Computadores contra a esquistossomose

Em 2005, quando começou o doutorado, Rosângela Silqueira Hickson desafiava a si mesma. Formada em engenharia mecânica, com mestrados em computação e em técnicas nucleares, apostava que conseguiria compreender temas específicos da biologia. Ela teria que fazer isso de alguma forma, porque só assim seria possível levar adiante a proposta sugerida por seu orientador, o pesquisador da Fiocruz Minas Guilherme Oliveira. “Ele tinha uma linha de pesquisa em bioinformática e achei interessante seguir este caminho”, explica. Assim surgiu um projeto para novas drogas contra a esquistossomose. A expectativa é de que soluções para esta doença milenar possam ser obtidas a partir de testes feitos em computador.

No Brasil, a esquistossomose é causada pela espécie Schistosoma mansoni e preocupa, especialmente, nas comunidades ribeirinhas do país.

Causada por parasitos do gênero Schistosoma, a doença é responsável por mais de 11 mil óbitos por ano no mundo, número que pode estar subestimado, pois grande parte dos casos não é notificada aos órgãos de saúde. Anualmente, cerca de 200 milhões de pessoas são infectadas em pelo menos 75 países das regiões tropicais e subtropicais do planeta. Isso coloca a esquistossomose como a segunda parasitose que mais infecta o homem, atrás somente da malária. No Brasil, é causada pela espécie Schistosoma mansoni e preocupa, especialmente, nas comunidades ribeirinhas do país.

O projeto trabalha, de um lado, com as proteínas do Schistosoma e, de outro, com milhares de compostos químicos num banco de dados. Na verdade, os pesquisadores não manipulam tubos de ensaio com os materiais biológicos e químicos – eles operam com estruturas tridimensionais, virtuais, produzidas por modelagem computacional. Assim, a estrutura tridimensional de cada proteína do parasito é contraposta à estrutura tridimensional de cada composto do banco de dados. O objetivo é prever qual seria a atividade dos compostos sobre as proteínas, para identificar alvos suscetíveis no parasito e novas drogas potenciais contra ele.

Inicialmente, com a participação da Fiocruz Minas e da Faculdade Infórium de Tecnologia de Belo Horizonte, os pesquisadores contavam com pouco mais de 200 computadores para a realização do trabalho. Se mantivessem esta estrutura, o projeto demoraria de cinco a dez anos para ser concluído. Entretanto, os cientistas já planejam que, no segundo semestre de 2011, o projeto esteja na fase final. Isso porque eles passaram a contar com a colaboração da multinacional IBM, por meio do World Community Grid (WCG).

A principal contribuição do WCG vem de um software que permite, de forma simples, realocar milhares de computadores ao redor do planeta para o desenvolvimento de estudos científicos. Qualquer pessoa no mundo pode entrar no site do WCG, fazer o download do programa e instalá-lo em seu computador pessoal. A partir daí, sempre que a máquina estiver ligada, sendo usada ou não, sua capacidade de processamento ociosa será canalizada para a realização de pesquisas. Isso resulta em economia de tempo e recursos, já que a capacidade de processamento é multiplicada, possibilitando a realização de trabalhos abrangentes em genômica. “O trabalho envolve, hoje, mais ou menos 300 mil computadores conveniados com a IBM, em todo o mundo, o que inclui muitas máquinas domésticas”, lembra Rosângela.

“O que consome a computação é a modelagem. É tentar encaixar a estrutura computacional de um composto na estrutura computacional de uma proteína. E isso requer poder computacional de primeira. Aí entra o WCG”, explica o chefe do Laboratório de Parasitologia Celular e Molecular da Fiocruz Minas e coordenador do Centro de Excelência em Bioinformática, Guilherme Oliveira. “Não temos nenhum pressuposto sobre qual proteína é um bom alvo e simplesmente testamos todas, de um banco de dados gigantesco. O que é muito mais barato do que um trabalho experimental”.

As experiências em laboratório são igualmente importantes, mas o projeto só entra na fase de bancada depois que as proteínas e os compostos mais promissores forem identificados pelas predições no computador. O método computacional possibilita, ainda, a descoberta de drogas contra outras doenças. “A esquistossomose vira um modelo. Se o projeto der certo, a chance de funcionar com outro organismo multicelular é maior. Então, estamos testando, de fato, uma nova abordagem, que pode ser útil para novas espécies”, argumenta Oliveira. A Fiocruz Minas participa de outras duas atividades que visam desenvolver novos medicamentos para esquistossomose pela abordagem da bioinformática: o SETtReND, um consórcio internacional que inclui três instituições brasileiras e seis europeias; e um projeto em parceria com a Universidade da Califórnia em São Francisco, nos Estados Unidos.

Além dos três trabalhos em bioinformática desenvolvidos pela Fiocruz Minas, projetos continuam sendo realizados no ambiente pioneiro para estudo da esquistossomose na unidade. “Atualmente, estamos testando uma associação de drogas. Pegamos uma droga usada hoje no Brasil contra essa parasitose e associamos com outra droga, clinicamente empregada para outra finalidade. O intuito é verificar se acontece uma ação sinérgica”, conta o vice-chefe do Laboratório de Esquistossomose da Fiocruz Minas, Naftale Katz, autor de livros considerados referências mundiais sobre o assunto. Ao serem associadas, as drogas podem aumentar sua capacidade de debelar o parasito. Por outro lado, também pode haver diminuição da atividade – um dado importante para pacientes que estejam tomando medicamentos para mais de uma doença.

Conheça o World Community Grid aqui.

Cabras transgênicas brasileiras produzem leite com medicamento

Fábricas ambulantes

Cientistas brasileiros estão usando cabras transgênicas para produzir o equivalente mais eficiente de um medicamento que custa R$500,00 cada ampola.

Os animais geneticamente modificados funcionam como uma espécie de "fábrica biológica" para os medicamentos - os cientistas as chamam de biorreatores.

A transgênese em mamíferos para produção de biorreatores é mais eficiente do que o método tradicional - cultivo de bactéria ou células de mamíferos - porque os animais produzem uma proteína mais similar à natural e de maneira mais econômica.

"De forma geral, os medicamentos assim produzidos seriam mais eficientes e mais baratos", afirma o pesquisador Vicente Freitas, do Instituto de Biofísica Carlos Chagas Filho (UFRJ).

Proteína hG-CSF

O foco do trabalho de Vicente e sua equipe, em parceria com cientistas da Rússia, é o uso de biotecnologias na reprodução dos animais para a multiplicação de caprinos transgênicos capazes de secretar a proteína hG-CSF.

A proteína hG-CSF é um medicamento importado amplamente utilizado devido à sua comprovada eficiência contra diferentes formas de neutropenia e leucopenia, induzidas por quimioterapia.

Existem no mercado duas apresentações do remédio: o Filgrastim e o Lenograstim, ambos custando em média R$ 500,00 a ampola.

Geração das cabras transgênicas

Pesquisas com animais transgênicos são alternativas viáveis no desenvolvimento de novos medicamentos para o tratamento de diversas doenças em humanos.

A transgênese em grandes animais, sobretudo em ruminantes, é uma importante aplicação biotecnológica para a produção de proteínas recombinantes em escala comercial.

"De uma maneira resumida, cabras doadoras de embriões são induzidas para superovular com uso de hormônios. Essas cabras são cobertas por bodes férteis e algumas horas após a fecundação faz-se a colheita cirúrgica dos embriões recém-fecundados. Os embriões são levados a um microscópio, acoplado a um micromanipulador, aonde é realizada a microinjeção. Após este procedimento, os embriões são transferidos para cabras receptoras que levarão a gestação até o parto. Após o nascimento, um teste de DNA irá detectar os animais transgênicos", explica Vicente.

Cabras transgênicas produzem medicamentos

A cabra geneticamente modificada é submetida a uma lactação induzida (sem a necessidade de uma gestação) e produz aproximadamente 630 microgramas de hG-CSF por mililitro (ml) de leite.

Isto equivale a quase duas ampolas do medicamento disponível no mercado. Cada paciente normalmente é submetido a um tratamento completo de 14 ampolas.

"Na hipótese de uma recuperação de 100% da proteína no leite, somente sete mililitros do leite de nossa cabra seriam suficientes para um tratamento. Imagine que esta cabra pode produzir até um litro de leite por dia e ter uma lactação que dura em torno de 150 dias. Dessa forma, acreditamos que um pequeno rebanho transgênico pode atender à necessidade de hG-CSF do Brasil" ressalta Vicente.

Após a colheita do leite e purificação da proteína é que o medicamento poderá ser produzido.

Rebanho transgênico

Contudo, antes da comercialização virá uma etapa longa, que consiste na validação do medicamento, com a realização de testes pré-clínicos, clínicos etc.

Para a produção da proteína em escala comercial será necessário um número adequado de cabras lactando e secretando a proteína recombinante em seu leite.

Para este objetivo estão sendo utilizadas duas estratégias: utilização do sêmen do macho transgênico para fecundação de cabras não transgênicas; e produção de embriões da fêmea transgênica (após fecundação com sêmen de macho não transgênico), com sua posterior transferência para cabras receptoras.

As estratégias têm-se mostrado eficientes: em menos de um ano de projeto o grupo já obteve descendentes tanto para o macho como para a fêmea transgênica.

Especialistas alertam para sintomas da dengue "camuflados" em crianças

Febre, dores no corpo e indisposição. Os sintomas da dengue podem ser facilmente confundidos, em crianças, com os de uma gripe. No entanto, o Ministério da Saúde alerta para a possibilidade de ser a doença transmitida pelo Aedes aegypti.

Leia cobertura completa sobre a dengue

Segundo especialistas, os sintomas da dengue podem ser facilmente "camuflados" no caso dos pequenos, o que leva à demora no tratamento.

Profissionais de saúde e pais devem estar atentos aos sinais da doença, alerta o secretário de Vigilância à Saúde, Jarbas Barbosa.

"Se a família percebe que a criança apresenta esse quadro de vômito continuado e de dor abdominal, tem que ser levada urgentemente ao serviço de saúde, porque ela pode estar fazendo uma forma grave de dengue que pode evoluir para um caso grave e, em poucas horas, até matar", diz.

A dengue pode ser mais perigosa ainda nos bebês, pois a evolução do quadro é súbita. Neste caso, os pais devem ficar alertas aos choros persistentes e à irritabilidade.

Casos

Uma jovem de 19 anos morreu vítima de dengue hemorrágica no Rio, neste fim de semana. Ela foi internada sábado (2) no hospital Barra D'Or, mas não resistiu e morreu pouco depois.

A Secretaria Municipal de Saúde informou que mapeou mais de 11 mil possíveis focos do mosquito Aedes aegypti durante a realização da Caminhada contra a Dengue. Foram identificados no total 11.354 criadouros do mosquito transmissor da dengue.

Desde o começo deste ano, 31 mil casos de dengue foram registrados no Estado, e mais de 20 pessoas morreram.

São Paulo

O governo de São Paulo confirmou nesta segunda-feira (4) o primeiro caso de dengue tipo 4 no Estado. Agora, a preocupação da Secretaria de Saúde é com a circulação desse novo vírus em 2012.

O vírus tipo 4 não é mais agressivo do que os outros três, mas aumenta o risco de epidemia porque menos pessoas estão imunizadas contra ele.

Clínica espanhola inicia teste de vacina personalizada contra câncer de mama

Teste foi aprovado recentemente e ainda mantém aberta a fase de recrutamento de pacientes: mulheres diagnosticadas com câncer de mama em estágios II e III

PAMPLONA - Uma clínica espanhola deu início a um teste para comprovar a eficiência da aplicação de vacinas personalizadas para reduzir as recaídas em pacientes que sofreram câncer de mama. As vacinas são elaboradas com células dendríticas (do sistema imune) da paciente e estimuladas com seu próprio tumor para reduzir a progressão do câncer de mama em um subgrupo determinado desta doença, aquele no qual as células tumorais não indicam a proteína HER2.

Veja também:

Pesquisa identifica mutações que ocorrem em células cancerígenas

Estudo contesta eficácia do controle médico contra câncer de próstata

Mortes por câncer diminuem nos Estados Unidos, diz estudo

O estudo, cujo início foi anunciado nesta terça-feira pela Clínica Universidade de Navarra, é pioneiro em aplicar este tratamento combinado com o tratamento padrão. Os resultados preliminares sobre um eventual aumento de respostas do tumor (redução de tamanho e, inclusive, desaparecimento) aos tratamentos combinados de quimioterapia e imunoterapia deste teste clínico poderiam ser obtidos em maio de 2012.

O teste foi aprovado recentemente e ainda mantém aberta a fase de recrutamento de pacientes: mulheres diagnosticadas com câncer de mama em estágios II e III, correspondentes a tumores não metastásicos, de mais de dois centímetros, com ou sem afetação ganglionar.

As participantes receberão o tratamento convencional (quimioterapia para reduzir o volume da doença, extirpação do tumor e radioterapia), além das vacinas personalizadas durante o tratamento com quimioterapia antes da cirurgia e posteriormente como manutenção.

O projeto complementa o tratamento oncológico tradicional com um calendário de dois anos de duração, com um mínimo de 6 e um máximo de 14 vacinas. Estas vacinas são elaboradas no laboratório de Tratamento Celular da Clínica Universidade de Navarra com as células tumorais extraídas da própria paciente. Para isso, é realizada uma biópsia do tumor, as células tumorais são processadas e delas são obtidos os antígenos (molécula capaz de induzir uma resposta do sistema imune).

Além disso, também são extraídas células do sistema imunológico da paciente (monocitos que se transformam em células dendríticas) para que no laboratório os antígenos do tumor sejam colocados em contato com as células do sistema imune com o objetivo de que as próprias defesas da paciente reconheçam o tumor como uma ameaça para o organismo.

Com as células dendríticas obtidas de seu sistema imune, processadas posteriormente com os antígenos do próprio tumor, são elaboradas as vacinas contra a doença que serão administradas na paciente. Segundo Marta Santisteban, principal pesquisadora do estudo, "se trata de reforçar o sistema imune para defender o organismo das células tumorais", um tratamento testado com sucesso em outro tipo de tumor, mas nunca em um câncer de mama antes da cirurgia e como manutenção.

'Volta' da anestesia em 3 minutos

Remédio que passou a ser usado por hospitais de SP acelera retomada dos movimentos após cirurgia

Hospitais da capital começaram a usar um novo medicamento capaz de promover em apenas três minutos a recuperação dos movimentos do corpo após a aplicação de uma anestesia geral. Sem ele, o paciente leva aproximadamente uma hora para retornar do relaxamento muscular profundo.

A medida não serve apenas para garantir conforto. O retorno rápido dos movimentos musculares reduz os riscos de problemas cardiovasculares, além de colaborar para que o paciente volte a respirar sem a ajuda de aparelhos, explicam os médicos.

A questão envolve, ainda, um lado emocional. Segundo a professora de anestesiologia da Universidade Federal de São Paulo (Unifesp) Maria Angela Tardelli, a demora para retomar as contrações musculares também pode provocar estresse psicológico.

“Há casos em que o paciente retoma a consciência, mas não consegue falar ou se mexer. É uma situação de extremo estresse que sobrecarrega o sistema cardiovascular”, diz Maria Angela. De acordo com a Sociedade Americana de Anestesiologia (ASA), 25% das pessoas postergam a operação justamente por medo dos efeitos da anestesia.

De acordo com um levantamento publicado pela revista da Sociedade Internacional de Snestesiologistas, Anesthesia & Analgesia, o bloqueio residual pós-operatório, ou seja, a não recuperação total dos movimentos musculares do corpo, é vivida por quase metade (47%) dos pacientes que passam mais de um dia no hospital após a cirurgia.

O mesmo ocorre com 38% das pessoas que recebem alta logo após o procedimento. “Nesses pacientes não deveria haver bloqueio residual”, garante Maria Angela.

O remédio usado na capital para apressar a recuperação dos movimentos após a anestesia é um composto à base de sugamadex sódico, comercialmente conhecido como Bridion. Ele age revertendo o relaxamento muscular profundo provocado por tipos específicos de bloqueadores neuromusculares, como os relaxantes Rocurônio e o Vecurônio.

“A tendência é que se aumente o uso de relaxantes musculares que possam ser bloqueados com o sugamarex. Assim, damos mais tranquilidade ao paciente, que sabe que pode ser despertado mais rapidamente”, afirma Marco Antônio P. Aranha, coordenador médico da área de anestesia do Hospital Santa Catarina.

Clique sobre a imagem para visualizar

Os anestésicos agem de três formas no corpo dos pacientes. Provocam a inconsciência, evitam a dor e relaxam os músculos. “Os anestésicos costumam ser de ação curta. São metabolizados rapidamente e o relaxante muscular era o que ficava para trás, demorando mais para parar de agir no corpo”, detalha o anestesista do Complexo Hospitalar Edmundo Vasconcelos, Marcos Euder Mendonça de Brito.

EFEITO RESIDUAL

Dificuldade para respirar

Fraqueza

Dificuldade para engolir

Tosse ineficiente, incapaz de expelir resíduos

Risco de engasgar

Estresse psicológico causado pelo despertar sem o movimento muscular

Esse estresse aumenta o risco de o paciente passar por problemas cardíacos

Hotspots of Genetic Rearrangement: Findings in Mice Could Aid Understanding of How Mammals Genetically Adapt

ScienceDaily (Apr. 5, 2011) — Researchers have zoomed in on mouse chromosomes to map hotspots of genetic recombination -- sites where DNA breaks and reforms to shuffle genes. The findings of the scientists at the National Institutes of Health and Uniformed Services University of Health Sciences (USU) have the potential to improve the detection of genes linked to disease and to help understand the root causes of genetic abnormalities.

In this image, hundredfold magnification of a single sperm precursor cell shows the chromosomes -- in green -- and the places where these chromosomes are most likely to break apart and re-form, called genetic recombination hotspots -- in red. Genetic rearrangements at these hotspots have the potential to shuffle maternal and paternal chromosomes, the end results of which ensure that the genetic information in every sperm cell is unique.

The research, published online April 3 in Nature, moves scientists one step closer to understanding how mammals evolve and respond to their environments.

In this image, hundredfold magnification of a single sperm precursor cell shows the chromosomes -- in green -- and the places where these chromosomes are most likely to break apart and re-form, called genetic recombination hotspots -- in red. Genetic rearrangements at these hotspots have the potential to shuffle maternal and paternal chromosomes, the end results of which ensure that the genetic information in every sperm cell is unique. Source: Fatima Smagulova, Ph.D., USU, and Kevin Brick, Ph.D., NIDDK, NIH.Genetic recombination occurs at hotspots in cells that form sperm and eggs. At these sites, rearrangements ensure that the combination of genes passed on to every sperm and egg cell is unique. By studying precursors of mouse sperm cells during the early stages of genetic recombination, the scientists have created a precise, first-of-its-kind map of recombination hotspots in a multi-celled organism.

With this map, researchers also hope to pinpoint where, how and why abnormalities in the number of chromosomes can occur. Such abnormalities -- for instance, the extra copy of chromosome 21 that gives rise to Down syndrome -- are the leading known cause of miscarriages, congenital birth defects, and mental retardation in the United States.

"We wanted to figure out how recombination varied across the genome," said R. Daniel Camerini-Otero, M.D., Ph.D., one of the senior authors on the paper and a researcher at the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "Hotspots are the starting point for the process that ensures that every person is unique. These hotspots facilitate the adaptation of populations to environmental influences through evolution. Our findings will allow us to explore things like how environment and genetic background affect the recombination landscape."

"Now that we have mapped recombination hotspots genome-wide, we can actually carry out studies on the whole mouse genome. This will be very beneficial in extending our knowledge to organisms as complex as humans," said Galina Petukhova, Ph.D., assistant professor in the USU Department of Biology and one of the paper's senior authors. "Faulty recombination can lead to infertility or birth defects, and this work brings us closer to our ultimate goal of helping to prevent these health issues."

Camerini-Otero compared the map's new level of precision to the difference between being able to zoom in to see a city block to being able to zoom in to see each building on the block. "What we were looking for was resolution that was much higher than ever seen before," said Camerini-Otero. "Now that we can actually see these individual events of genetic recombination, we can begin to understand their molecular structure."

The researchers -- including lead authors Fatima Smagulova, Ph.D., of USU, and Ivan V. Gregoretti, Ph.D., of NIDDK -- used cutting-edge DNA sequencing technology and lots of computational power to take a snapshot of all the individual pieces of DNA that were taking part in recombination at a given moment in living cells. They then used this snapshot of short DNA pieces to draw a map of where chromosomes have an increased potential to be broken and to come back together in new ways.

Mice were used as subjects for this study because the researchers needed a population that could be created with a specific and identical genetic background. With this initial study a success, they hope to apply the same techniques to study recombination in people in the near future.

The end result is a catalog of about 10,000 hotspots and resembles a detailed map of where diversity can arise in the genome and of sites where such processes may go awry. The researchers next plan to apply what they've seen and learned with this new map to further understand chromosomal abnormalities, genetic recombination, genome stability and evolution.

The NIH's National Institute of General Medical Sciences and the March of Dimes Foundation helped fund this research through grants to Petukhova.

Autism: Exceptional Visual Abilities Explained

ScienceDaily (Apr. 5, 2011) — Researchers directed by Dr. Laurent Mottron at the University of Montreal's Centre for Excellence in Pervasive Development Disorders (CETEDUM) have determined that people with autism concentrate more brain resources in the areas associated with visual detection and identification, and conversely, have less activity in the areas used to plan and control thoughts and actions. This might explain their outstanding capacities in visual tasks.

This is the spatial distribution of regions showing more task-related activity in autistics than non-autistics for the three processing domains: "faces" in red, "objects" in green, and "words" in blue. 

The team published their findings inHuman Brain Mapping on April 4, 2011.

Aiming to understand why autistic individuals have strong abilities in terms of processing visual information, the researchers collated 15 years of data that covered the ways autistic brain works when interpreting faces, objects and written words. The data came from 26 independent brain imaging studies that looked at a total of 357 autistic and 370 non-autistic individuals. "Through this meta-analysis, we were able to observe that autistics exhibit more activity in the temporal and occipital regions and less activity in frontal cortex than non-autistics. The identified temporal and occipital regions are typically involved in perceiving and recognizing patterns and objects. The reported frontal areas subserve higher cognitive functions such as decision making, cognitive control, planning and execution,'' explained first author Fabienne Samson, who is also affiliated with the CETEDUM.

"This stronger engagement of the visual processing brain areas in autism is consistent with the well documented enhanced visuo-spatial abilities in this population," Samson said. The current findings suggest a general functional reorganization of the brain in favor of perception processes -- the processes by which information is recorded the brain. This allows autistic individuals to successfully perform, albeit in their own way, higher-level cognitive tasks that would usually require a strong involvement of frontal areas in typical individuals. These are tasks that require reasoning -- for example, a research participant would be asked if a statement is true or false, or to categorize a range of objects into groups.

"We synthesized the results of neuroimaging studies using visual stimuli from across the world. The results are strong enough to remain true despite the variability between the research designs, samples and tasks, making the perceptual account of autistic cognition currently the most validated model," Mottron said. "The stronger engagement of the visual system, whatever the task, represents the first physiological confirmation that enhanced perceptual processing is a core feature of neural organization in this population. We now have a very strong statement about autism functioning which may be ground for cognitive accounts of autistic perception, learning, memory and reasoning." This finding shows that the autistic brain successfully adapt by reallocating brain areas to visual perception, and offers many new lines of enquiry with regards to developmental brain plasticity and visual expertise in autistics.

Dr. Isabelle Soulières of the CETEDUM and the Neural Systems Group at the Massachusetts General Hospital (NSGMGH) and Dr.Thomas Zeffiro of the NSGMGH, also contributed to the findings. The CETEDUM is based at the University of Montreal affiliated Rivière-des-Prairies Hospital and is part of the Fernand-Seguin Research Centre. It is officially known as Centre d'Excellence en Troubles Envahissants du Développement de l'Université de Montréal. The research was financed in part by grants from Autism Speaks, the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes for Health Research and the Fonds de la Recherche en Santé du Québec.

Adipose Cells and Breast Cancer: A Dangerous Combination

ScienceDaily (Apr. 5, 2011) — Apart from its direct effect on health (such as cardiovascular diseases and diabetes), obesity is increasingly suspected of playing a role in the prognosis of breast cancer and, in particular, its propensity to spread. However, no direct cause and effect relationship had been demonstrated until now.

Section of tumor (mauve) in the presence of adipocytes (white discs). The arrows indicate adipocytes modified by the tumor. (Credit: Copyright 

This breakthrough has finally been made through the collaborative work of two teams of researchers from Inserm, CNRS and the Université Paul Sabatier. Their research has made it possible to highlight, both in vitro and in vivo, the presence of adipose cells (known as adipocytes) near breast tumors. These adipocytes have specific biological characteristics. When associated with tumors, they are capable of modifying the characteristics of cancerous cells, making them more aggressive. The results of this work are published in Cancer Research on 1st April 2011.

Numerous statistical studies have already established a link between obesity and the "aggressiveness" of breast cancer in women, without ever succeeding to explain this phenomenon. In order to find an explanation, the researchers studied the cross-talk between adipose cells and tumor cells.

The external part of the breast essentially contains fat tissue, mainly composed of adipose cells. Apart from storing/releasing fats, these cells are capable of secreting numerous proteins. The researchers therefore attempted to find out whether these proteins play a role in the development of breast cancers.

To do so, the teams headed by Philippe Valet at the Institut des Maladies Métaboliques et Cardiovasculaires (Inserm/Université Paul Sabatier) and Catherine Muller at the Institut de Pharmacologie et de Biologie Structurale (CNRS/Université Paul Sabatier) used an original co-culture system between mammary tumor cells and adipocytes. In the presence of tumor cells, the adipocytes exhibit a modification in the secretion of some of their proteins, including inflammatory proteins such as interleukin-6 (IL-6). Adipose cells progressively establish a real interaction with the tumor, which leads to an increase in its "colonization potential" and thus its aggressiveness.

Indeed, when injecting mice with tumor cells co-cultivated beforehand with adipocytes, the researchers observed that the tumor was more likely to form metastases. A significant factor is that these specific modifications in adipocytes have been observed in human tumors, confirming the importance of the phenomenon. In addition, the researchers observed that the adipocytes near large human tumors, with ganglionic invasion, contained more IL-6. The protein could thus play an important role in the adipocyte-induced spread of breast cancer.

This works shows that adipocytes undoubtedly play an unexpected role in the spread of such tumors. "Our results now demonstrate how adipocytes actively participate in the progression of breast cancer, orchestrated by tumor cells. They suggest that in the case of obesity, the adipocytes associated with breast cancer could be more likely to amplify the 'aggressive' effect of tumors," the researchers say. "This hypothesis still needs to be verified both in mice and humans."

The study targets the development of specific strategies for overweight patients suffering from the most aggressive cancers. For example, identifying the signals supplied by the adipocytes to stimulate the invasive properties of tumor cells could represent a new lead for treating these patients.

This work is financially supported by the French National Cancer Institute.

New Technology Capable of Detection of 150 Genetic Syndromes from an Amniocentesis

ScienceDaily (Apr. 5, 2011) — Genetadi Biotech has presented to the scientific community -- meeting at the XXVI National Congress on Human Genetics held in Murcia -- a prenatal diagnostic device based on amniocentesis. More concretely, it is based on microarray technology (genomic hybridisation genetic chips) and with a diagnostic resolution 100 times greater than the common cytogenetic techniques.

The new device, known as Amniochip, is able to detect 150 genetic syndromes. "This involves currently validated genetic syndromes, including malformations and idiopathic mental deficiency not detected with a conventional kariotype," explained Ms Silvia Ávila, co-director of Genetadi.

The scientists pointed out that one of the advantages of this innovative technique is the fact that "a cell culture is not necessary." Thus, "the waiting time for the results with the new device drops to 48 hours, in contrast to the three weeks it currently takes through conventional kariotype technique."

Nevertheless, from a clinical perspective, the procedure for the diagnosis does not change, starting with a standard amniocentesis undertaken by the specialist gynaecologist. "The sample of amniotic liquid does not differ at all from the current amniocentesis procedure," explained doctor Ávila. "With the Amniochip only 8 or 10 ml of amniotic liquid are necessary in a tube, and which is sent to a laboratory via messenger, exactly as with the usual genetic trials."

The application of this new technology, through a prescription from the specialist in gynaecology and obstetrics, is especially suitable for all those pregnant women who require a conventional genetic study (kariotype or FISH). That is, those suspected from ecographs of having malformations, or with positive triple marker, or the over 35s. It is also suitable for couples with a history of miscarriage, or with a family history of genetic syndromes.

In those cases in which the research using this new technology found a result with doubtful clinical significance, "the DNA of the two progenitors were also analysed; in order to discard any family polymorphic alterations," explained Dr Ávila.

The new device for enhanced prenatal diagnosis, developed by Genetadi "is based on Comparative Genomic Hybridisation" (aCGH) microarray technology. Using this technique, "the sample to study and a reference are marked with different fluorochromes. These DNA hybridise on a crystal which contains thousands of different segments of human DNA. The regions selected on the Amniochip belong to regions of the human genome involved in more than 150 already known syndromes. Subsequently, computer software is used to identify the areas of differential hybridisation between the patient and the DNA control, thus indicating the existence of an alteration in its dosage (microdeletion or microduplication)."

Call of the Riled: Stress Signal in Cancer Cells Triggers Similar Response in Other Cells, Aiding Tumor Growth

ScienceDaily (Apr. 5, 2011) — Researchers at the University of California, San Diego School of Medicine say a "stress response" mechanism used by normal cells to cope with harsh or demanding conditions is exploited by cancer cells, which transmit the same stress signal to surrounding cells, triggering an inflammatory response in them that can aid tumor growth.

An artist's representation shows how stress signals from cancer cells prompt similar signals in neighboring cells, aiding and abetting tumor growth. Left: To survive in a harsh environment (low oxygen, nutrient deprivation), tumor cells produce constant endoplasmic reticulum (ER) stress response. Center: These ER stress signals are transmitted to nearby macrophages -- white blood cells charged with recognizing and removing tumor cells and pathogens. The macrophages react with their own ER stress signals, initiating an inflammation response. Right: The resulting macrophage-amplified inflammation encourages more tumor growth.

The findings are reported by Maurizio Zanetti, MD, professor of medicine and director of the Laboratory of Immunology at the UC San Diego Moores Cancer Center, and colleagues, and published in the April 4 early online edition ofProceedings of the National Academy of Sciences.

The endoplasmic reticulum (ER) is the protein-making factory inside all cells. Increased physiological demands or disease conditions can sometimes cause proteins to misfold and accumulate in the ER. Cells typically respond by an ER stress response, which attempts to reset normal ER balance.

For normal cells, the ER stress response is transient. For tumor cells, it's life. Because they exist in an environment that's invariably difficult (their host is always trying to kill them, and oxygen and nutrient deprivation are frequent), tumor cells produce an on-going ER stress response, which helps them not only to survive, but to thrive.

According to Zanetti and colleagues, tumor cells generate "transmissible ER stress." Specifically, they induce bystander cells to issue a similar stress response, most notably nearby macrophages -- a type of white blood cell employed by the body's immune system to recognize and remove pathogens and cellular debris.

Recently, several laboratories, including some at UC San Diego, have underscored the crucial role of inflammation in promoting cancer growth. A consequence of "transmissible ER stress" points to "receiver" macrophages as an important source of inflammation, which serves as an environmental cue for cancer development.

"It's well-known that macrophages entering the tumor microenvironment lose the ability to aid the immune system in rejecting the tumor, and that they may actually play a role in actively suppressing anti-tumor immunity," said Zanetti. "We believe that transmissible ER stress could be an important initial tumor-derived signal that promotes the 'brainwashing' of macrophages in the tumor microenvironment. It could be the first event in a cascade that results in the commandeering of macrophages by the tumor."

If so, transmissible ER stress may represent a unifying mechanism that explains at least some of the earliest interactions between tumors and the immune system. "Our paper details the first evidence of this phenomenon," Zanetti said, adding that transmissible ER stress also presents a new, potential target for tumor-specific therapies and drugs.

"Our findings suggest that development of therapies targeted against the tumor ER stress response may be doubly effective," said Zanetti. "Such therapies would target not only the tumor's intrinsic ability to cope with microenvironmental insults, but, at the same time, would impede the tumor cells' ability to nullify the anti-tumor immune response, perhaps allowing our bodies to more easily fight off tumors."

Co-authors of the study are Navin R. Mahadevan and Jeffrey Rodvold, Laboratory of Immunology UC San Diego Moores Cancer Center and Biomedical Sciences Program; Homero Sepulveda, BD Biosciences, San Diego; Steven Rossi, UCSD Department of Pediatrics, Cancer Symptom Control Program; and Angela F. Drew, Department of Cancer and Cell Biology, University of Cincinnati.

Funding for this research came, in part, from grants from the UCSD Academic Senate, UCSD Medical Scientist Training Program and the National Institute on Drug Abuse.

Bone Marrow Cells That Transform Into Skin Cells Could Revolutionize Approach to Wound Treatment

ScienceDaily (Apr. 5, 2011) — Researchers at King's College London and Osaka University in Japan have identified specific bone marrow cells that can transform into skin cells to repair damaged skin tissue, according to a study published inProceedings of the National Academy of Sciences(PNAS).

Bone marrow cells (green) can regenerate skin, including the outer epidermal layer (red).

The team has uncovered how this process works, providing new insights into the mechanisms behind skin repair. This significant advance has the potential to revolutionise approaches to wound treatment in the future, which could benefit people with chronic wounds such as leg ulcers, pressure sores and burns, as well as genetic skin diseases such as epidermolysis bullosa, which causes painful blisters on the skin.

The current management of chronic wounds in UK patients costs more than a billion pounds every year so this new scientific discovery could lead to significant future cost savings for the NHS.

It was already known that bone marrow may play a role in skin wound healing, but until now it was not known which specific bone marrow cells this involves, how the process is triggered, and how the key cells are recruited to the affected skin area. The team of researchers carried out experiments in mice, specifically looking at the mechanisms involved when skin grafts are used, compared with non-grafted wound healing.

The findings showed that in mice with non-grafted wound healing, very few bone marrow cells travelled to the wound to repair it and they did not make a major contribution to epidermal repair. But in mice where a skin graft was used, a significantly higher number of specific bone marrow-derived cells travelled to the skin graft to heal the area more quickly and build new skin directly from the bone marrow cells.

The research showed that around one in every 450 bone marrow cells has the capacity to transform into skin cells and regenerate the skin.

The team also identified the signal that triggers recruitment of the bone marrow cells to repair skin. Damaged skin can release a distress protein called HMGB1 that can mobilise the cells from bone marrow and direct them to where they are needed.

Mice with skin grafts express high levels of HMGB1 in their blood that can drive the bone marrow repair process. The findings provide new insight into how skin grafts work in medicine -- they do not simply cover wounds, but act as bioreactors that can kick-start regenerative skin repair.

The research also showed that patients with epidermolysis bullosa have high levels of HMGB1 in their blood and that the source here is the roofs of the blisters in their skin. This finding demonstrates that HMGB1 is also important in human skin damage and wound healing responses.

Professor John McGrath, Head of the Genetic Skin Disease Group at King's, recently spent several months working on the project in Osaka. He said: "This work is tremendously exciting for the field of regenerative medicine. The key achievement has been to find out which bone marrow cells can transform into skin cells and repair and maintain the skin as healthy tissue, and to learn how this process happens.

"Understanding how the protein HMGB1 works as a distress signal to summon these particular bone marrow cells is expected to have significant implications for clinical medicine, and could potentially revolutionise the management of wound healing.

"Chronic wounds and tissue injury represent a significant cost to the NHS, not to mention the debilitating effects on peoples' quality of life. Our plan is to see if we can now use this scientific advance to develop more effective treatments to improve tissue repair in skin and perhaps other organs."

Professor McGrath is working together with colleagues at Osaka University to harness the key parts of the HMGB1 protein to create a drug treatment that can augment tissue repair. It is expected that the developed treatment will be tested in animal models in about a year and enter clinical trials shortly afterwards.

Protein Found to Be the Link Missing Between HPV Infection and Cervical Cancer Development

ScienceDaily (Apr. 5, 2011) — Most women are infected with human papillomavirus (HPV), which can cause cervical cancer -- yet few develop the cancer. Now researchers at Georgetown Lombardi Comprehensive Cancer Center, a part of Georgetown University Medical Center, believe they have found the missing link explaining why: activation of the beta-catenin oncogene.

At the American Association for Cancer Research (AACR) 102nd Annual Meeting 2011, the researchers say that a new mouse model they developed demonstrates that switching the oncogene on in the cervix of HPV infected mice promoted development of aggressive cervical cancer.

These early findings suggest clinical implications that are both preventive and therapeutic, says the study's senior investigator, Aykut Üren, M.D., an associate professor of oncology at Lombardi

"We can potentially develop a screening method to check for HPV and beta-catenin activation in pap smears," he says. "That will identify individuals at a higher risk of developing cancer compared to ones who are only HPV positive. Then they can be more closely followed for cancer development."

Secondly, Üren points out that there are new drugs being developed to target the Wnt pathway that includes the beta-catenin protein. "Activation of this pathway is very common in colon cancer and is found in a dozen other cancers, so these same novel drugs might be useful in treating advanced stage cervical cancer patients," he says.

Üren points out that while cervical cancer has been kept in check in the U.S. and other developed nations due to use of Pap smears and, of late, the HPV vaccine that protects uninfected females, cervical cancer is the second leading cause of cancer deaths in women worldwide. "New international approaches to control and treat cervical cancer are desperately needed," he says.

Their novel mouse model was created by cross-breeding two other strains of transgenic mice -- one that expresses HPV genes in the cervix and the other that forces the beta catenin/Wnt pathway to be constantly activated, also in the cervix. While the HPV infected mice are programmed to develop cervical cancer, the tumors that grew in the double transgenic mice were larger and more aggressive.

The study was funded by the National Cancer Institute. Gülay Bulut, Ph.D., a postdoctoral researcher in Üren's laboratory, will present the results at a poster session.

The authors report having no personal financial interests related to the study.

Toward a Solution to Nerve Agent Exposure: Chemist Uses Supercomputers to Test Reagents for New Treatments

ScienceDaily (Apr. 5, 2011) — Scientists are working to develop a new drug that will regenerate a critical enzyme in the human body that "ages" after a person is exposed to deadly chemical warfare agents.

Preliminary simulations conducted by Ohio State Professor Christopher Hadad identify catalytic amino acid residues and other critical binding residues in the active site of AChE.

Christopher Hadad, Ph.D., professor of chemistry at The Ohio State University (OSU), is leveraging Ohio Supercomputer Center (OSC) resources to help develop a more effective antidote to lethal chemicals called organophosphorus (OP) nerve agents.

"This project is a combination of synthetic and computational organic chemistry conducted through OSC at Ohio State, and biochemical studies conducted by colleagues at the U.S. Army Medical Research Institute of Chemical Defense at Aberdeen Proving Ground in Maryland," said Hadad.

OP nerve agents inhibit the ability of an enzyme called acetylcholinesterase (AChE) to turn off the messages being delivered by acetylcholine (ACh), a neurotransmitter, to activate various muscles, glands and organs throughout the body. After exposure to OP agents, AChE undergoes a series of reactions, culminating in an "aging" process that inactivates AChE from performing its critical biological function. Without the application of an effective antidote, neurosynaptic communication continues unabated, resulting in uncontrolled secretions from the mouth, eyes and nose, as well as severe muscle spasms, which, if untreated, result in death.

Conventional antidotes to OP nerve agents block the activity of the nerve agent by introducing oxime compounds, which have been the focus of a number of studies. These compounds attach to the phosphorus atom of the nerve agent, after the OP is bound to AChE, and then split it away from the AChE enzyme, allowing the AChE to engage with receptors and finally relax the tissues.

However, in some cases, the combined nerve agent/AChE molecule undergo a process called aging, in which groups of single-bonded carbon and hydrogen atoms called alkyl groups are removed from the molecule and a phosphonate residue is left behind in the AChE active site. Relatively unstudied in nerve agents, this process, called dealkylation, makes the nerve agent/AChE molecule unreceptive to oximes -- an unfortunate situation, considering that certain nerve agents (e.g., soman) can undergo aging within minutes of exposure to AChE.

Hadad's study is focused on the identification of compounds that would return an appropriate alkyl group to the aged nerve agent/AChE molecule, thus allowing treatment with oximes to provide for complete recovery. The project is investigating common OP nerve agents Tabun, VX, VR, Sarin, Soman, Cyclosarin and Paraoxon, all of which take on a similar molecular structure upon aging.

"Computational studies of the interaction of the alkylating compounds with AChE were used to provide insight for the design of selective reagents," Hadad explained. "Ligand-receptor docking, followed by molecular dynamics simulations of the interactions of alkylating compounds with aged OP-AChE, was carried out in conjunction with experimental studies to investigate the binding of alkylating compounds to AChE. These results were then used to suggest interactions that aided in the orientation of alkylating compounds for maximal efficacy."

Throughout the project, Hadad employed computational studies to guide the progress of each objective, as well as to rationalize the observed experimental results.

"Dr. Hadad's work on this project has made use of a range of the tools of electronic structure theory, molecular docking, molecular dynamics and hybrid quantum mechanical/molecular mechanical methods," said Ashok Krishnamurthy, interim co-executive director of OSC. "It was by design that OSC's flagship system, the Glenn IBM 1350 Opteron cluster, was developed to meet the needs of the bioscience research investigators, such as Dr. Hadad."

Hadad's investigations of nerve agent antidotes are funded by the Defense Threat Reduction Agency (W81XWH-10-2-0044) and supported by the award of an OSC Discovery Account.

Chimp, Bonobo Study Sheds Light on the Social Brain

ScienceDaily (Apr. 5, 2011) — It's been a puzzle why our two closest living primate relatives, chimpanzees and bonobos, have widely different social traits, despite belonging to the same genus. Now, a comparative analysis of their brains shows neuroanatomical differences that may be responsible for these behaviors, from the aggression more typical of chimpanzees to the social tolerance of bonobos.

Neuroanatomical differences between the brain of the chimpanzee (left) and the bonobo (right) match what we know about the human brain and behavior. 

"What's remarkable is that the data appears to match what we know about the human brain and behavior," says Emory anthropologist James Rilling, who led the analysis. "The neural circuitry that mediates anxiety, empathy and the inhibition of aggression in humans is better developed in bonobos than in chimpanzees."

The journal Social Cognitive and Affective Neuroscience published the results, the most comprehensive comparative analysis to date of the neural systems of chimpanzees and bonobos.

"By contributing to our basic understanding of how brain anatomy relates to social behavior, this study may provide clues to the brain dysfunction underlying human social behavioral disorders like psychopathy and autism," Rilling says.

Chimpanzees and bonobos diverged from a common ancestor with humans about six million years ago, and from each other just one-to-two million years ago. Despite this relatively brief separation in evolutionary terms, the two species exhibit significant differences in social behavior. Compared with chimpanzees, bonobos are more anxious, less aggressive, more socially tolerant, more playful, more sexual and perhaps more empathic.

"Chimpanzees tend to resolve conflict by using aggression, while bonobos are more likely to use behavioral mechanisms like sex and play to diffuse tension," Rilling says. "The social behaviors of the two species mirror individual differences within the human population."

Rilling heads Emory's Laboratory for Darwinian Neuroscience, a leader in the use of non-invasive neuro-imaging technology to compare the neurobiology of humans and other primates. The anthropology department lab draws on resources of Emory's Yerkes National Primate Research Center.

"In addition to exploring links between neuroanatomy and different social behaviors, we're mapping the underlying biology for how species evolve and differentiate," Rilling says.

A range of imaging and analytical techniques were used in the chimpanzee-bonobo study. Voxel-based morphometry compared the gray matter in standard structural scans of the brains. Diffusion tensor imaging (DTI) captured the white matter connections, to compare the fiber tracts that "wire" the brain.

The results showed that bonobos have more developed circuitry for key nodes within the limbic system, the so-called emotional part of the brain, including the amygdala, the hypothalamus and the anterior insula. The anterior insula and the amygdala are both implicated in human empathy.

"We also found that the pathway connecting the amygdala and the prefrontal cortex is larger in bonobos than chimpanzees," Rilling says. "When our amygdala senses that our actions are causing someone else distress, we may use that pathway to adjust our behavior in a prosocial direction."

Chimpanzees have better developed visual system pathways, according to the analysis. Previous research has suggested that those pathways are important for tool use, a skill which chimpanzees appear better at than bonobos.

Rilling conducted the research with Yerkes neuroscientist Todd Preuss; DTI experts Timothy Behrens and Jan Scholz from Oxford University; Emory graduate student Bhargav Errangi; and former Emory student Matthew Glasser.