286 research outputs found

    Synergy of NVP-BEZ235 and enzastaurin in mantle cell lymphoma

    Get PDF
    Mantle cell lymphoma (MCL) is a neoplasm classified as a B-cell malignancy, that accounts for approximately 3 to 8% of Non-Hodgkin's lymphoma (NHL) cases diagnosed annually. MCL is difficult to treat and seldom considered cured. The pathobiology of MCL is complex and includes alteration in the cell cycle, abnormalities in the DNA damage response, and constitutive activation of key antiapoptotic pathways including phosphatidyl-inositol 3-kinase (PI3K)/Akt and nuclear factor-kB. This has promoted the identification of new targeted treatments and new agents that have shown promising efficacy for future MCL therapies. The phosphatidylinositol 3-kinase (PI3K) mammalian target of rapamicin (mTOR) pathway mediates proliferation, survival, and drug resistance in lymphoma cells. NVP-BEZ235 (BEZ235) is a new, orally bioavailable inhibitor of PI3K and mTOR and a representative of a new class of anti-tumour agents.In this study, we analysed the in vitro inhibitory effects of NVP-BEZ235 on mantle lymphoma cell lines (GRANTA-519 and JeKo-1) and its effects in combination with enzastaurin, everolimus and perifosine. Our data suggest that in mantle lymphoma cell lines, BEZ235 in combination with enzastaurin elicits its antitumour effect better than combined with perifosine and everolimus. Our data reveal that the drug combination targets phosphorylation of PI3K/Akt/mTOR pathways and induces both intrinsic and extrinsic apoptosis pathways. Furthermore, inhibition of Bcl-2 anti-apoptosis family members may, in part, explain the efficacy of signalling blockade in lymphoma cells and suggests an additional therapeutic targeting strategy. Therefore, these preclinical data support the potential use of BEZ235 in patients with mantle lymphoma, and in particular provide rationale for combination with enzastaurin

    Ricolinostat, a selective HDAC6 inhibitor, shows anti-lymphoma cell activity alone and in combination with bendamustine

    Get PDF
    Histone deacetylase inhibitors (HDACis) have emerged as a new class of anticancer agents, targeting the biological process including cell cycle and apoptosis. We investigated and explained the anticancer effects of an HDAC6 inhibitor, ricolinostat alone and in combination with bendamustine in lymphoma cell lines. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) generation, Bcl-2 protein expression, cell cycle progression and tubuline expression were determined by flow cytometry. The effects of ricolinostat alone and in combination on the caspases, PI3K/Akt, Bcl-2 pathways, ER stress and UPR were assessed by immunoblotting. Ricolinostat shows anti lymphoma activity when used as single agent and its capability to induce apoptosis is synergistically potentiated by the bendamustine in lymphoma cell lines. Drug combination reduced the proportion of cells in the G0/G1and S phases and caused an increase of âsub-G0/G1â peak. The synergistic effect accompanied with the increased ROS, activation of caspase-8, -9, and -3, the cleavage of PARP and modulated by Bcl-2 proteins family. In addition, the exposure of ricolinostat induced the acetylation level of α-tubulin, the extend of which was not further modified by bendamustine. Finally, the apoptosis effect of ricolinostat/bendamustine may be mediated by a corresponding effect on microtubule stabilization. Our data suggest that ricolinostat in combination with bendamustine may be a novel combination with potential for use as an antitumor agent in lymphoma

    To Chase or not to Chase: A Study on the Role of Mentalization and Alcohol Consumption in Chasing Behavior

    Get PDF
    Background and aims: Chasing is a behavioral marker and a diagnostic criterion for gambling disorder. Although chasing has been recognized to play a central role in gambling disorder, research on this topic is relatively scarce. This study investigated the association between chasing, alcohol consumption, and mentalization among habitual gamblers. Method: A total of 132 adults took part in the study. Participants were administered the South Oaks Gambling Screen, the Alcohol Use Disorders Identification Test, the Reflective Functioning Questionnaire, and a laboratory task assessing chasing behavior. Participants were randomly assigned to three experimental conditions (Control, Loss, and Win). To deeply investigate chasing behavior, participants were requested to indicate the reasons for stopping or continuing playing at the end of the experimental session. Results: Logistic regression analysis showed that the choice to stop or continue playing depended on experimental condition and alcohol use. Hierarchical linear regression indicated that chasing propensity was affected by experimental condition, alcohol consumption, and deficit in mentalization. The results of path analysis showed that hypermentalizing predicts chasing not only directly, but also indirectly via alcohol consumption. Conclusions: Overall, these results for the first time showed that hypermentalization plays a key role in chasing behavior over and above gambling severity. Since these findings support the idea that chasers and non-chasers are different subtypes of gamblers, clinical interventions should consider the additive role of chasing in gambling disorder

    Interictal brain SPECT in patients with medically refractory temporal lobe epilepsy

    Get PDF
    The objective of this study was to evaluate the utility of interictal brain SPECT in localizing the epileptogenic focus in a population of patients of Epilepsy Clinic of Hospital Universitário Clementino Fraga Filho (HUCFF/UFRJ), with medically refractory temporal lobe epilepsy (TLE) and normal computed tomography (CT) scans, studying the correlation between SPECT, electroencephalogram (EEG) and, in 11 cases, brain magnectic resonance imaging (MRI), and to compare the results to the other six literatura series. Twelve (52.2%) patients presented abnormal SPECT. Among these, five (41.6% of abnormal SPECTs) presented unilateral SPECT changes at the same side of EEG (hypoperfusion in four and hyperperfusion in one), three (25% of abnormal SPECTs) presented bilateral hypoperfusion and bilateral EEG changes too, and four (33.3%) presented unilateral hypoperfusion and bilateral EEG changes. The statistical analysis was based on fuzzy logic. The correlation index among SPECT X EEG, SPECT X MRI and SPECT X EEG X MRI were highly significant, with signifcance levels at 0.01, p < 0.0005 and trust interval at 99% in all correlations. The correlation studies between the series presented similar results.O objetivo desse estudo foi avaliar a utilidade do SPECT cerebral interictal na localização do foco epileptogênico em 23 pacientes do Ambulatório de Epilepsias do Hospital Universitário Clementino Fraga Filho (HUCFF/UFRJ), com epilepsia do lobo temporal (ELT) de difícil controle e tomografia computadorizada (TC) do crânio normal, estudando a correlação entre SPECT interictal, eletrencefalograma (EEG) e, em 11 casos, ressonância magnética (RM) do crânio, e comparar os resultados com os de outras seis séries da literatura. Doze (52,2%) pacientes apresentaram SPECT anormal. Entre esses, cinco (41,6% dos SPECTs anormais) apresentaram alteração unilateral ao SPECT do mesmo lado do EEG (hipoperfusão em 4 e hiperperfusão em 1), três (25% dos SPECTs anormais) apresentaram hipoperfusão bilateral ao SPECT e alterações também bilaterais ao EEG e 4 (33,3% dos SPECTs anormais) apresentaram hipoperfusão unilateral ao SPECT e EEG bilateral. A análise estatística fundamentou-se na lógica fuzzy. Os índices de correlação entre SPECT X EEG, SPECT X RM e SPECT X EEG X RM foram altamente significativos, com níveis de significância de 0,01, p < 0,0005 e intervalo de 99% de confiança em todas as correlações. Os estudos de correlação entre as séries estudadas apresentaram resultados semelhantes entre si.Universidade Federal do Rio de Janeiro Faculdade de MedicinaUniversidade Federal do Rio de Janeiro Coordenação dos Programas de Pós-Graduação em EngenhariaLaboratoire d'Analyse et d'Architecture de Systèmes de ToulouseUniversidade Federal do Rio de JaneiroUniversidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM)Universidade Federal do Rio de Janeiro HUCFF Serviço de NeurologiaUniversidade do Rio de Janeiro Serviço de NeurologiaUNIFESP, EPMSciEL

    The Role of Physical Medicine and Rehabilitation in Shoulder Disorders

    Get PDF
    Shoulder pain is a common problem and it is responsible for a high proportion of patients presenting to general practice, causing work absenteeism and claims for sickness. A lot of factors and conditions can contribute to shoulder pain. The most prevalent cause is rotator cuff tendinitis; its relevance is correlated not only to its high prevalence rate but also to the fact that is disabling, causing high direct and indirect cost in industrialized country. Other causes of shoulder pain are shoulder impingement syndrome, calcific tendonitis, frozen shoulder, etc. In this context, physical medicine and rehabilitation plays a fundamental role. The conservative approach consists of several interventions. The aim is to decrease shoulder pain and to regain shoulder function, with the goal to reduce the degree of impingement, decreasing swelling and inflammation, and to minimize the risk of further injuries. The purpose of this chapter is to give an overview about shoulder disorders and their conservative treatment by means of physical therapy

    Rehabilitation in Sarcopenic Elderly

    Get PDF
    Sarcopenia is a complex problem and an important emerging field in rehabilitation of the elderly. In 2010, the European working group on sarcopenia in older people (EWGSOP) described sarcopenia as a syndrome characterised by progressive and generalised loss of skeletal muscle mass and strength, associated with a risk of adverse outcomes such as physical disability, poor quality of life and death. This field of rehabilitation has been defined as ‘evaluative, diagnostic and therapeutic interventions whose purpose is to restore functional ability or enhance residual functional capability in elderly people with disabling impairments’. With growing numbers of frail older people, there is an increasing need for appropriate geriatric rehabilitation services. Definitely, sarcopenia needs a specific rehabilitation program to improve muscular mass and strength that must be integrated with a global approach with the aim to recover postural assessment, amplify sensory‐motor systems, in order to gain the necessary information for proper motor planning, to reduce risk of falls. Several physical agents in medicine permit to treat sarcopenia, like vibrations or electrical stimulation. The aim of this chapter is to give an overview about rehabilitative medicine for sarcopenia, highlighting the state of the art, presenting the most significative clinical researches and giving some inputs to set a rehabilitation protocol

    Sarcopenia in Chronic Illness and Rehabilitative Approaches

    Get PDF
    Primary sarcopenia is considered to be age-related when no other cause is evident, other than aging itself. Secondary sarcopenia should be considered when one or more other causes are evident, such as multiple chronic conditions. Previous studies have reported that low muscle strength and impaired physical performance can be found in chronic diseases, including metabolic disease (diabetes, hypertension, and obesity), arthritis, osteoporosis, cancer, chronic kidney disease, chronic obstructive pulmonary disease, neuromuscular disease, and chronic infection. The development of preventive and therapeutic strategies against secondary sarcopenia and wasting disorders in general is an epidemiological need. The planning of a complex rehabilitation program in sarcopenia associated to chronic conditions, in the context of a comprehensive treatment, is made up of a nutritional support, exercise, correction of lifestyles, and the use of advanced physical energies. Therefore, for the purposes of the optimal management, it is essential to identify the pathogenesis and clinical characteristics that can affect the different rehabilitative treatment

    Nonsteroidal Anti-inflammatory Drugs: Integrated Approach to Physical Medicine and Rehabilitation

    Get PDF
    Inflammation is an immediate response to damage; in acute phase, it is a form of defense for body and it aims to restitutio ad integrum, in the chronic form itself becomes disease. This mechanism determines inflammatory diseases that are a group of clinical disorders which are characterized by abnormal inflammatory responses such as osteoarthritis, in myalgic syndromes (like fibromyalgia or miofascial sindrome), in some forms of headache, in peripheral vascular disease, in many malignancies. In Physical and Rehabilitation Medicine, the use of analgesic drugs (including NSAIDs) is a crucial resource inside a complex bioprogressive rehabilitative project. A part of the classic use per os is characterized by a serious and systemic side effect and there is also a possibility to administer drugs through other routes. Antalgic and rehabilitative mesotherapy (ARM) is a minimally invasive technique consisting of subcutaneous injections of bioactive substances. Other alternatives are represented by iontophoresis, phonophoresis, phytotherapy, and topical application. The purpose of this chapter is to give an overview about the state of the art regarding the use of NSAIDs in physical medicine and rehabilitation

    A consideração do clima no projeto de arquitetura e localização industrial - Uma proposta em benefício do homem e da produção

    Get PDF
    The aim of this paper is to discuss the different values of the Modern Era as regards the occupation of the geographical areas by industrial plants. Although these are general considerations, the proposed model derives from the effective applications in the scientific and occupational fields. Issues related to environmental impact and the climate ought to be considered because human-beings are the crucial element in the model.This fact brings about ambiguities which are to be treated by a non-deterministic logic. The uncertainty and the imprecision when determining the locational attributes suggest the usage of linguistic representation when interpreting the facts and happenings. The theory of the fuzzy sets furnish the means for the representation of the uncertainties and it is here proposed as a form of a locational model and as an important toot to shape the uncertainty associated to imprecision

    The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines

    Get PDF
    We investigated the cytotoxic interactions of romidepsin, a histone deacetylase inhibitor, and lenalidomide, an immunomodulatory agent, in a T-cell lymphoma preclinical model. Hut-78 and Karpas-299 cells were treated with romidepsin and lenalidomide alone and in combination. The interaction between romidepsin and lenalidomide was evaluated by the Chou–Talalay method, and cell viability and clonogenicity were also evaluated. Apoptosis, reactive oxygen species (ROS) levels, and cell cycle distribution were determined by flow cytometry. ER stress, caspase activation, and the AKT, MAPK/ERK, and STAT-3 pathways were analyzed by Western blot. Combination treatment with romidepsin and lenalidomide had a synergistic effect in Hut-78 cells and an additive effect in Karpas-299 cells at 24 hours and did not decrease the viability of normal peripheral blood mononuclear cells. This drug combination induced apoptosis, increased ROS production, and activated caspase-8, −9, −3 and PARP. Apoptosis was associated with increased hallmarks of ER stress and activation of UPR sensors and was mediated by dephosphorylation of the AKT, MAPK/ERK, and STAT3 pathways.The combination of romidepsin and lenalidomide shows promise as a possible treatment for T-cell lymphoma. This work provides a basis for further studies
    corecore