27 results on '"Oliveira, Vasco"'
Search Results
2. Ratings matter: Announcements in times of crisis and the dynamics of stock markets
- Author
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Rosati, Nicoletta, Bellia, Mario, Matos, Pedro Verga, and Oliveira, Vasco
- Published
- 2020
- Full Text
- View/download PDF
3. Educação e linguagem: elementos para uma introdução crítica ao preconceito linguístico
- Author
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Edinei Oliveira Vasco and Veralúcia Pinheiro
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denominação cultural ,educação ,linguagem ,preconceito linguístico ,Education ,Education (General) ,L7-991 ,Theory and practice of education ,LB5-3640 - Abstract
O presente artigo tem como objetivo analisar alguns conceitos e concepções referentes à interação moderna entre dois fenômenos - educação e linguagem - cuja indissociabilidade aparente, tanto epistemológica quanto funcional, apresenta elementos que contribuem para o desenvolvimento de uma introdução crítica ao preconceito linguístico. Este é entendido como uma forma peculiar de preconceito social, que se efetiva no interior das relações sociais, por meio do sistema educacional - no qual a escola moderna é considerada o local privilegiado e legítimo de transmissão e imposição da língua caracterizada como padrão, oficial ou “culta” - e através da dominação cultural e da imposição linguística daí proveniente. Trata-se, portanto, de uma pesquisa de caráter qualitativo e de natureza analítico-descritiva que utilizará como metodologia um referencial bibliográfico a respeito da temática e dos objetos de estudos propostos. Palavras-chave: Denominação cultural. Educação. Linguagem. Preconceito linguístico.
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- 2016
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4. Development of a market study for the portuguese swimwear brand Guadalupissima
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Oliveira, Vasco Neffe da Costa, Salvado, João Cotter, and Xavier, Rute
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Estatística descritiva ,Portuguese market ,Redes sociais ,Market analysis ,Fatos de banho e biquínis ,Swimwear ,Ciências Sociais::Economia e Gestão [Domínio/Área Científica] ,Social media ,Social segmentation matrix ,Descriptive statistics ,Matriz de segmentação social ,Grupos estratégicos ,Análise de mercado ,Mercado português ,Strategic groups - Abstract
Submitted by Maria Helena Ribeiro (helena.ribeiro@lisboa.ucp.pt) on 2021-10-06T15:47:49Z No. of bitstreams: 1 152119198_Vasco Oliveira_DPDFA.pdf: 1815888 bytes, checksum: 9dadcfe40849a6b1e6c2705b2859f158 (MD5) Made available in DSpace on 2021-10-06T15:47:49Z (GMT). No. of bitstreams: 1 152119198_Vasco Oliveira_DPDFA.pdf: 1815888 bytes, checksum: 9dadcfe40849a6b1e6c2705b2859f158 (MD5) Previous issue date: 2021-04-30
- Published
- 2021
5. A phase 2 cooperative group adjuvant trial using a biomarker-based decision algorithm in patients with stage I non-small cell lung cancer (SWOG-0720, NCT00792701)
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Bepler, Gerold, Zinner, Ralph G., Moon, James, Calhoun, Royce, Kernstine, Kemp, Williams, Charles C., Mack, Philip C., Oliveira, Vasco, Zheng, Zhong, Stella, Philip J., Redman, Mary W., and Gandara, David R.
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- 2014
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6. Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma
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Nishihori, Taiga, Alekshun, Todd J., Shain, Kenneth, Sullivan, Daniel M., Baz, Rachid, Perez, Lia, Pidala, Joseph, Kharfan-Dabaja, Mohamed A., Ochoa-Bayona, Jose L., Fernandez, Hugo F., Yarde, Danielle N., Oliveira, Vasco, Fulp, William, Han, Gang, Kim, Jongphil, Chen, Dung-Tsa, Raychaudhuri, Jyoti, Dalton, William, Anasetti, Claudio, and Alsina, Melissa
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- 2012
- Full Text
- View/download PDF
7. Ratings matter: announcements in times of crisis and the dynamics of stock markets
- Author
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ROSATI NICOLETTA, BELLIA MARIO, VERGA MATOS PEDRO, and OLIVEIRA VASCO
- Abstract
In this paper we propose a novel approach in analysing the impact of changes in sovereign credit ratings on stock markets. We study the evolution of a segmented form of the stock market index for several crisis-hit countries, including both European and Asian markets. Such evolution is modelled by a homogeneous Markov chain, where the transition probabilities from one starting level of the index to a new (lower or higher) level in the next period depend on some explanatory variables, namely the country's rating, GDP and interest rate, through a generalised ordered probit model. The credit ratings turn out to be determinant in the dynamics of the stock markets for all three European countries considered - Portugal, Spain and Greece, while not all considered Asian countries show evidence of correlation of market indices with the ratings., JRC.B.1-Finance and Economy
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- 2019
8. Ratings matter: Announcements in times of crisis and the dynamics of stock markets
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Rosati, Nicoletta, Bellia, Mario, Matos, Pedro Verga, and Oliveira, Vasco
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Europe ,Credit ratings ,Markov chains ,G24 ,financial crisis ,G15 ,generalized ordered probit models ,ddc:330 ,E44 ,C25 ,C58 ,G01 - Abstract
In this paper we propose a novel approach in analysing the impact of changes in sovereign credit ratings on stock markets. We study the evolution of a segmented form of the stock market index for several crisis-hit countries, including both European and Asian markets. Such evolution is modelled by a homogeneous Markov chain, where the transition probabilities from one starting level of the index to a new (lower or higher) level in the next period depend on some explanatory variables, namely the country's rating, GDP and interest rate, through a generalised ordered probit model. The credit ratings turn out to be determinant in the dynamics of the stock markets for all three European countries considered - Portugal, Spain and Greece, while not all considered Asian countries show evidence of correlation of market indices with the ratings.
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- 2019
9. Characterization of the human GARP (Golgi associated retrograde protein) complex
- Author
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Liewen, Heike, Meinhold-Heerlein, Ivo, Oliveira, Vasco, Schwarzenbacher, Robert, Luo, Guorong, Wadle, Andreas, Jung, Martin, Pfreundschuh, Michael, and Stenner-Liewen, Frank
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- 2005
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10. Impact of credit ratings in crisis-hit countries : an application with Markov Chains
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Oliveira, Vasco Miguel Silva and Rosati, Nicoletta
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Financial Crisis ,Ordered Probit Models ,Cadeias de Markov ,Notações de Crédito ,Credit Ratings ,Modelos Probit Ordenados ,Markov Chains ,Crise Financeira - Abstract
Mestrado em Ciências Actuariais As notações de crédito têm sido amplamente discutidas em anos recentes, principalmente devido aos possíveis impactos que estes têm na economia. Após a crise financeira de 2008 e sem possibilidade de desenvolverem uma política monetária expansionária, os países mais atingidos pela crise tais como Portugal e Espanha continuam a tentar simultaneamente reduzir a despesa pública e reanimar as suas economias, de modo a ver os seus esforços recompensados com um aumento da notação das suas dívidas soberanas. Nesta dissertação estudamos uma abordagem diferente ao analisar o impacto de alterações nas notações de crédito soberano nos mercados bolsistas. Começamos por estimar um modelo probit ordenado para uma forma segmentada do mercado bolsista. Prosseguimos a análise ao observar a reacção do modelo assumindo diferentes percentis da notação de crédito. Terminamos com algumas sugestões de possíveis aprofundamentos de investigação. Credit ratings have been fairly discussed in recent years, primarily because of the possible impacts they have in the economy. After the financial crisis of 2008 and with no autonomy to pursue an expansionary monetary policy, crisis-hit countries such as Portugal and Spain are still struggling to control their public debt and reviving the economy simultaneously, while trying to be upgraded in their sovereign credit ratings. In this dissertation we propose a different approach in analysing the impact of changes in sovereign credit ratings on stock markets. We study the evolution of a segmented form of the stock market index for several crisis-hit countries, including both European and Asian markets. Such evolution is initially modelled by a homogeneous Markov chain, where the transition probabilities from one starting level of the index to a new (lower or higher) level in the next period depend on some explanatory variables, which include the country's rating, GDP and interest rate, through an ordered probit model. We then inspect the model's reaction to changes of credit ratings at different percentiles of their distribution. Finally, we suggest some possible extensions of research and applications.
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- 2015
11. Influence of chronic obstructive pulmonary disease and ventilotherapy on hearing.
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Graça, Rita and de Oliveira, Vasco
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OBSTRUCTIVE lung disease treatment , *CONFERENCES & conventions , *ARTIFICIAL respiration , *RISK assessment , *OBSTRUCTIVE lung diseases , *HEARING disorders , *DISEASE risk factors , *DISEASE complications , *EVALUATION - Abstract
Background: Chronic Obstructive Pulmonary Disease is a disease that affects the airways, characterized by its chronic and progressive inflammation, resulting in obstruction of the respiratory flow. It's pathogenesis leads to states of hypoxia and hypercapnia (states of low oxygen content and high carbon dioxide content, respectively, in the bloodstream), which several authors advocate as causes for the development of hearing loss. At the same time, ventilation therapy is commonly used in the treatment of this pathology, as it prevents this same respiratory obstruction. In doing so, this therapy is thought to have the potential to counteract the effects of the disease on hearing ability. This study aims to investigate whether chronic obstructive pulmonary disease has any influence on the auditory system, and therefore whether it can be considered a risk for the development of hearing loss, and also to assess the possibility of ventilation therapy, indirectly, effect on its attenuation or reversal. Material and methods: The investigation is classified as a case series study, in which the sample, of three participants, is divided into two groups according to the parameter to be evaluated. For each participant, pure tone tonal audiograms were compared prior to diagnosis or to the initiation of ventilation therapy, with audiograms after diagnosis or the initiation of ventilation therapy, according to the parameter under analysis. Results: Regarding the analysis of the influence of chronic obstructive pulmonary disease on hearing thresholds, the respective participants had minor, and sometimes inconstant, changes in hearing thresholds. As for the question concerning the analysis of the influence of ventilation therapy on hearing thresholds, the participants involved showed improvements, quite notorious in one case of the hearing ability. Conclusions: The results of this study do not allow us to give a concrete answer to the first part of the question, inasmuch as it is not possible to attribute, without a doubt, the responsibility to chronic obstructive pulmonary disease for the alterations observed. On the other hand, the results referring to ventilation therapy support the hypothesis that this therapeutic action can positively influence hearing in these clinical conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
12. Role of Wnt signaling in heart disease
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Oliveira, Vasco Sequeira, Pinho, Sónia, Moreira, Adelino Leite, Sousa, Maria João, and Universidade do Minho
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616.12-008.46 - Abstract
Dissertação de mestrado em Molecular Genetics, Heart failure has a major social-economic impact in our society. Despite major advances in the understanding of this pathology, the mechanisms of its development, as well as its pathophysiology, remain unclear. Therefore, it is our priority to clarify how extra- and intracellular factors are able to modulate heart function. Several pathways and/or factors had already been associated with different phases of heart failure development namely TGF-β, IGF, calcineurin, several GPCRs, MAPK, Akt and GSK-3. More recently, several studies started shedding some light on a putative role of Wnt signaling in heart failure development. Wnt signaling is a major regulator of cell-fate specification during development, proliferation, survival, migration and adhesion. Several diseases including cancer, diabetes, osteoporosis and psychiatric disorders are the result of deregulation of canonical Wnt signaling, due to either genetic alterations or changes in the levels of its effectors. The role of canonical Wnt signaling in heart development is well established and it has been shown to be biphasic, in the sense that its activation is initially required for the commitment of cells to a cardiac lineage and in its inhibition, cardiogenesis is triggered. In heart failure development, a possible role for Wnt signaling has only recently been reported, yet, its results are contradictory. Nonetheless, it was not addressed a possible role exerted by extracellular modulators and receptors of the Wnt pathway. Because of its role in the development of other diseases, and since its extracellular and membrane effectors are regarded as potential targets of pharmacological intervention in the treatment of such pathologies, it became imperative the understanding of Wnt signaling regulation in heart disease and how these interventions would affect heart function. Taking these facts into account, our first goal was to perform a detailed gene expression analysis of different Wnt ligands, receptors and co-receptors, during heart disease development in a type 1 diabetes mellitus rat model. Since in other contexts, Wnt signaling interacts with other pathways known to present a role in the development of diabetic heart disease, such as PPARs and FOXO proteins, we also checked their expression levels. With this approach we aimed starting to unveil a possible role for Wnt signaling in heart disease development as well as possible interactions with other pathways, known to be important of this pathology., A insuficiência cardíaca apresenta um impacto socioeconómico grande na nossa sociedade. Apesar de grandes avanços na compreensão desta patologia, os mecanismos do seu desenvolvimento, assim como a sua fisiopatologia, permanecem obscuros. De tal forma, é nossa prioridade o esclarecimento de como factores extra- e intracelulares são capazes de modular a função cardíaca. Diversas vias e/ou factores já foram associados a diferentes fases do desenvolvimento de insuficiência cardíaca, nomeadamente TGF-β, IGF, calcineurina, várias GPCRs, MAPK, Akt e GSK-3. Mais recentemente, vários estudos sugerem/apontam um potencial papel da via dos Wnts, no desenvolvimento de insuficiência cardíaca. A via das Wnts é um importante regulador do desenvolvimento, proliferação, sobrevivência e adesão celulares. Várias doenças como cancro, diabetes, osteoporose e disfunções psiquiátricas, são o resultado da desregulação da via canónica das Wnts, devido a alterações genéticas ou alterações a nível celular dos seus factores. A sua função no desenvolvimento cardíaco é bem conhecida e revelou-se bifásica, já que, inicialmente, a sua activação é necessária para diferenciação numa linhagem cardíaca e posteriormente, a sua inibição activa a cardiogénese. Vários estudos sugerem um potencial envolvimento da via das Wnts na insuficiência cardíaca, no entanto, os seus resultados são contraditórios. Assim, não foi possível identificar o papel desempenhado por moduladores extracelulares e receptores desta via. Devido ao seu papel no evoluir de outras doenças, e porque os seus receptores são potenciais alvos de intervenções farmacológicas no tratamento de tais patologias, tornou-se indispensável o conhecimento da via das Wnts na doença cardíaca e como essas intervenções poderão afectar o coração. Assim, o nosso primeiro objectivo passou por realizar uma análise à expressão genética dos vários ligandos, receptores e co-receptores, durante o desenvolvimento da doença cardíaca num modelo de rato com diabetes tipo 1. Dado que em outros contextos a via das Wnts interagir com outras vias conhecidas por deterem um papel no desenvolvimento da cardiomiopatia diabética, tais como PPARs e FOXOs, também analisamos os seus níveis de expressão. Com esta abordagem, pretendemos revelar o potencial papel da via das Wnts na fisiopatologia da doença cardíaca, assim como, possíveis interacções com outras vias relevantes e associadas a esta patologia.
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- 2010
13. Bortezomib salvage followed by a Phase I/ II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma.
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Nishihori, Taiga, Alekshun, Todd J., Shain, Kenneth, Sullivan, Daniel M., Baz, Rachid, Perez, Lia, Pidala, Joseph, Kharfan-Dabaja, Mohamed A., Ochoa-Bayona, Jose L., Fernandez, Hugo F., Yarde, Danielle N., Oliveira, Vasco, Fulp, William, Han, Gang, Kim, Jongphil, Chen, Dung-Tsa, Raychaudhuri, Jyoti, Dalton, William, Anasetti, Claudio, and Alsina, Melissa
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KARYOTYPES ,CHROMOSOME abnormalities ,STATISTICAL hypothesis testing ,MULTIPLE myeloma ,MESSENGER RNA ,STEM cells - Abstract
We conducted a Phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received two cycles of salvage bortezomib followed by stem cell mobilization with granulocyte colony-stimulating factor and harvest. Melphalan 100 mg/m
2 per day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4·35 mg/l (range: 1·8-11·4); albumin was 37 g/l (range: 3·1-4·9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1·3 mg/m2 was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (≥partial response) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 [95% confidence interval ( CI): 11-21] months and the median overall survival was 35 (95% CI: 22-43) months. Correlative studies demonstrated decreased expression of BRCA2 ( P = 0·0072) and FANCF ( P = 0·0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well-tolerated conditioning with some activity in patients with resistant myeloma. [ABSTRACT FROM AUTHOR]- Published
- 2012
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14. A Protective Role for the Human SMG-1 Kinase against Tumor Necrosis Factor-α Apoptosis.
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Oliveira, Vasco, Romanow, William J., Geisen, Christoph, Otterness, Diane M., Mercurio, Frank, Hong Gang Wang, Dalton, William S., and Abraham, Robert T.
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MORPHOGENESIS , *PROTEIN kinases , *SUPPRESSOR cells , *MESSENGER RNA , *TUMOR necrosis factors - Abstract
The human suppressor of morphogenesis in genitalia-1 (hSMG-1) protein kinase plays dual roles in mRNA surveillance and genotoxic stress response pathways in human cells. Here, we report that small interfering RNA-mediated depletion of hSMG-1, but not ATM, ATR, hUpf1, or hUpf2, in human U2OS osteosarcoma cells markedly increases the magnitude and accelerates the rate of apoptosis induced by tumor necrosis factor-α (TNFα) stimulation. The increase in TNFα-mediated cell killing observed in hSMG-1-depleted cells is not related to the suppression of nonsense-mediated mRNA decay or to the inhibition of TNFα-induced NF-κB activation. Rather, we observed that loss of hSMG-1 accelerates the degradation of the long form of the FLICE-inhibitory protein (FLIPL), an inhibitor of death-inducing signaling complex-mediated caspase-8 activation, in TNFα- treated cells. These results suggest that hSMG-1 plays an important role in cell survival during TNFα-induced stress. [ABSTRACT FROM AUTHOR]
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- 2008
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15. NF-kB as a Regulator of FA/BRCA Gene Expression in Multiple Myeloma.
- Author
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Oliveira, Vasco A., Mathews, Linda, Yarde, Danielle, Wang, Xingyu, Boulware, David, Hazlehurst, Lori A., Chen, Dung-Tsa, Beg, Amer, and Dalton, William S.
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- 2007
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16. Author Correction: Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells.
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Knox, Tessa, Sahakian, Eva, Banik, Debarati, Hadley, Melissa, Palmer, Erica, Noonepalle, Satish, Kim, Jennifer, Powers, John, Gracia-Hernandez, Maria, Oliveira, Vasco, Cheng, Fengdong, Chen, Jie, Barinka, Cyril, Pinilla-Ibarz, Javier, Lee, Norman H., Kozikowski, Alan, and Villagra, Alejandro
- Subjects
HISTONE deacetylase inhibitors ,MACROPHAGES ,CANCER cells - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]
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- 2019
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17. Emotional and Psychological Aspects of Tinnitus Patients.
- Author
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De Oliveira, Vasco
- Subjects
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TINNITUS treatment , *AUDIOLOGY associations , *CONFERENCES & conventions , *EMOTIONS , *TINNITUS , *HEALTH outcome assessment - Abstract
Introduction: Clinical experience with tinnitus patients, previous research, and the literature show that many tinnitus patients have psychological/psychosocial problems and reduced quality of life (QOL), and many therapies often have a low degree of success. Quality of life: The QOL corresponds to the perception of position in life, cultural context, system of values, and the relation between goals, expectations, standards, and concerns. Tinnitus triggers changes in one's life, a sense of loss of silence, and calling for readjustment. Patients with tinnitus may suffer multiple disturbing states, such as despair, anger, anxiety, and depression. The THI can be used to evaluate the QOL of patients with tinnitus, although the THI was originally used as a way to quantify the severity of tinnitus. Emotional aspects: There are many studies that link tinnitus with emotional problems, highlighting significant psychological disorders. The identification of anxiety and depression in tinnitus patients is important for therapeutic intervention. Coping: Heinecke et al. (2008) found that physiological and psychological aspects were associated with stress responses. Tinnitus patients had a lesser capacity to resolve stressful situations. Intervention programs for tinnitus should consider ways of providing coping mechanisms under stress. A connection exists between maladaptive coping and subjective perception of tinnitus severity, something that does not exist when strategies are effective, which confirms the usefulness of psychological therapy. Self-efficacy: Self-efficacy refers to how individuals perceive their own ability to organize and carry out activities in unfamiliar situations which are usually uncontrolled and unpredictable. Self-efficacy is an indicator of how effective an intervention is likely to be. Intervention: There are examples of collaboration between ENT and psychotherapy, like the University Hospital of Geneva. Patients who do not accept their auditory dysfunction, or are very focused on tinnitus, are sent to a joint appointment with an ENT doctor and a psy-chologist. This consultation addresses the social and psychological aspects, trying to make the patient understand the relation between tinnitus and some aspects in their daily life which have been disturbed. CBT is a therapeutic strategy used with these patients, and has had positive results. It is therefore important to develop intervention strategies that enhance self-efficacy, optimism, and coping strategies as well as reducing anxiety/depression and promoting their QOL. Conclusions: Motivated by clinical practice and the literature, this work has systematized an approach for implementing a QOL promotion program. It takes a psychological approach and complements standard therapy. Apart from psychotherapy such as CBT, specific strategies can lessen anxiety and depression. The aim is to increase optimism, self-efficacy, and coping strategies, allowing patients to cope more effectively with tinnitus. As the subjective discomfort gradually decreases, a stage may be reached where tinnitus no longer has an aversive connotation. [ABSTRACT FROM AUTHOR]
- Published
- 2015
18. REPORT ON THE 2ND INTERNATIONAL CONGRESS OF AUDIOLOGY (APTA-PORTUGAL).
- Author
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Tomé, David, de Oliveira, Vasco, Cravo, Melissa, Santos, Nicole, Batista, Odete, and Martins, Jorge Humberto
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AUDIOLOGY associations , *AUDIOLOGISTS , *AUDIOLOGY , *CONFERENCES & conventions - Published
- 2017
19. PROMOTE HEALTH BENEFITS OF WOOL.
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De Oliveira, Vasco
- Abstract
Presents a letter to the editor on the marketing of the health benefits of wool.
- Published
- 2005
20. Kinome Sirna Screen Identifies SMG-1 as a Negative Regulator of Hypoxia-inducible Factor-1α in Hypoxia.
- Author
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Run-Qiang Chen, Qing-Kai Yang, Yan-Ling Chen, Oliveira, Vasco A., Dalton, William S., Fearns, Colleen, and Jiing-Dwan Lee
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HYPOXEMIA , *CANCER invasiveness , *GENETIC regulation , *CELL motility , *PHOSPHOINOSITIDES , *MITOGEN-activated protein kinases - Abstract
Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinasespecific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HLF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinasedead SMG-1 effectively inhibited the activity of HIF1α. In addition, cellular SMG-1 deficiency increased secretion of the HIF1 α-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1α activity in hypoxia, in part through blocking MAPK activation. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
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21. The mRNA Surveillance Protein hSMG-1 Functions in Genotoxic Stress Response Pathways in Mammalian Cells
- Author
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Brumbaugh, Kathryn M., Otterness, Diane M., Geisen, Christoph, Oliveira, Vasco, Brognard, John, Li, Xiaojie, Lejeune, Fabrice, Tibbetts, Randal S., Maquat, Lynne E., and Abraham, Robert T.
- Subjects
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GENETIC toxicology , *PROTEIN kinases , *EUKARYOTIC cells , *PHOSPHORYLASES - Abstract
Members of the PI 3-kinase-related kinase (PIKK) family function in mitogenic and stress-induced signaling pathways in eukaryotic cells. Here, we characterize the newest PIKK family member, hSMG-1, as a genotoxic stress-activated protein kinase that displays some functional overlap with the related kinase, ATM, in human cells. Both ATM and hSMG-1 phosphorylate Ser/Thr-Gln-containing target sequences in the checkpoint protein p53 and the nonsense-mediated mRNA decay (NMD) protein hUpf1. Expression of hSMG-1 is required for optimal p53 activation after cellular exposure to genotoxic stress, and depletion of hSMG-1 leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR). Moreover, IR exposure triggers hUpf1 phosphorylation at Ser/Thr-Gln motifs, and both ATM and hSMG-1 contribute to these phosphorylation events. Finally, NMD is suppressed in hSMG-1- but not ATM-deficient cells. These results indicate that hSMG-1 plays important roles in the maintenance of both genome and transcriptome integrity in human cells. [Copyright &y& Elsevier]
- Published
- 2004
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22. Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells.
- Author
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Knox T, Sahakian E, Banik D, Hadley M, Palmer E, Noonepalle S, Kim J, Powers J, Gracia-Hernandez M, Oliveira V, Cheng F, Chen J, Barinka C, Pinilla-Ibarz J, Lee NH, Kozikowski A, and Villagra A
- Subjects
- Animals, Anti-Inflammatory Agents therapeutic use, B7-H1 Antigen immunology, Histone Deacetylase 6 immunology, Immune Tolerance drug effects, Macrophages immunology, Male, Mice, Mice, Inbred C57BL, Neoplasms immunology, Programmed Cell Death 1 Receptor immunology, Tumor Microenvironment drug effects, Antineoplastic Agents, Immunological therapeutic use, Histone Deacetylase 6 antagonists & inhibitors, Histone Deacetylase Inhibitors therapeutic use, Macrophages drug effects, Neoplasms drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Histone deacetylases (HDACs) are involved in diverse cellular regulatory mechanisms including non-canonical functions outside the chromatin environment. Several publications have demonstrated that selective HDAC inhibitors (HDACi) can influence tumor immunogenicity and the functional activity of specific immune cells. In particular, the selective inhibition of HDAC6 has been reported to decrease tumor growth in several malignancies. However, there is still no clarity about the cellular components mediating this effect. In this study, we evaluated the HDAC6i Nexturastat A as a priming agent to facilitate the transition of the tumor microenvironment from "cold" to "hot", and potentially augment immune check-point blockade therapies. This combination modality demonstrated to significantly reduce tumor growth in syngeneic melanoma tumor models. Additionally, we observed a complete neutralization of the up-regulation of PD-L1 and other immunosuppressive pathways induced by the treatment with anti-PD-1 blockade. This combination also showed profound changes in the tumor microenvironment such as enhanced infiltration of immune cells, increased central and effector T cell memory, and a significant reduction of pro-tumorigenic M2 macrophages. The evaluation of individual components of the tumor microenvironment suggested that the in vivo anti-tumor activity of HDAC6i is mediated by its effect on tumor cells and tumor-associated macrophages, and not directly over T cells. Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically "cold" tumors and subsequently improve ongoing immune check-point blockade therapies.
- Published
- 2019
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23. Monitoring a nuclear factor-κB signature of drug resistance in multiple myeloma.
- Author
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Xiang Y, Remily-Wood ER, Oliveira V, Yarde D, He L, Cheng JQ, Mathews L, Boucher K, Cubitt C, Perez L, Gauthier TJ, Eschrich SA, Shain KH, Dalton WS, Hazlehurst L, and Koomen JM
- Subjects
- Antineoplastic Agents, Alkylating therapeutic use, Apoptosis, Bone Marrow Cells metabolism, Cell Line, Tumor, Chromatography, Liquid, Electrophoresis, Polyacrylamide Gel, Fanconi Anemia Complementation Group Proteins genetics, Fanconi Anemia Complementation Group Proteins metabolism, Gene Expression Profiling, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Melphalan therapeutic use, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Protein Isoforms genetics, Protein Isoforms metabolism, Signal Transduction, Spectrometry, Mass, Electrospray Ionization, Syndecan-1 metabolism, Transcription Factor RelA genetics, Transcription Factor RelA metabolism, Transcription Factor RelB genetics, Transcription Factor RelB metabolism, Antineoplastic Agents, Alkylating pharmacology, Drug Resistance, Neoplasm, Melphalan pharmacology, Multiple Myeloma metabolism, NF-kappa B metabolism
- Abstract
The emergence of acquired drug resistance results from multiple compensatory mechanisms acting to prevent cell death. Simultaneous monitoring of proteins involved in drug resistance is a major challenge for both elucidation of the underlying biology and development of candidate biomarkers for assessment of personalized cancer therapy. Here, we have utilized an integrated analytical platform based on SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring mass spectrometry, a versatile and powerful tool for targeted quantification of proteins in complex matrices, to evaluate a well-characterized model system of melphalan resistance in multiple myeloma (MM). Quantitative assays were developed to measure protein expression related to signaling events and biological processes relevant to melphalan resistance in multiple myeloma, specifically: nuclear factor-κB subunits, members of the Bcl-2 family of apoptosis-regulating proteins, and Fanconi Anemia DNA repair components. SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring methods were developed for quantification of these selected target proteins in amounts of material compatible with direct translation to clinical specimens (i.e. less than 50,000 cells). As proof of principle, both relative and absolute quantification were performed on cell line models of MM to compare protein expression before and after drug treatment in naïve cells and in drug resistant cells; these liquid chromatography-multiple reaction monitoring results are compared with existing literature and Western blots. The initial stage of a systems biology platform for examining drug resistance in MM has been implemented in cell line models and has been translated to MM cells isolated from a patient. The ultimate application of this platform could assist in clinical decision-making for individualized patient treatment. Although these specific assays have been developed to monitor MM, these techniques are expected to have broad applicability in cancer and other types of disease.
- Published
- 2011
- Full Text
- View/download PDF
24. Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma.
- Author
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Yarde DN, Oliveira V, Mathews L, Wang X, Villagra A, Boulware D, Shain KH, Hazlehurst LA, Alsina M, Chen DT, Beg AA, and Dalton WS
- Subjects
- Boronic Acids pharmacology, Bortezomib, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Synergism, Fanconi Anemia genetics, Fanconi Anemia Complementation Group D2 Protein antagonists & inhibitors, Fanconi Anemia Complementation Group D2 Protein biosynthesis, Fanconi Anemia Complementation Group D2 Protein genetics, Gene Expression drug effects, Humans, Imidazoles pharmacology, Melphalan pharmacology, Multiple Myeloma genetics, NF-kappa B, Pyrazines pharmacology, Quinoxalines pharmacology, Transcription Factor RelB metabolism, Fanconi Anemia metabolism, Fanconi Anemia Complementation Group D2 Protein metabolism, Multiple Myeloma drug therapy, Multiple Myeloma metabolism
- Abstract
The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma cell lines. However, the transcriptional regulation of the FA/BRCA pathway is not understood. In this report, we describe for the first time a novel function of the NF-kappaB subunits, RelB/p50, as transcriptional activators of the FA/BRCA pathway. Specifically, our findings point to constitutive phosphorylation of IkappaB kinase alpha and subsequent alterations in FANCD2 expression and function as underlying events leading to melphalan resistance in repeatedly exposed multiple myeloma cells. Inhibiting NF-kappaB by small interfering RNA, blocking the IkappaB kinase complex with BMS-345541, or using the proteasome inhibitor bortezomib drastically reduced FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished DNA damage repair and enhanced melphalan sensitivity. Importantly, we also found that bortezomib decreases FA/BRCA gene expression in multiple myeloma patients. These results show for the first time that NF-kappaB transcriptionally regulates the FA/BRCA pathway and provide evidence for targeting Fanconi anemia-mediated DNA repair to enhance chemotherapeutic response and circumvent drug resistance in myeloma patients.
- Published
- 2009
- Full Text
- View/download PDF
25. Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia.
- Author
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Chen RQ, Yang QK, Chen YL, Oliveira VA, Dalton WS, Fearns C, and Lee JD
- Subjects
- Antigens, Neoplasm biosynthesis, Carbonic Anhydrase IX, Carbonic Anhydrases biosynthesis, Cell Hypoxia genetics, Cell Line, Tumor, Cell Movement, Gene Library, HeLa Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors, MAP Kinase Signaling System, Phosphoinositide-3 Kinase Inhibitors, Protein Array Analysis, Protein Serine-Threonine Kinases, Proteome, Vascular Endothelial Growth Factor A biosynthesis, Cell Hypoxia physiology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, RNA, Small Interfering genetics
- Abstract
Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinase-specific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HIF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinase-dead SMG-1 effectively inhibited the activity of HIF-1alpha. In addition, cellular SMG-1 deficiency increased secretion of the HIF-1alpha-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1alpha activity in hypoxia, in part through blocking MAPK activation.
- Published
- 2009
- Full Text
- View/download PDF
26. Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses.
- Author
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Damiano JS, Oliveira V, Welsh K, and Reed JC
- Subjects
- Apoptosis Regulatory Proteins, CARD Signaling Adaptor Proteins, Calcium-Binding Proteins metabolism, Carrier Proteins antagonists & inhibitors, Carrier Proteins metabolism, Cell Line, Cloning, Molecular, DNA, Complementary genetics, Humans, Interleukin-1 metabolism, Kidney embryology, Macromolecular Substances, Molecular Sequence Data, Monocytes metabolism, NF-kappa B antagonists & inhibitors, NF-kappa B metabolism, Neuronal Apoptosis-Inhibitory Protein, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Nucleoside-Phosphate Kinase metabolism, Peptidoglycan metabolism, Protein Isoforms metabolism, Protein Kinases metabolism, Protein Structure, Tertiary, Receptor-Interacting Protein Serine-Threonine Kinase 2, Adaptor Proteins, Signal Transducing, Immunity, Innate, Intracellular Signaling Peptides and Proteins, Nerve Tissue Proteins chemistry, Nerve Tissue Proteins metabolism, Peptides metabolism
- Abstract
Proteins of the NACHT [NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein)] family may serve as critical pathogen-sensing and signal-transducing molecules within the innate immune system. In the present paper, we show that CLAN [CARD (caspase-recruitment domain), LRR (leucine-rich repeat) and NACHT domain-containing protein], a NACHT-containing protein originally demonstrated to bind and activate pro-caspase 1, is also capable of influencing the functions of other members of the NACHT family. Through heterotypic NACHT-domain interactions, CLAN was found to associate with Nod1, Nod2 and NAC [nucleotide-binding domain and CARD-containing protein; NALP1 (NACHT, LRR and PYRIN protein 1)] when co-expressed in HEK-293T (human embryonic kidney) cells. NF-kappaB (nuclear factor kappaB) reporter assays demonstrated that co-expression of either full-length CLAN or the NACHT domain of CLAN significantly inhibited NF-kappaB activation induced by Nod1 or Nod2 overexpression. In addition, co-expression of CLAN or the NACHT domain of CLAN with Nod1 or Nod2 inhibited the ability of these proteins to generate active IL-1beta (interleukin 1beta) through their association with pro-caspase 1. The NACHT domain of CLAN was demonstrated by co-immunoprecipitation experiments to bind all NACHT domains that were tested, including the NACHT domains from CLAN itself, Nod1, Nod2, cryopyrin, NAC, PAN2 [PAAD [pyrin, AIM (absent-in-melanoma), ASC (apoptosis-associated speck-like protein containing a CARD) and death-domain-like]- and NACHT-containing protein] and NAIP (neuronal apoptosis inhibitory protein). Finally, monocyte-expressed CLAN was found to associate with Nod2 following exposure to bacterial peptidoglycan, implying a regulatory role for interaction of these NACHT proteins in the innate immune response. These studies suggest that by mediating hetero-oligomerization, NACHT domains provide a means by which various NACHT-containing proteins may interact, creating protein-interaction networks that potentially modulate immune responses to invading pathogens.
- Published
- 2004
- Full Text
- View/download PDF
27. A novel PAAD-containing protein that modulates NF-kappa B induction by cytokines tumor necrosis factor-alpha and interleukin-1beta.
- Author
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Fiorentino L, Stehlik C, Oliveira V, Ariza ME, Godzik A, and Reed JC
- Subjects
- Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Base Sequence, Cloning, Molecular, DNA Primers, Electrophoretic Mobility Shift Assay, Enzyme Activation, Humans, I-kappa B Kinase, Molecular Sequence Data, Protein Serine-Threonine Kinases metabolism, Proteins chemistry, Proteins genetics, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Interleukin-1 physiology, NF-kappa B biosynthesis, Proteins physiology, Tumor Necrosis Factor-alpha physiology
- Abstract
PAAD domains are found in diverse proteins of unknown function and are structurally related to a superfamily of protein interaction modules that includes death domains, death effector domains, and Caspase activation and recruitment domains. Using bioinformatics strategies, cDNAs were identified that encode a novel protein of 110 kDa containing a PAAD domain followed by a putative nucleotide-binding (NACHT) domain and several leucine-rich repeat domains. This protein thus resembles Cryopyrin, a protein implicated in hereditary hyperinflammation syndromes, and was termed PAN2 for PAAD and NACHT-containing protein 2. When expressed in HEK293 cells, PAN2 suppressed NF-kappaB induction by the cytokines tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta), suggesting that this protein operates at a point of convergence in these two cytokine signaling pathways. This PAN2-mediated suppression of NF-kappaB was evident both in reporter gene assays that measured NF-kappaB transcriptional activity and electromobility shift assays that measured NF-kappaB DNA binding activity. PAN2 also suppressed NF-kappaB induction resulting from overexpression of several adapter proteins and protein kinases involved in the TNF or IL-1 receptor signal transduction, including TRAF2, TRAF6, RIP, IRAK2, and NF-kappaB-inducing kinase as well as the IkappaB kinases IKKalpha and IKKbeta. PAN2 also inhibited the cytokine-mediated activation of IKKalpha and IKKbeta as measured by in vitro kinase assays. Furthermore, PAN2 association with IKKalpha was demonstrated by co-immunoprecipitation assays, suggesting a direct effect on the IKK complex. These observations suggest a role for PAN2 in modulating NF-kappaB activity in cells, thus providing the insights into the potential functions of PAAD family proteins and their roles in controlling inflammatory responses.
- Published
- 2002
- Full Text
- View/download PDF
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