RESUMO
Deep space travel presents a number of measurable risks including exposure to a spectrum of radiations of varying qualities, termed galactic cosmic radiation (GCR) that are capable of penetrating the spacecraft, traversing through the body and impacting brain function. Using rodents, studies have reported that exposure to simulated GCR leads to cognitive impairments associated with changes in hippocampus function that can persist as long as one-year post exposure with no sign of recovery. Whether memory can be updated to incorporate new information in mice exposed to GCR is unknown. Further, mechanisms underlying long lasting impairments in cognitive function as a result of GCR exposure have yet to be defined. Here, we examined whether whole body exposure to simulated GCR using 6 ions and doses of 5 or 30 cGy interfered with the ability to update an existing memory or impact hippocampal synaptic plasticity, a cellular mechanism believed to underlie memory processes, by examining long term potentiation (LTP) in acute hippocampal slices from middle aged male mice 3.5-5 months after radiation exposure. Using a modified version of the hippocampus-dependent object location memory task developed by our lab termed "Objects in Updated Locations" (OUL) task we find that GCR exposure impaired hippocampus-dependent memory updating and hippocampal LTP 3.5-5 months after exposure. Further, we find that impairments in LTP are reversed through one-time systemic subcutaneous injection of the histone deacetylase 3 inhibitor RGFP 966 (10 mg/kg), suggesting that long lasting impairments in cognitive function may be mediated at least in part, through epigenetic mechanisms.
Assuntos
Hipocampo/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Acrilamidas/farmacologia , Animais , Radiação Cósmica , Hipocampo/efeitos da radiação , Histona Desacetilases , Masculino , Memória/efeitos da radiação , Camundongos , Plasticidade Neuronal/efeitos da radiação , Neurônios/efeitos da radiação , Fenilenodiaminas/farmacologia , Exposição à RadiaçãoRESUMO
Ahead of Print article withdrawn by publisher.
RESUMO
The aim of this study was to investigate the effect of local administration of odanacatib (ODN) on orthodontic root resorption and the status of alveolar bone metabolism in rat molars. All specimens were scanned using microcomputed tomography and then the raw images were reconstructed. The total volume of the root resorption craters of the 60 g-NS (normal saline) group was higher than in the 60 g-ODN group and the control group. In the 60 g-NS group, the bone volume fraction values of alveolar bone were significantly decreased compared with the other 2 groups. There were no significant differences in the bone volume fraction values of the tibiae among the 3 groups. The results of tartrate-resistant acid phosphatase-positive (TRAP+) numbers showed that there was no difference between the 60 g-NS group and the 60 g-ODN group. The expression of cathepsin K was decreased significantly in the 60 g-ODN group. These results indicate that ODN reduces orthodontics-induced external root resorption and increases alveolar bone metabolism. This may be because ODN inhibits the activity of odontoclasts, but maintains the quantity of odontoclasts and enhances bone formation. ODN promotes local alveolar bone metabolism, but does not affect systemic bone metabolism.
Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Compostos de Bifenilo/administração & dosagem , Osso e Ossos/metabolismo , Reabsorção da Raiz/tratamento farmacológico , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/patologia , Animais , Osso e Ossos/efeitos dos fármacos , Catepsina K/biossíntese , Humanos , Dente Molar/metabolismo , Dente Molar/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ratos , Reabsorção da Raiz/metabolismo , Reabsorção da Raiz/patologia , Técnicas de Movimentação Dentária , Microtomografia por Raio-XRESUMO
Epithelial-mesenchymal transition (EMT) induced by transforming growth factor-ß (TGF-ß) is implicated in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, which belongs to the CD147 family, is an HCC-associated antigen that has a crucial role in tumor invasion and metastasis. The goal of this study was to investigate the role of HAb18G/CD147 during EMT in hepatocarcinogenesis. Human normal hepatic cell lines QZG and L02, primary mouse hepatocytes and nude mouse models were used to determine the role of HAb18G/CD147 in EMT, and the involvement of the TGF-ß-driven pathway. A dual-luciferase reporter assay and ChIP were used to investigate the transcriptional regulation of the CD147 gene. Samples from patients with liver disease were assessed to determine the relationship between HAb18G/CD147 and typical markers for EMT. Our results show that upregulation of HAb18G/CD147 is induced by TGF-ß coupled with downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The expression of HAb18G/CD147 is controlled by the cell survival PI3K/Akt/GSK3ß signaling pathway, and is directly regulated by the transcription factor Slug. Transfection of CD147 also induces an elevated expression of TGF-ß. CD147-transfected hepatocytes have mesenchymal phenotypes that accelerate tumor formation and tumor metastasis in vivo. Immunohistochemistry analysis shows a negative correlation between HAb18G/CD147 and E-cadherin expression (r(s)=-0.3622, P=0.0105), and a positive correlation between HAb18G/CD147 and Slug expression (r(s)=0.3064, P=0.0323) in human HCC tissues. Our study uncovers a novel role of HAb18G/CD147 in mediating EMT in the process of HCC progression and showed that CD147 is a Slug target gene in the signaling cascade TGF-ßâPI3K/AktâGSK3ßâSnailâSlugâCD147. Our results suggest that CD147 may be a potential target for the treatment and prevention of HCC.
Assuntos
Basigina/metabolismo , Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Caderinas/metabolismo , Linhagem Celular , Transformação Celular Neoplásica , Progressão da Doença , Humanos , Camundongos , Camundongos Nus , Transdução de Sinais , Fatores de Transcrição da Família SnailRESUMO
Obtaining insight into microscopic cooperative effects is a fascinating topic in condensed matter research because, through self-coordination and collectivity, they can lead to instabilities with macroscopic impacts like phase transitions. We used femtosecond time- and angle-resolved photoelectron spectroscopy (trARPES) to optically pump and probe TbTe3, an excellent model system with which to study these effects. We drove a transient charge density wave melting, excited collective vibrations in TbTe3, and observed them through their time-, frequency-, and momentum-dependent influence on the electronic structure. We were able to identify the role of the observed collective vibration in the transition and to document the transition in real time. The information that we demonstrate as being accessible with trARPES will greatly enhance the understanding of all materials exhibiting collective phenomena.
RESUMO
We observe unidirectional charge density wave (CDW) ordering on the quasi-2D material TbTe3 with a scanning tunneling microscope at approximately 6 K. Our analysis indicates that the CDW is fully incommensurate, with wave vector qCDW approximately 0.71x2pi/c. By imaging at various tip-sample voltages, we highlight effects of the subsurface layer and its effect on the CDW. We also observe an additional (possibly surface) dimerization and approximately 0.68x2pi/a ordering perpendicular to the CDW.
RESUMO
We investigate the pressure dependence of the optical properties of CeTe3, which exhibits an incommensurate charge-density-wave (CDW) state already at 300 K. Our data are collected in the midinfrared spectral range at room temperature and at pressures between 0 and 9 GPa. The energy for the single particle excitation across the CDW gap decreases upon increasing the applied pressure, similarly to the chemical pressure by rare-earth substitution. The broadening of the bands upon lattice compression removes the perfect nesting condition of the Fermi surface and therefore diminishes the impact of the CDW transition on the electronic properties of RTe3.
RESUMO
CeTe3 is a layered compound where an incommensurate charge density wave (CDW) opens a large gap ( approximately 400 meV) in optimally nested regions of the Fermi surface (FS), whereas other sections with poorer nesting remain ungapped. Through angle-resolved photoemission, we identify bands backfolded according to the CDW periodicity. They define FS pockets formed by the intersection of the original FS and its CDW replica. Such pockets illustrate very directly the role of nesting in the CDW formation but they could not be detected so far in a CDW system. We address the reasons for the weak intensity of the folded bands, by comparing different foldings coexisting in CeTe3.
RESUMO
Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. Despite the tremendous efforts that have been made to improve the early detection of this disease and to design new treatment modalities, there is still an urgent need for new markers and therapeutic targets for the management of prostate cancer patients. Using differential display analysis to compare the mRNA expression patterns of normal versus tumor tissue of the human prostate, we identified a cDNA, DD3, which is highly overexpressed in 53 of 56 prostatic tumors in comparison to nonneoplastic prostatic tissue of the same patients. Reverse transcription-PCR analysis using DD3-specific primers indicated that the expression of DD3 is very prostate specific because no product could be amplified in 18 different normal human tissues studied. Also, in a sampling of other tumor types and a large number of cell lines, no expression of DD3 could be detected. Molecular characterization of the DD3 transcription unit revealed that alternative splicing and alternative polyadenylation occur. The fact that no extensive open reading frame could be found suggests that DD3 may function as a noncoding RNA. The DD3 gene was mapped to chromosome 9q21-22, and no homology of DD3 to any gene present in the computer databases was found. Our data indicate that DD3 is one of the most prostate cancer-specific genes yet described, and this makes DD3 a promising marker for the early diagnosis of prostate cancer and provides a powerful tool for the development of new treatment strategies for prostate cancer patients.
Assuntos
Cromossomos Humanos Par 9 , Regulação Neoplásica da Expressão Gênica , Próstata/metabolismo , Neoplasias da Próstata/genética , Transcrição Gênica , Sequência de Bases , Mapeamento Cromossômico , Éxons , Humanos , Íntrons , Cariotipagem , Masculino , Dados de Sequência Molecular , Neoplasias da Próstata/cirurgia , RNA Mensageiro/genética , Valores de Referência , Mapeamento por Restrição , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The p16 protein plays a key role in cell cycle control by preventing CDK4 from inactivating the retinoblastoma protein (pRb). The corresponding tumor suppressor gene (p16/MTS1/CDKN2) has recently been implicated in malignant progression of astrocytomas and could potentially serve as an important marker for patient prognosis and for guiding specific therapeutic strategies. We have undertaken a study to evaluate 2 methods of detecting p16 deletion. Thirty diffuse gliomas were analyzed for p16 gene dosage. Dual color fluorescence in situ hybridization (FISH) was performed on cytologic preparations using paired centromeric (CEN) and locus-specific probes for CEN9/p16, CEN8/RB, and CEN12/CDK4. Quantitative PCR was performed using primers for p16, MTAP, and reference genes. Eleven cases were also studied using comparative genomic hybridization (CGH). Abnormalities of the p16-CDK4-RB pathway were identified in 21 (70%) cases by FISH and/or PCR. These included 15 (50%) with p16 deletion, 9 of which were detected by both techniques, 3 by FISH alone, and 3 by PCR alone (concordance rate = 81%). FISH analysis further revealed tetraploidy/aneuploidy in 14 (47%), RB deletion in 11 (37%) and CDK4 amplification in 1 (3.3%). There were 94% and 100% concordance rates between CGH and FISH or PCR, respectively. Quantitative PCR was noninformative in 4 cases. Although FISH and quantitative PCR are both reliable techniques, each has limitations. PCR is likely to miss p16 deletions when there is significant normal cell contamination or clonal heterogeneity, whereas the p16 YAC probe used for FISH analysis may miss small deletions. Replacement of the latter with a cosmid probe may improve the sensitivity of FISH in future experiments.
Assuntos
Neoplasias Encefálicas/genética , Proteínas de Transporte/genética , Deleção de Genes , Glioma/genética , Inibidor p16 de Quinase Dependente de Ciclina , Humanos , Hibridização in Situ Fluorescente , Hibridização de Ácido Nucleico , Reação em Cadeia da PolimeraseRESUMO
Considerable evidence now exists to support an important role for the E-cadherin-mediated cell-cell adhesion pathway as a suppressor of the invasive phenotype in adenocarcinoma cells. Previous studies have found that this pathway is frequently aberrant in prostate cancers, particularly those that are likely to metastasize. In this study, we report on the effects of re-establishment of this pathway in a prostate cancer cell line, PC-3, in which this adhesion system is dysfunctional by virtue of a deletion of the gene that codes for alpha-catenin, an E-cadherin-associated protein necessary for normal E-cadherin function. Re-expression of alpha-catenin was accomplished either by transfection of PC-3 cells with a copy of the alpha-catenin cDNA under the control of a heterologous promoter or by microcell-mediated transfer of chromosome 5, which contains the alpha-catenin gene and its normal regulatory elements. In both cases, re-expression of alpha-catenin is associated with a similar, dramatic alteration in cell morphology, whereby extensive cell-cell contact is observed. In the case of transfection of the cDNA, this expression is only transient, because the transfected cells either cease to proliferate or, more commonly, revert to the parental phenotype with concomitant cessation of alpha-catenin expression. In contrast, cells containing one or more copies of microcell-transferred chromosome 5 express alpha-catenin in a stable manner and continue to proliferate. Upon injection into nude mice, these latter cells are no longer tumorigenic, or form only slowly growing tumors with greatly extended doubling times when compared to the parental PC-3 cells. During passage in culture, clones that contain only one transferred copy of chromosome 5 reproducibly revert to the parental phenotype. This reversion is associated with loss of the chromosome 5 region containing the alpha-catenin gene and consequent loss of alpha-catenin expression, as well as re-emergence of tumorigenicity. Transfer of chromosome 5 into prostate cancer cells that are E-cadherin negative does not result in either morphological transformation or suppression of tumorigenicity, suggesting that these effects of alpha-catenin expression are dependent upon concomitant expression of E-cadherin. These data demonstrate the tumor suppressive ability of chromosome 5 in the PC-3 prostate cancer cells and suggest that re-expression of alpha-catenin with resultant restoration of E-cadherin function plays a critical role in this process.
Assuntos
Caderinas/fisiologia , Cromossomos Humanos Par 5 , Proteínas do Citoesqueleto/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Adesão Celular/fisiologia , Comunicação Celular/fisiologia , Divisão Celular/fisiologia , Proteínas do Citoesqueleto/fisiologia , DNA/genética , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Fenótipo , Transfecção , Células Tumorais Cultivadas , alfa CateninaRESUMO
Metastasis suppressor activities have previously been mapped to human chromosomes 17 and 11. Decreased expression of the metastasis suppressor gene NM23, which is located on chromosome 17, has been correlated with increased metastatic potential in mammary cancers. A region on human chromosome 11, from 11p11.2-p13, has been shown to suppress metastasis in rat prostatic carcinoma cells. In both cases the metastasis suppressor activity had no effect on tumorigenicity or tumor growth rate, demonstrating that the encoded activities are distinct from effects of tumor suppression. To determine whether these human chromosomes encode general or tissue-specific metastasis suppressor activities, a truncated human chromosome 17 (i.e., pter-q23) and a full-length human chromosome 11 were separately transferred into highly metastatic rat mammary and prostate cancer cell lines and tested for their ability to suppress spontaneous metastasis in vivo. These studies demonstrated that when the pter-q23 region of human chromosome 17 is retained by the microcell hybrids, the metastatic ability of both mammary and prostatic cancer cells is suppressed. In contrast, when the pter-q14 region of human chromosome 11 is retained, only the metastatic ability of prostatic cancer cells is suppressed. Additional studies demonstrated that the metastasis suppressor activity encoded by the chromosome 17 pter-q23 region is p53-independent and not due to enhanced expression of NM23 protein.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 17 , Neoplasias Mamárias Experimentais/patologia , Proteínas Monoméricas de Ligação ao GTP , Metástase Neoplásica/prevenção & controle , Núcleosídeo-Difosfato Quinase , Neoplasias da Próstata/patologia , Fatores de Transcrição/genética , Animais , Feminino , Genes p53/fisiologia , Humanos , Masculino , Nucleosídeo NM23 Difosfato Quinases , Metástase Neoplásica/genética , Ratos , Células Tumorais CultivadasRESUMO
BACKGROUND: Carboplatin is an analogue of cisplatin with less nonhematologic toxicity than the parent compound. It has been demonstrated previously to have activity against a spectrum of pediatric brain tumors. This Phase II study was undertaken to assess the activity of carboplatin in children with various solid tumors. METHODS: Between October 1985 and March 1988, the Childrens Cancer Group entered 117 patients with drug-resistant, recurrent lymphomas and solid tumors, excluding primary central nervous system tumors, into a Phase II trial of carboplatin given intravenously at a dosage of 560 mg/m2 over 1 hour every 4 weeks. RESULTS: A complete response was seen in 1 of 15 evaluable patients with Ewing's sarcoma. Partial responses were seen in 2 of 17 evaluable patients with neuroblastoma, 1 of 16 with soft tissue sarcoma, 2 of 5 with Wilms' tumor, and 1 with an endodermal sinus tumor of the testis. Objective responses were not seen in patients with malignant lymphoma, osteosarcoma, or hepatoma. Four of 7 patients who responded to carboplatin had previously received cisplatin. Sixty-two percent of patients had a platelet count nadir of less than 50,000/mm3, and 41% had an absolute neutrophil count nadir of less than 1,000/mm3. Ototoxicity, nephrotoxicity, hypomagnesemia, hypertransaminasemia, and nausea and vomiting each were seen in fewer than 10% of patients. CONCLUSIONS: Carboplatin has some activity against Wilms' tumor, Ewing's sarcoma, neuroblastoma, soft tissue sarcoma, and endodermal sinus tumor of the testis. Activity was not demonstrated against osteosarcoma, malignant lymphoma, hepatoma, and miscellaneous other tumors. Myelosuppression was seen commonly, and nonhematologic toxicity was infrequent.
Assuntos
Carboplatina/uso terapêutico , Linfoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Carboplatina/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , RecidivaRESUMO
Seventy-five children with recurrent, progressive or metastatic primary brain tumors were treated with aziridinylbenzoquinone (AZQ; Diaziquone) at 9 mg/m2/day by 30-minute intravenous infusion for five days every three weeks. Sixty-six patients were evaluable for response by imaging studies. There were five partial responses and one complete response for a combined response rate of 9%. A complete response lasting for 35+ months occurred in one of twelve patients with metastatic or locally recurrent ependymoma. Objective responses were also seen in patients with primitive neuroectodermal tumors (PNET) (1/8), low-grade glioma (1/6), and primary central nervous system lymphoma (1/1). Stable disease of greater than six months duration was seen in patients with ependymoma, PNET and medulloblastoma. Profound and prolonged myelo-suppression was the significant toxicity observed. As administered in this study, AZQ has marginal activity and severe toxicity.
Assuntos
Antineoplásicos/uso terapêutico , Aziridinas/uso terapêutico , Benzoquinonas/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos/toxicidade , Aziridinas/toxicidade , Benzoquinonas/toxicidade , Criança , Pré-Escolar , Avaliação de Medicamentos , Feminino , Humanos , Lactente , MasculinoRESUMO
Seventy-two children with recurrent, progressive, or metastatic lymphomas and other solid tumors, exclusive of primary central nervous system (CNS) tumors, were treated with aziridinylbenzoquinone (AZQ, diaziquone) at 9 mg/m2/day by 30-min intravenous infusion for 5 days every 3 weeks. Fifty-four patients were evaluable for response. Three partial responses occurred, two in patients with recurrent Hodgkin's disease and one in a patient with intraocular retinoblastoma. Sufficient numbers of patients with osteosarcoma, neuroblastoma, and Wilms' tumor were evaluable to demonstrate inactivity of this dosing regimen in these tumor types. Numbers of evaluable patients for other tumor types were insufficient to conclusively demonstrate inactivity. Myelosuppression, which was profound and prolonged, was observed. As administered in this study, AZQ has marginal activity and severe myelotoxicity in children with solid tumors.