Malignant pleural mesothelioma: current treatments and emerging drugs

Background: Malignant pleural mesothelioma (MPM) is an uncommon disease whose incidence is increasing worldwide over the past 30 years. Surgical resection and radiotherapy represent the standard treatment in patient with resectable MPM. Chemotherapy is also necessary to reduce incidence of distant metastases, but the optimal setting of treatment (neoadjuvant, adjuvant and intrapleural) is not clarified. For the patients with unresectable MPM, the combination cisplatin and pemetrexed or ralitrexed is the standard treatment as supported by a Phase III study. Better understanding of molecular pathways involved in MPM has enabled inclusion of new drugs targeted against pathways responsible for proliferation, cell survival and angiogenesis. Objective: This review discusses the current treatment option, the specific signal pathways activated in MPM and the novel agents under evaluation in clinical trials. Methods: We use for this article abstracts, papers, oral presentations from ASCO and the website http://www.clinical-trials.gov. Results/conclusion: This review summarizes the activity of chemotherapy and of new agents under evaluation in clinical trials. The better understanding of molecular pathways activated in MPM will hopefully provide new therapeutic options for these patients in the future.

BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma

Therapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid vinorelbine exhibits clinical activity; however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons; however, its role in regulating vinorelbine-induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine-induced apoptosis, as evidenced by (1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level; (2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides; (3) dramatic down-regulation of BRCA1 following selection for vinorelbine resistance; and (4) the re-activation of vinorelbine-induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of samples. Together, these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker.

SAHA overcomes FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma

Malignant pleural mesothelioma (MPM) is a highly pro-inflammatory malignancy that is rapidly fatal and increasing in incidence. Cytokine signaling within the pro-inflammatory tumor microenvironment makes a critical contribution to the development of MPM and its resistance to conventional chemotherapy approaches. SMAC mimetic compounds (SMCs) are a promising class of anticancer drug that are dependent on tumor necrosis factor alpha (TNFa) signaling for their activity. As circulating TNFa expression is significantly elevated in MPM patients, we examined the sensitivity of MPM cell line models to SMCs. Surprisingly, all MPM cell lines assessed were highly resistant to SMCs either alone or when incubated in the presence of clinically relevant levels of TNFa. Further analyses revealed that MPM cells were sensitized to SMC-induced apoptosis by siRNA-mediated downregulation of the caspase 8 inhibitor FLIP, an antiapoptotic protein overexpressed in several cancer types including MPM. We have previously reported that FLIP expression is potently downregulated in MPM cells in response to the histone deacetylase inhibitor (HDACi) Vorinostat (SAHA). In this study, we demonstrate that SAHA sensitizes MPM cells to SMCs in a manner dependent on its ability to downregulate FLIP. Although treatment with SMC in the presence of TNFa promoted interaction between caspase 8 and the necrosis-promoting RIPK1, the cell death induced by combined treatment with SAHA and SMC was apoptotic and mediated by caspase 8. These results indicate that FLIP is a major inhibitor of SMC-mediated apoptosis in MPM, but that this inhibition can be overcome by the HDACi SAHA. © 2013 Macmillan Publishers Limited All rights reserved.

A social-cognitive model of monitoring and its relationship to behaviour in a naturalistic observation : development and individual differences

years 8 months) and 24 older (M == 7 years 4 months) children. A Monitoring Process Model (MPM) was developed and tested in order to ascertain at which component process ofthe MPM age differences would emerge. The MPM had four components: (1) assessment; (2) evaluation; (3) planning; and (4) behavioural control. The MPM was assessed directly using a referential communication task in which the children were asked to make a series of five Lego buildings (a baseline condition and one building for each MPM component). Children listened to instructions from one experimenter while a second experimenter in the room (a confederate) intetjected varying levels ofverbal feedback in order to assist the children and control the component ofthe MPM. This design allowed us to determine at which "stage" ofprocessing children would most likely have difficulty monitoring themselves in this social-cognitive task. Developmental differences were obselVed for the evaluation, planning and behavioural control components suggesting that older children were able to be more successful with the more explicit metacomponents. Interestingly, however, there was no age difference in terms ofLego task success in the baseline condition suggesting that without the intelVention ofthe confederate younger children monitored the task about as well as older children. This pattern ofresults indicates that the younger children were disrupted by the feedback rather than helped. On the other hand, the older children were able to incorporate the feedback offered by the confederate into a plan ofaction. Another aim ofthis study was to assess similar processing components to those investigated by the MPM Lego task in a more naturalistic observation. Together the use ofthe Lego Task ( a social cognitive task) and the naturalistic social interaction allowed for the appraisal of cross-domain continuities and discontinuities in monitoring behaviours. In this vein, analyses were undertaken in order to ascertain whether or not successful performance in the MPM Lego Task would predict cross-domain competence in the more naturalistic social interchange. Indeed, success in the two latter components ofthe MPM (planning and behavioural control) was related to overall competence in the naturalistic task. However, this cross-domain prediction was not evident for all levels ofthe naturalistic interchange suggesting that the nature ofthe feedback a child receives is an important determinant ofresponse competency. Individual difference measures reflecting the children's general cognitive capacity (Working Memory and Digit Span) and verbal ability (vocabulary) were also taken in an effort to account for more variance in the prediction oftask success. However, these individual difference measures did not serve to enhance the prediction oftask performance in either the Lego Task or the naturalistic task. Similarly, parental responses to questionnaires pertaining to their child's temperament and social experience also failed to increase prediction oftask performance. On-line measures ofthe children's engagement, positive affect and anxiety also failed to predict competence ratings.

Ligand Design for Dual Property Single Molecule Magnets

This thesis describes two different approaches for the preparation of polynuclear clusters with interesting structural, magnetic and optical properties. Firstly, exploiting p-tert-butylcalix[4]arene (TBC4) macrocycles together with selected Ln(III) ions for the assembly of emissive single molecule magnets, and secondly the preparation and coordination of a chiral mpmH ligand with selected 3d transition metal ions, working towards the discovery of chiral polynuclear clusters. In Project 1, the coordination chemistry of the TBC4 macrocycle together with Dy(III) and Tb(III) afforded two Ln6[TBC4]2 complexes that have been structurally, magnetically and optically characterized. X-ray diffraction studies reveal that both complexes contain an octahedral core of Ln6 ions capped by two fully deprotonated TBC4 macrocycles. Although the unit cells of the two complexes are very similar, the coordination geometries of their Ln(III) ions are subtly different. Variable temperature ac magnetic susceptibility studies reveal that both complexes display single molecule magnet (SMM) behaviour in zero dc field and the energy barriers and associated pre-exponential factors for each relaxation process have been determined. Low temperature solid state photoluminescence studies reveal that both complexes are emissive; however, the f-f transitions within the Dy6 complex were masked by broad emissions from the TBC4 ligand. In contrast, the Tb(III) complex displayed green emission with the spectrum comprising four sharp bands corresponding to 5D4 → 7FJ transitions (where J = 3, 4, 5 and 6), highlighting that energy transfer from the TBC4 macrocycle to the Tb(III) ion is more effective than to Dy. Examples of zero field Tb(III) SMMs are scarce in the chemical literature and the Tb6[TBC4]2 complex represents the first example of a Tb(III) dual property SMM assembled from a p-tert-butylcalix[4]arene macrocycle with two magnetically derived energy barriers, Ueff of 79 and 63 K. In Project 2, the coordination of both enantiomers of the chiral ligand, α-methyl-2-pyridinemethanol (mpmH) to Ni(II) and Co(II) afforded three polynuclear clusters that have been structurally and magnetically characterized. The first complex, a Ni4 cluster of stoichiometry [Ni4(O2CCMe3)4(mpm)4]·H2O crystallizes in a distorted cubane topology that is well known in Ni(II) cluster chemistry. The final two Co(II) complexes crystallize as a linear mixed valence trimer with stoichiometry [Co3(mpm)6]·(ClO4)2, and a Co4 mixed valence complex [Co(II)¬2Co(III)2(NO3)2(μ-mpm)4(ONO2)2], whose structural topology resembles that of a defective double cubane. All three complexes crystallize in chiral space groups and circular dichroism experiments further confirm that the chirality of the ligand has been transferred to the respective coordination complex. Magnetic susceptibility studies reveal that for all three complexes, there are competing ferro- and antiferromagnetic exchange interactions. The [Co(II)¬2Co(III)2(NO3)2(μ-mpm)4(ONO2)2] complex represents the first example of a chiral mixed valence Co4 cluster with a defective double cubane topology.

Marketing performance measurement : overview of approaches and practices for high technology firms

Um levantamento de 320 executivos de marketing feito pelo Conselho CMO e divulgado em junho de 2004 indicou que poucas companhias de alta tecnologia (menos de 20% das empresas entrevistadas) têm desenvolvido medidas e métricas úteis e expressivas para as suas organizações de marketing. Porém a pesquisa também revelou que companhias que estabeleceram medidas formais e compreensivas atingiram resultados financeiros superiores e tiveram mais confiança do CEO na função de marketing. Esta dissertação provê uma visão geral da informação precisa para executivos de marketing entenderem e implementarem processos para medição de performance de marketing (MPM) em suas organizações. Ela levanta questões para gerentes de marketing na industria de alta tecnologia com respeito às demandas para maior responsabilidade final, valor de medição para o melhoramento dos processos de marketing, iniciativas para determinar a lucratividade dos investimentos em marketing, e a importância das atividades de marketing nos relatórios corporativos. Esta dissertação defende a implementação de MPM, mapeando seus benefícios de medição para ambos gerentes de marketing e as suas empresas. o trabalho logo explora alguns conceitos gerais de medição de marketing e investiga algumas abordagens a MPM propostas pela industria, pela comunidade acadêmica, e pelos analistas. Finalmente, a dissertação descreve algumas práticas que todo gerente de marketing na industria de alta tecnologia deve considerar quando adotando MPM. As sugestões são gerais, mas devem familiarizar o leitor com as informações precisas para habilitar processos e rigor na sua organização com respeito a MPM.

Avaliação das atividades antioxidantes e citotóxicas de extratos ricos em polissacarídeos extraídos das hastes de mandacaru (Cereus Jamacaru de Candolle, Cactaceae)

The use of medicinal plants to cure and treat various diseases is a common practice in the world and in Brazil. In several regions of the Brazil´s Northeast, the cactus Cereus jamacaru, known as mandacaru, is used popularly as a treatment to many diseases, including those related to heart respiratory diseases, gastric ulcers, scurvy, and kidney diseases. However, there is a scarcity in the scientific literature that proves scientifically the popular application of this cactus. Like other plants, Cereus jamacaru synthesizes several potentially bioactive molecules, like as polysaccharides. In this work, three polysaccharides-rich aqueous extracts, MCA80, MPM and MCP60, were obtained from this plant and analyzed chemically, as well as their cytotoxic and antioxidant potential. The data showed that all extracts consist mainly of polysaccharides (89.42 to 95.76%), but also protein (> 2%) and phenolic (3 to 8.87%) contaminants were detected. All extracts are rich in galactose, glucose and mannose. In addition, glucuronic acid was found in MCA80 and MCP60. The extracts showed total antioxidant capacity ranged from 55.21 to 68.13 of ascorbic acid equivalents (AAE). Besides, they exhibited reducer power and cupric chelation in a dose-dependent manner. None of the extracts inhibited the MTT reduction in the presence of prostate tumor cells (PC-3). However, MCP60 was the most effective extract by preventing the reduction of MTT by about 80% in the presence of cells 786. Nuclear fragmentation tests showed that this extract induces cell death. The data indicated that mandacaru synthesizes bioactive polysaccharides with potential as antioxidant and antitumor agents. For future studies, it is intended to purify and characterize these polysaccharides and its antioxidant and antitumor mechanisms

Ecologia alimentar e comportamento de forrageamento de Ameivula aff. ocellifera (Squamata: Teiidae) em área de caatinga do nordeste do Brasil

This study investigated the influence of intrinsic and extrinsic factors on the feeding ecology and foraging behavior of the whiptail lizard Ameivula aff. ocellifera, a new species widely distributed in the Brazilian Caatinga, and that is in process of description. In attendance to the objectives, the Dissertation was structured in two chapters, which correspond to scientific articles, one already published and the other to be submitted for publication. In Chapter 1 were analyzed the general diet composition, the relationship between lizard size and prey size, and the occurrence of sexual and ontogenetic differences in the diet. Chapter 2 contemplates a seasonal analysis of diet composition during two rainy seasons interspersed with a dry season, and the quantitative analysis of foraging behavior during two distinct periods. The diet composition was determined through stomach analysis of lizards (N = 111) collected monthly by active search, between September 2008 and August 2010, in the Estação Ecológica do Seridó (ESEC Seridó), state of Rio Grande do Norte. Foraging behavior was investigated during a rainy and a dry month of 2012 also in ESEC Seridó, by determining percent of time moving (PTM), number of movements per minute (MPM) and prey capture rate by the lizards (N = 28) during foraging. The main prey category in the diet of Ameivula aff. ocellifera was Insect larvae, followed by Orthoptera, Coleoptera and Araneae. Termites (Isoptera) were important only in numeric terms, having negligible volumetric contribution (<2%) and low frequency of occurrence, an uncommon feature among whiptail lizards. Males and females did not differ neither in diet composition nor in foraging behavior. Adults and juveniles ingested similar prey types, but differed in prey size. Maximum and minimum prey sizes were positively correlated with lizard body size, suggesting that in this population individuals experience an ontogenetic change in diet, eating larger prey items while growing, and at the same time excluding smaller ones. The diet showed significant seasonal differences; during the two rainy seasons (2009 and 2010), the predominant prey in diet were Insect larvae, Coleoptera and Orthoptera, while in the dry season the predominant prey were Insect larvae, Hemiptera, Araneae and Orthoptera. The degree of mobility of consumed prey during the rainy seasons was lower, mainly due to a greater consumption of larvae (highly sedentary prey) during these periods. Population niche breadth was higher in the dry season, confirming the theoretical prediction that when food is scarce, the diets tend to be more generalized. Considering the entire sample, Ameivula aff. ocellifera showed 61,0 ± 15,0% PTM, 2,03 ± 0,30 MPM, and captured 0,13 ± 0,14 per minute. Foraging mode was similar to that found for other whiptail lizards regarding PTM, but MPM was relatively superior. Seasonal differences were verified for PTM, which was significantly higher in the rainy season (66,4 ± 12,1) than in the dry season (51,5 ± 15,6). It is possible that this difference represents a behavioral adjustment in response to seasonal variation in the abundance and types of prey available in the environment in each season

Implications of intrauterine protein malnutrition on prostate growth, maturation and aging

Aims Maternal malnutrition by low protein diet is associated with an increased incidence of metabolic disorders and decreased male fertility in adult life. This study aimed to assess the impact of maternal protein malnutrition (MPM) on prostate growth, tissue organization and lesion incidence with aging. Main methods Wistar rat dams were distributed into two groups, which were control (NP; fed a normal diet containing 17% protein) or a restricted protein diet (RP, fed a diet containing 6% protein) during gestation. After delivery all mothers and offspring received a normal diet. Biometrical parameters, hormonal levels and prostates were harvested at post-natal days (PND) 30, 120 and 360. Key findings MPM promoted low birth weight, decreased ano-genital distance (AGD) and reduced androgen plasma levels of male pups. Prostatic lobes from RP groups presented reduced glandular weight, epithelial cell height and alveolar diameter. The epithelial cell proliferation and collagen deposition were increased in RP group. Incidences of epithelial dysplasia and prostatitis were higher in the RP offspring than in the NP offspring at PND360. Significance Our findings show that MPM delays prostate development, growth and maturation until adulthood, probably as a result of low testosterone stimuli. The higher incidence of cellular dysplasia and prostatitis suggests that MPM increases prostate susceptibility to diseases with aging. © 2013 Elsevier Inc.

Determinação do escore Apgar, dos valores hemogasométricos e do proteinograma sérico em cordeiros (Ovis aries) nascidos de partos normais e de cesarianas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Efeitos da dexmedetomidina administrada em infusão intravenosa contínua, associada ou não ao butorfanol, em equinos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Programaçao fetal por restrição proteica in utero: avaliação do imprinting estrogênico nas próstatas ventral e dorsolateral do rato Wistar

Pós-graduação em Biologia Geral e Aplicada - IBB

Efeito do treinamento contrarresistência e isoflavona na densidade mineral óssea em mulheres na pós-menopausa

This study aimed to investigate the independent and additive effects of counter-resistance training (RT) and soy isoflavone supplement (ISO) on bone mineral density (BMD) and bone turnover in postmenopausal women. This study used a placebo-controlled, double-blinded (soy), randomized two (ISO vs. placebo) x two (RT vs. no RT) design. Eighty sedentary postmenopausal women, aged 45-70 years, were randomly assigned to one of four groups (71 completed a 9-month intervention): RT+ISO (n=15); no RT+ISO (n=20); RT+placebo (n=18); no RT+placebo (n=18). Participants randomized to ISO received 100mg/ day/oral of soy isoflavone; and those to RT attended supervised counter-resistance training sessions at least twice a week. At baseline and 9-month, BMD was estimated by dual-energy X-ray absorptiometry (DXA). Serum levels of C-terminal cross-linked telopeptide of type I collagen (CTX), osteocalcin, and insulin-like growth factor-1 (IGF-1) were measured as bone turnover. ANOVA with time as the repeated measure and test t were used in the statistical analysis. After 9 months of intervention, neither ISO nor RT alone affected BMD at any site or levels of CTX, osteocalcin, and IGF-1 (p>0.05). ISO and RT had no additive effects on BMD and bone turnover. RT groups showed significantly increased muscle strength (+ 35.2%) (p=0.02). We found no additive effects of resistance training and soy isoflavone on bone mineral density or bone turnover in postmenopausal women after 9-months.

Anestesia total intravenosa em uma mula

Apesar da literatura sobre anestesia em equinos ser ampla, referências sobre técnicas e fármacos anestésicos em muares são escassas. Nesse contexto objetivou-se relatar o caso de uma mula com um ano e meio de idade, fêmea, pesando 232 Kg, que foi atendida no Hospital Veterinário da UNESP de Araçatuba no dia com queixa de ferida granulomatosa no membro torácico direito, na região da quartela. Ao exame físico o animal apresentava frequência cardíaca (FC) de 56 batimentos por minuto (bpm), respiratória (f) de 44 movimentos por minuto (mpm), temperatura retal de 38,1 (T°), mucosas róseas e tempo de preenchimento capilar (TPC) de dois segundos. A ferida apresentava-se com tecido de granulação exuberante, em que a remoção cirúrgica foi indicada. O hemograma completo foi realizado antes da cirurgia, não apresentando alterações significativas. Como medicação pré-anestésica (MPA) utilizou-se xilazina 2% (0,5 mg/Kg/IV) associada com Acepromazina 1% (0,05 mg/Kg/IV). Em seguida, foi feita a indução anestésica com Cetamina 10% (2 mg/kg/IV) e Midazolam 0,5% (0,05 mg/kg/IV). Concomitantimente, foi realizado o bloqueio do nervo sesamóide abaxial lateral e medial com 5 ml de Lidocaína 2% em cada ponto. A cirurgia foi realizada com o animal em decúbito lateral esquerdo, empregando-se anestesia total intavenosa (TIVA), empregando-se a associação do Éter Gliceril Guaiacol (EGG) 5%, Xilazina 2% (1mg/ML) e Cetamina 10% (2 mg/ML). O volume total infundido, totalizando duas bolsas de 250 ml, foi administrado em uma hora e meia de cirurgia. O paciente manteve-se estável durante toda a cirurgia e foi continuamente monitorado quanto a profundidade anestésica por meio dos estágios e planos de Guedel, bem como com a mensuração das frequências cardíaca (FC), que se manteve entre 35 a 40 bpm e respiratória (f) mantida entre 25 a 28 mpm. Ao termino do procedimento cirúrgico o paciente permaneceu assistido durante toda a recuperação, sendo essa tranquila e de boa qualidade, com o paciente assumindo a posição quadrupedal em 15 minutos. A técnica anestésica empregada foi adequada, eficiente e se mostrou viável para realização de cirurgias a campo em muares.

Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed

Malignant pleural mesothelioma (MPM) is a lethal cancer of the mesothelium with high chemotherapeutic resistance via unknown mechanisms. A prevailing hypothesis states that cancer stem cells (CSCs) persist in tumors causing relapse after chemotherapy, thus, rendering these cells as critical targets responsible for tumor resistance and recurrence. We selected candidate CSC markers based on expansion under hypoxic conditions, a hallmark for the selection of chemoresistant cells; and investigated the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in three MPM cell lines and normal mesothelial cells by quantitative RT-PCR. Furthermore, we evaluated the chemotherapeutic resistance associated with each CSC marker by determining the change in CSC marker-mRNA levels as an index of drug-resistance following treatment with either cisplatin or pemetrexed. We demonstrate the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in both normal and MPM cell lines. Bmi-1+, uPAR+ and ABCG2+ cells show a distinct role in conferring chemoresistance to cisplatin and pemetrexed in the malignant setting. By contrast, these markers have no apparent participation in chemoresistance to drug treatments in normal mesothelial cells. Intriguingly, CD133 revealed chemoresistant properties in both normal mesothelial and malignant pleural mesothelioma cells. This study provides evidence of putative CSCs conferring drug-resistance to cisplatin and pemetrexed in MPM cell lines. Specific targeting of these drug-resistant cells, while considering the functional heterogeneity of the MPM subtypes, may contribute to more focused and effective chemotherapeutic regimens for malignant pleural mesothelioma.