mostly in the peripheral portions of the lung. A transition from early adenomas to later adenocarcinomas was observed. Morphologically, tumors were characterized as cuboidal epithelial cells with a type II cell phenotype, grew along the alveolar walls, and projected into the alveolar septa. RON was highly expressed and constitutively activated in tumors. These results indicate that overexpression of human wild-type RON causes the formation of lung tumors with unique biological characteristics in vivo. This model provides opportunities to study the role of RON in the pathogenesis of lung tumors and to elucidate the mechanisms underlying this distinct lung tumor.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Pulmonares/etiologia , Receptores Proteína Tirosina Quinases/genética , Receptores de Superfície Celular/genética , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Camundongos , Camundongos Transgênicos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/biossíntese , Receptores de Superfície Celular/biossíntese , Transgenes
17.
Oncogene ; 22(2): 186-97, 2003 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-12527888

RESUMO

The RON receptor tyrosine kinase is a member of the MET proto-oncogene family that has been implicated in regulating motile-invasive phenotypes in certain types of epithelial cancers. The purpose of this study was to determine if RON expression is altered in primary human colorectal adenocarcinomas. Results from immunohistochemical staining showed that RON is highly expressed in the majority of colorectal adenocarcinomas (29/49 cases). Accumulated RON is also constitutively active with autophosphorylation in tyrosine residues. Moreover, three splicing variants of RON, namely RONdelta165, RONdelta160, and RONdelta155 were detected and cloned from two primary colon cancer samples. These RON variants were generated by deletions in different regions in extracellular domains of the RON beta chain. Functional studies showed that expression of RONdelta160 or RONdelta155 in Martin-Darby canine kidney cells resulted in increased cell dissociation (scatter-like activity). RON variants, RONdelta160 and RONdelta155, also exerted the ability to induce multiple focus formation and sustain anchorage-independent growth of transfected NIH3T3 cells. Moreover, NIH3T3 cells expressing RONdelta160 or RONdelta155 formed tumors in athymic nude mice and colonized in the lungs. These data suggest that RON expression is altered in certain primary colon cancers. Abnormal accumulation of RON variants may play a role in the progression of certain colorectal cancers in vivo.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Células 3T3/patologia , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Animais , Sequência de Bases , Testes de Carcinogenicidade , Transformação Celular Neoplásica , Células Cultivadas , Clonagem Molecular , Neoplasias Colorretais/genética , Feminino , Variação Genética , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proto-Oncogene Mas , Receptores Proteína Tirosina Quinases/genética , Receptores de Superfície Celular/genética , Valores de Referência
18.
Stroke ; 36(5): 1059-64, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15817890

RESUMO

BACKGROUND AND PURPOSE: The purpose of this study is to investigate whether apocynin, an NADPH oxidase inhibitor, attenuates vasospasm after experimental subarachnoid hemorrhage (SAH) in rats. METHODS: Rats were subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Beginning 2 hours after SAH, rats were administered 50 mg/kg apocynin or vehicle by intraperitoneal injection 3 times daily for 2 days. RESULTS: In SAH rats, apocynin treatment enlarged basilar artery diameter (SAH/apocynin=253+/-71 microm, SAH/saline=191+/-60 microm, P<0.01; SAH=190+/-58 microm, sham=276+/-52 microm, P<0.01), reduced neurological deficits (SAH/apocynin=24+/-6.5, SAH/saline=18+/-5.3, P<0.05; SAH=18+/-4.7, sham=27+/-0, P<0.01), decreased NADPH oxidase activity (SAH/apocynin=18.4+/-3.7, SAH/saline=25.7+/-5.2, P<0.05; SAH=27.5+/-5.8, sham=15.4+/-4.5 nmol/min per mg protein, P<0.05), decreased superoxide level (SAH/apocynin=6.5+/-1.8, SAH/saline=9.6+/-2.2, P<0.05; SAH=9.8+/-1.9, sham=4.9+/-0.9 arbitrary units, P<0.05), and lowered membrane translocation of NADPH oxidase subunit p47phox. CONCLUSIONS: Inhibition of NADPH oxidase attenuates delayed cerebral vasospasm after experimental SAH, suggesting that the inhibition of NADPH oxidase may provide a therapeutic strategy for vasospasm after SAH.


Assuntos
Acetofenonas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , NADPH Oxidases/antagonistas & inibidores , Hemorragia Subaracnóidea/complicações , Vasoespasmo Intracraniano/tratamento farmacológico , Animais , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/patologia , Masculino , Fosfoproteínas/metabolismo , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/metabolismo
19.
Brain Res Mol Brain Res ; 134(1): 155-61, 2005 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-15790539

RESUMO

Gene transfer of glial cell line-derived neurotrophic factor (GDNF) in rodent models of Parkinson's disease (PD) has been shown to protect against neurodegeneration either prior to or immediately after neurotoxin-induced lesions; however, the nigrostriatal pathway was largely intact when gene delivery was completed in these models, which may not accurately reflect the clinical situation encountered with Parkinson's patients. In this study, replication-incompetent adenoviral vectors encoding the rat GDNF gene were administered into the striatum 4 weeks following 6-hydroxydopamine (6-OHDA) injection in the unilateral striatum, more closely resembling fully developed PD. Apomorphine-induced rotational behavior testing was performed every week following 6-OHDA injection. At the 10th week after gene transfer, the striatal dopamine concentrations were measured by HPLC with an electrochemical detector and the number of tyrosine hydroxylase (TH)-positive dopamine neurons in the substantia nigra (SN) was determined by immunohistochemistry. Injection of 6-OHDA into the striatum produced stable increases in rotation, which reached a plateau between 4 and 5 weeks post-injection. The number of TH-positive neuron in the SN and dopamine levels in the striatum was significantly lower in the 6-OHDA group compared to the normal group. Gene transfer of GDNF, but not beta-galactosidase, significantly increased the number of TH-positive neurons and dopamine levels, with a subsequent behavioral recovery between 5 and 10 weeks following GDNF transduction. These findings demonstrate that adenovirus-mediated gene transfer of GDNF is efficacious even in the late stages of 6-OHDA-induced PD rats. They also provide further evidence on the effectiveness of GDNF-based gene therapy for experimental Parkinson's disease.


Assuntos
Terapia Genética/métodos , Fatores de Crescimento Neural/uso terapêutico , Doença de Parkinson/terapia , Adenoviridae/fisiologia , Adrenérgicos/administração & dosagem , Análise de Variância , Animais , Comportamento Animal , Contagem de Células/métodos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Vetores Genéticos/fisiologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Imuno-Histoquímica/métodos , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Fatores de Crescimento Neural/genética , Oxidopamina/administração & dosagem , Doença de Parkinson/etiologia , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod/métodos , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismo
20.
J Leukoc Biol ; 71(2): 359-66, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11818458

RESUMO

RON is a receptor tyrosine kinase activated by macrophage-stimulating protein. We demonstrate here that RON activation inhibits LPS-induced apoptosis of mouse peritoneal macrophages and Raw264.7 cells expressing RON or a constitutively active RON mutant. The antiapoptotic effect of RON was accompanied with the inhibition of LPS-induced production of nitric oxide (NO), a molecule responsible for LPS-induced cell apoptosis. This conclusion is supported by experiments using a chemical NO donor GSNO, in which RON activation directly blocked GSNO-induced apoptotic death of Raw264.7 cells and inhibited LPS-induced p53 accumulation. Furthermore, we showed that treatment of cells with wortmannin, which inhibits phosphatidylinositol (PI)-3 kinase, prevents the inhibitory effect of RON on LPS-induced macrophage apoptosis. These results were confirmed further by expression of a dominant inhibitory PI-3 kinase p85 subunit. These data suggest that by activating PI-3 kinase and inhibiting p53 accumulation, RON protects macrophage from apoptosis induced by LPS and NO. The antiapoptotic effect of RON might represent a novel mechanism for the survival of activated macrophages during inflammation.


Assuntos
Apoptose/fisiologia , Macrófagos Peritoneais/patologia , Macrófagos Peritoneais/fisiologia , Receptores Proteína Tirosina Quinases/fisiologia , Receptores de Superfície Celular/fisiologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C3H , Mutação , Transdução de Sinais/fisiologia
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