The role of the neuropilins in tumour angiogenesis and tumour progression

Neuropilins (NRPs) are multifunctional receptors for class 3 semaphorins, which are responsible for axon guidance during the development of the nervous system in vertebrates, and for vascular endothelial growth factors (VEGFs), essential for vascular development and angiogenesis in disease. There is now a large body of evidence that NRPs also mediate tumour angiogenesis and progression, and they have also emerged as novel therapeutic targets in cancer. Many neoplastic cell types express NRPs, and NRP1 and NRP2 upregulation is positively correlated with tumour progression and poor patient prognosis in several cancer types (Pellet-Many et al. Biochem J 411:211–226, 2008). Recently, NRPs have been shown to play novel roles in the tumour stem cell niche and in regulation of tumour immunity. This chapter focuses on the role of NRPs in tumour angiogenesis and tumour progression, focusing on the role of the NRPs as modulators of VEGF function and highlighting approaches to therapeutic targeting of NRPs in cancer

Dba-free" Palladium Intermediates Of The Heck-matsuda Reaction."

The dba-free Heck-Matsuda reaction was investigated via direct ESI-MS(/MS) monitoring. Palladium species involved in the reduction of Pd(II) during a Wacker type reaction and several dba-free arylpalladium transient complexes were detected and characterized. Based on these findings, a more comprehensible catalytic cycle for this pivotal reaction is suggested.113277-8

Reproductive health services for populations at high risk of HIV: Performance of a night clinic in Tete province, Mozambique

<p>Abstract</p> <p>Background</p> <p>Different models exist to provide HIV/STI services for most-at-risk populations (MARP). Along the Tete traffic corridor in Mozambique, linking Malawi and Zimbabwe, a night clinic opening between 4 and 10 PM was established targeting female sex workers (FSW) and long-distance truck drivers (LDD). The clinic offers free individual education and counselling, condoms, STI care, HIV testing, contraceptive services and outreach peer education. To evaluate this clinic model, we assessed relevance, service utilisation, efficiency and sustainability.</p> <p>Methods</p> <p>In 2007-2009, mapping and enumeration of FSW and LDD was conducted; 28 key informants were interviewed; 6 focus group discussions (FGD) were held with FSW from Mozambique and Zimbabwe, and LDD from Mozambique and Malawi. Clinic outputs and costs were analysed.</p> <p>Results</p> <p>An estimated 4,415 FSW work in the area, or 9% of women aged 15-49, and on average 66 trucks stay overnight near the clinic. Currently on average, 475 clients/month visit the clinic (43% for contraception, 24% for counselling and testing and 23% for STI care). The average clinic running cost is US$ 1408/month, mostly for human resources. All informants endorsed this clinic concept and the need to expand the services. FGD participants reported high satisfaction with the services and mentioned good reception by the health staff, short waiting times, proximity and free services as most important. Participants were in favour of expanding the range of services, the geographical coverage and the opening times.</p> <p>Conclusions</p> <p>Size of the target population, satisfaction of clients and endorsement by health policy makers justify maintaining a separate clinic for MARP. Cost-effectiveness may be enhanced by broadening the range of SRHR-HIV/AIDS services, adapting opening times, expanding geographical coverage and targeting additional MARP. Long-term sustainability remains challenging and requires private-public partnerships or continued project-based funding.</p

Small molecule neuropilin-1 antagonists combine anti-angiogenic and anti-tumour activity with immune modulation through reduction of transforming growth factor beta (TGFβ) production in regulatory T-cells

We report the design, synthesis and comprehensive studybiological evaluation of a range ofsome potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumours, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229, EG00229 which was used a starting point for optimisation. Through targeting of specific amino-acid residues additional H-bonding interactions were introduced, which led to increases in binding affinity and potency. The design of these molecules was informed and supported by X-ray crystal structures. Pharmacokinetic data was obtained for some of the most potent compounds, and cCompound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays, and was shown to have anti-angiogenic, anti-migratory and anti-tumour effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, CD25+ populations of Tregs from mice 1 was able to block a glioma conditioned medium induced increase in TGFβ production. This study therefore represents a comprehensive characterisation of a small-molecule NRP1 antagonist, and provides the basis for future in vivo studies

"Comparação das respostas ao Teste Cardiopulmonar de exercício entre corredores capixabas de ciferentes níveis de desempenho".

Existe na literatura um grande número de estudos relacionados ao desempenho dos corredores. No entanto, nenhum deles investigou o nível de desempenho em corredores de rua (atletas de elite, amadores e não atletas) de modo que haja comparação entre eles. O objetivo principal foi identificar o perfil e cardiopulmonar no teste de esforço máximo de corredores de rua capixabas. Foram avaliados 59 sujeitos de ambos os sexos, moradores do estado do Espírito Santo, Brasil, treinados há pelo menos seis meses em corrida de rua, com idade entre 20 e 45 anos, divididos em grupos homogêneos por nível de desempenho (elite - GE, amador GA, e não atleta -GNA), a partir de um ranking em provas de corrida de rua. Todos passaram por um teste cardiopulmonar de exercício (TCPE) com protocolo de rampa em esteira (Cortex metalyser 3B), sendo analisados nas fases do limiar anaeróbio ventilatório (LAV), ponto de compensação respiratória (PCR) e máximo (MÁX). Comparou-se os dados dos três grupos por análise de variância de uma via, seguida do teste post-hoc de Tukey (p<0.05). Houve diferenças significativas entre os grupos em relação ao VO&#8322; (ml.kg-1.min-1), VE e velocidade no LAV, PCR e MÁX em ambos os sexos. Entre os homens os valores são superiores para os grupos com maior nível de desempenho em todas as fases do TCPE. Em relação as mulheres, GE foi semelhante em relação a GA, diferindo apenas de GNA. Para VE não houve diferenças significativas entre os grupos, assim como para as variáveis VO2 (L.min-1), frequência cardíaca (FC) e razão da troca respiratória (RTR), nas fases do TCPE em ambos os sexos. Conclui-se que a eficiência respiratória e a característica de desempenho (velocidade de corrida), entre os homens, são superiores para os grupos com maior nível de desempenho. Entre as mulheres não há diferença entre GE e GA, assim como entre GA e GNA

ENZYMATIC, CHEMOENZYMATIC AND PHOTOENZYMATIC CASCADE REACTIONS: PERSPECTIVES FOR A MORE SUSTAINABLE ORGANIC SYNTHESIS

Chemicals are rarely the result of a single transformation but rather the consequence of several individual reaction steps. Classically, these individual steps are carried out in sequence, including isolation and purification of the intermediate products. However, the reasons for choosing to carry out cascade reactions can be multiple, such as (i) the chance to prepare unstable and/or toxic intermediates, which are consumed directly in a subsequent step, (ii) the option to shift the equilibrium of a reaction by removing the co (product), or (iii) simply bypass the tedious work of isolating and purifying intermediates, saving reagents, solvents, time and money, and still generating less waste. Therefore, it is not surprising that so-called cascade reactions are gaining considerable interest in academic and industrial research. The purpose of this review is to show recent, promising research and new trends, the potential and current limitations of cascade reactions in organic synthesis that involves at least one enzymatic step in the cascade. This review will address cascades involving multi enzymatic, chemoenzymatic, and photoenzymatic cascades, where all steps are performed in one reaction vessel simultaneously or sequentially and the cascades in the regime of continuous flow.</div

The role of biocatalysis in green and sustainable chemistry

Biocatalysis is well recognized as a greener tool for organic synthesis with many successful ongoing industrial processes. Additionally, besides the research component, it can be used in outreach activities and the Chemistry and Chemical Engineering curriculum to introduce and discuss green and sustainable chemistry. An overview of the Brazilian chemical sector's contribution to the UN sustainable goals is also provided.Institute of Chemistry São Paulo State University (Unesp)Institute of Chemistry São Paulo State University (Unesp