Sistema para monitorar dengue deve operar nesta semana, diz ministro

Informações diárias sobre óbitos pela doença serão disponibilizados. Ministro da Saúde se reuniu com secretários de saúde e apresentou sistema.

O ministro da Saúde, Alexandre Padilha, afirmou nesta quarta-feira (19) que o sistema para monitoramento de casos de dengue com dados atualizados deve passar a funcionar a partir desta semana. O sistema será abastecido semanalmente com informações de casos de dengue, e diaramente com as mortes provocadas pela doença.

Padilha recebeu nesta quarta (19) secretários e representantes das secretarias de saúde dos 16 estados com risco "muito alto" de epidemia de dengue, de acordo com levantamento do ministério divulgado na semana passada. O ministro aproveitou para apresentar o sistema aos secretários.

"Viemos apresentar o sistema de monitoramento semanal dos casos de dengue e diário das suspeitas de óbito por dengue, sobretudo com foco nos municípios de mais alto risco. Eu estou inclusive revendo a portaria que orienta o processo de notificação. Nós devemos publicar o mais rápido possível", afirmou.

Os 16 estados considerados com risco "muito alto" são Acre, Amazonas, Pará, Maranhão, Piauí, Ceará, Rio Grande do Norte, Paraíba, Pernambuco, Alagoas, Sergipe, Bahia, Tocantins, Mato Grosso, Espírito Santo e Rio de Janeiro.

Segundo ele, o sistema contará com o auxílio de uma nova ferramenta, em fase de implantação: o site Dengue Online, que ainda não está no ar.

"Nós estamos implantando também uma nova ferramenta para auxiliar esse monitoramento, o que não significa que a gente não possa fazer esse monitoramento através do contato telefônico e via e-mail, que já estamos fazendo", disse Padilha.

Funasa

Alexandre Padilha falou ainda sobre a reunião que teve na manhã desta quarta com a diretoria da Fundação Nacional de Saúde (Funasa). "Estou me reunindo toda semana com a diretoria da Funasa, desde que assumi o ministério, com três grandes objetivos. O primeiro é acelerar a execução dos recursos do PAC [Programa de Aceleração do Crescimento]. Nós, inclusive, já identificamos volume importante de recursos, foram feitas vistorias de obras, resolvidas pendências de projetos para acelerar essa execução", afirmou.

O segundo objetivo, de acordo com Padilha, é a determinação de que a Funasa acelere a execução dos recursos, "sobretudo nos municípios que têm mais alto nível de infestação da dengue". "Isso está sendo feito pelas superintendências regionais. Nos estados que eu estou indo em combate à dengue, me reúno com os superintendentes da Funasa".

Padilha afirmou ainda que o terceiro objetivo é preparar propostas de ação na área de saneamento para contribuir com o plano de combate à miséria, que será apresentado pela presidente Dilma Rousseff.

Dinheiro

O ministro também afirmou que não irá especular sobre possíveis cortes que a saúde pode sofrer dentro das ações que vem tomando a presidente Dilma Rousseff.

"A presidenta e a ministra do Planejamento (Miriam Belchior) deixaram muito claro que qualquer corte é especulação que está sendo feita, e nós não entramos nessa bolsa de especulação", disse.

Segundo ele, as ações contra a dengue no início deste ano devem ser garantidas por dinheiro do Teto Financeiro de Vigilância em Saúde (TFVS) dos estados, ainda referente ao ano passado.

"Tem um conjunto de recursos do teto de vigilância do ano passado que não estava sendo executado, que é o que vai garantir as ações de janeiro e fevereiro. Tinha cerca de R$ 200 milhões do teto de vigilância de vários estados", explicou.

"Não vai ser por falta de recursos que nós vamos deixar de estruturar uma rede de atenção forte para garantir o combate à dengue", declarou o ministro, defendendo a participação de diversos setores da sociedade na campanha contra a doença.

Chip da Saúde detecta oito doenças no consultório médico

"Faça os exames e volte"

Uma das coisas mais irritantes quando procuramos um médico é a longa espera pelos resultados dos exames - e uma nova espera pela marcação do retorno.

Chamado por seus criadores de chip da saúde, o aparelho do tamanho de um cartão de crédito pode detectar viroses, doenças bacterianas e até câncer, tudo no consultório do médico

Todas as pesquisas no campo dos biochips têm como objetivo criar testes rápidos para vários tipos de doenças, que o médico possa aplicar no próprio consultório - ou que você possa comprar na farmácia.

E os resultados começam a aparecer.

O projeto MicroActive, financiado pela União Europeia, acabar de apresentar um biochip que permite que o próprio médico conduza o exame laboratorial durante a consulta.

Chamado por seus criadores de "chip da saúde", o minúsculo aparelho pode detectar viroses, doenças bacterianas e até câncer.

Chip da saúde

O avançado sistema integrado, que se baseia na microtecnologia - a mesma usada para fabricar os processadores de computador - e na biotecnologia, dispensa a ida ao laboratório, a longa espera, e mantém seus dados médicos restritos ao seu médico de confiança.

Mas a grande vantagem é que o minúsculo chip automatiza a análise, dando resultados mais precisos do que uma análise feita mesmo por técnicos experientes.

Segundo a equipe do projeto MicroActive, o novo chip da saúde contém um laboratório completo, embutido dentro de um plástico similar a um cartão de crédito.

Os experimentos iniciais foram feitos usando células colhidas para diagnóstico de câncer de colo uterino - um exame com alto índice de interpretações incorretas.

Mas o biochip pode diagnosticar várias doenças causadas por bactérias ou vírus, assim como diferentes tipos de câncer.

Laboratório portátil

O biochip contém vários canais muito estreitos, que contêm substâncias químicas e enzimas nas proporções corretas para as análises individuais. Quando a amostra do paciente é injetada nos canais, estes reagentes são misturados.

"O chip de saúde pode analisar o seu sangue ou células para oito doenças diferentes," explicam Liv Furuberg e Michal Mielnik, membro do grupo SINTEF, com sede na Noruega.

"O que essas doenças têm em comum é que elas são identificadas por meio de marcadores especiais, que são encontrados na amostra de sangue. Estas 'etiquetas' podem ser proteínas, que deveriam ou não deveriam estar ali, fragmentos de DNA [ácido desoxirribonucleico] ou enzimas.

"Este pequeno chip é capaz de realizar os mesmos processos que um grande laboratório, e não somente executá-los mais rápido, mas os resultados também são muito mais precisos. O médico simplesmente insere o cartão em uma pequena máquina, acrescenta umas gotas da amostra do paciente através de um tubo no cartão, e os resultados são mostrados rapidamente," explicam os cientistas.

Ansiosos para comercializar o chip da saúde, os pesquisadores estão trabalhando com um hospital, na qualidade de usuários finais, para validar a usabilidade do sistema e sua precisão clínica.

Vacinação seletiva pode ser melhor que vacinação em massa

Vacinação quântica

A recente epidemia de gripe A demonstrou a confiança que a população tem nas vacinas: todo o mundo queria vacinar-se contra a nova ameaça.

Isso só não foi feito porque a vacina simplesmente ainda não existia.

Mas será que a vacinação em massa é a melhor opção para cuidar da saúde pública, diminuindo a taxa de mortalidade, qualquer que seja a ameaça ou a doença?

Surpreendentemente, três físicos desenvolveram uma nova estratégia para uma vacinação intensiva, mas limitada, contra as doenças infecciosas (como a gripe), que substituiria a prática atual de inoculação em massa.

Os físicos desenvolveram sua teoria utilizando uma técnica emprestada da mecânica quântica.

Vacinação seletiva

Como funcionaria essa vacinação seletiva? O programa baseia-se em acelerar a extinção natural da doença através da vacinação seletiva.

O professor Baruch Meerson, um dos autores da nova estratégia explica a estratégia:

"Considere uma situação infeliz, quando uma doença infecciosa se espalhou sobre uma população, e uma determinada parcela da população está doente. A maioria dos indivíduos infectados recupera-se da doença e desenvolve imunidade a ela. Por outro lado, os indivíduos infectados podem espalhar a doença na população por meio de contatos com indivíduos suscetíveis.

"Para reduzir a propagação da infecção, pode-se vacinar todos os possíveis indivíduos suscetíveis. Se todos eles estiverem dispostos a serem vacinados e houver vacina suficiente para todos, a campanha de vacinação vai erradicar a doença com segurança.

"Muitas vezes, porém, há uma grande parcela de indivíduos suscetíveis se recusam a ser vacinados. Além disso, a vacina pode ser escassa, cara para produzir, ou difícil de armazenar."

Meerson e seus colegas Mark Dykman e Michael Khasin, da Universidade de Michigan (EUA), desenvolveram a estratégia para lidar com essa situação, muito mais plausível do que a situação onde há vacinas para todos e todos querem ser vacinados.

Desaparecimento natural das doenças

Os pesquisadores se aproveitaram do fato de que, mesmo sem vacinação, uma doença acaba se extinguindo por conta própria, como a própria história humana documenta, em períodos quando as vacinas ainda não haviam sido inventadas.

Mas, para grandes populações, como no mundo moderno, o tempo típico que leva para que uma doença desapareça por si só pode ser muito longo.

Essencialmente, os cientistas sugeriram uma estratégia de vacinação ideal que acelera, da melhor forma possível, este processo natural de desaparecimento da doença.

Nesta estratégia, a vacina deve ser aplicada para as populações mais suscetíveis, por exemplo, a faixa etária onde a doença se manifesta inicialmente ou com maior intensidade.

Seriam períodos curtos de vacinação, mas intensos, adaptados aos altos e baixos das "ondas" que ocorrem naturalmente na propagação das doenças infecciosas.

Além disso, quando a doença tem uma variação sazonal (como o resfriado comum), esse fator deve ser levado em consideração nos cálculos do calendário de vacinação.

Física da epidemiologia

A questão que permanece é: por que físicos abordaram um problema que pertence à epidemiologia?

Eles afirmam que o modelo matemático que usaram em sua análise se assemelha ao modelo de mecânica quântica que os físicos usam quando analisam a dinâmica de partículas microscópicas (como os elétrons) em armadilhas em miniatura.

Ajustando o tamanho das armadilhas é possível aumentar ou diminuir as chances de os elétrons escaparem.

Foi essa analogia inesperada que tornou possível tirar as conclusões surpreendentes sobre o protocolo de vacinação periódica - ou seja, para mostrar como uma vacinação seletiva, bem direcionada, pode realmente limitar a "fuga" desses germes infecciosos e permitir que a doença morra em grande parte através de um processo natural.

Os físicos agora querem modelar seu esquema de vacinação periódica utilizando dados do mundo real.

Mas eles afirmam que seus cálculos mostram que a vacinação de um percentual pequeno da população pode reduzir o tempo necessário para erradicar uma doença, digamos, de cinco meses, para entre três e quatro, com menores gastos e sem a necessidade de envolver toda a população.

Bloqueio de proteína pode ajudar tratamento de câncer de pele, diz estudo

Um grupo de cientistas demonstrou que bloquear a atividade da proteína interferon gama (IFN-gama) com remédios pode ser útil para o tratamento do câncer de pele. O estudo está na revista "Nature", em sua última edição.

A equipe, liderada pelo cientista Glenn Merlino, fez vários testes em ratos e observou como a radiação ultravioleta sobre o organismo desencadeia a produção de um tipo de glóbulo branco denominado macrófagos, o que favorece a criação da interferon gama e o desenvolvimento de melanomas.

Merlino, do National Câncer Institute de Maryland (EUA), garante que bloquear com anticorpos a interferon gama, uma proteína de tipo 2, inibe o crescimento anômalo de células na pele, enquanto bloquear da mesma forma interferons de tipo 1 não produz o mesmo efeito.

Ao contrário, se considera que os interferons de tipo 1 são moléculas que impedem o desenvolvimento de tumores, ao ponto de uma delas, a IFN-alpha, ser utilizada clinicamente para tratar o melanoma.

Deste modo, a ideia de que a IFN-gama favorece o progresso dos tumores cancerígenos significa uma "potencial mudança de paradigma" no campo da medicina e um importante avanço tanto na prevenção como no tratamento do câncer de pele, aponta Merlino na publicação.

Apesar de a comunidade científica aceitar que existe uma relação entre a radiação ultravioleta e a formação de melanomas, o mecanismo subjacente a esta associação ainda não está descrito de maneira exaustiva, adverte o estudo.

Aparelho mede pressão do cérebro sem furar o crânio

Uma nova técnica para medir a pressão interna do crânio foi desenvolvida por pesquisadores da USP.

O método não requer a perfuração do crânio e é mais barato do que o usado hoje.

A tecnologia, criada por uma equipe da USP de São Carlos, já foi testada em oito pacientes do Hospital das Clínicas de Ribeirão Preto.

O monitoramento é necessário quando há suspeita de aumento da pressão do crânio, como em derrames, tumores cerebrais, traumatismos e hidrocefalia.

No método tradicional, os médicos perfuram a calota craniana para medir a alteração da pressão com um sensor, o que pode causar infecções pelo contato entre o cérebro e o meio externo.

Com a nova técnica, é feita uma incisão no couro cabeludo e um sensor é colado no crânio, sem perfurar o osso.

"É muito difícil haver infecção e, se houver, será na pele e de fácil tratamento", diz o farmacêutico-bioquímico Gustavo Frigieri, que fez os testes com o equipamento em sua tese de doutorado.

"O corte na cabeça pode ser feito em ambulância, ambulatório e não precisa nem de centro cirúrgico."

Segundo o físico Sérgio Mascarenhas Oliveira, coordenador do grupo que desenvolveu a tecnologia, a técnica pode beneficiar centenas de milhares de pessoas.

"O número de traumas é muito grande, sobretudo no trânsito", diz.

Para medir a pressão sem furar o osso, a equipe de Mascarenhas usou um sensor que mede a deformação de materiais na engenharia.

O equipamento foi adaptado para o uso em seres humanos e mede a pressão pela dilatação do crânio. "Quanto maior a pressão, maior a dilatação", diz Frigieri.

CUSTO

O equipamento da USP é mais barato do que o utilizado hoje: o sensor custa R$ 400 e o monitor, R$ 5.000.

Já o método tradicional usa equipamentos importados. Segundo Frigieri, o monitor custa cerca de R$ 50 mil e um sensor descartável, pelo menos R$ 1.500.

Além disso, a nova tecnologia não requer uma equipe de cirurgiões; basta um médico que faça o corte na pele e que seja treinado a operar a máquina.

Os pesquisadores esperam que, com o baixo custo, a tecnologia possa ser oferecida no Sistema Único de Saúde, que não cobre os gastos do monitoramento tradicional, usado só na rede privada e em hospitais universitários, segundo o pesquisador.

MAIS TESTES

Para José Marcus Rotta, presidente da Sociedade Brasileira de Neurocirurgia, a técnica traz avanços.

Segundo ele, o aparelho pode adiantar o trabalho se o paciente tiver sofrido traumatismo longe do hospital.

"Seria fantástico usá-la numa ambulância, já que não se pode fazer a perfuração do paciente na rua."

Mas ele lembra que, em alguns casos, a perfuração do crânio é feita não só para monitorar a pressão mas também para tratar o problema. Além disso, o médico diz que mais testes são necessários.

Os pesquisadores da USP esperam atingir a marca de 30 pacientes monitorados com o novo equipamento e registrá-lo na Anvisa até o final do ano para iniciar sua comercialização.

Nova técnica reduz replicação do vírus HIV em camundongos

Método usa moléculas de RNA para sabotar infecção; tecnologia poderia combater outros vírus

SÃO PAULO - Uma nova técnica desenvolvida por pesquisadores americanos para combater a multiplicação das células infectadas pelo HIV demonstrou ser bastante promissora no controle do vírus, ao menos em camundongos.

Cientistas do Beckman Research Institute, nos EUA, conseguiram desenvolver em laboratório uma combinação de moléculas de RNA que, quando aplicadas no sangue dos animais, procuram e invadem as células infectadas pelo HIV, preservando as saudáveis. Os resultados foram publicados na mais recente edição da revista Science.

Essa molécula combinada funciona como uma espécie de míssil guiado: ao localizar as células doentes, ela se liga à cápsula que envolve o HIV e inicia um processo de degradação do vírus, impedindo que ele continue o processo de replicação.

“O RNA assume uma forma específica, que se une seletivamente à proteína da capa do vírus HIV”, afirmou por e-mail o professor John J. Rossi, um dos autores principais do estudo.

A substância foi aplicada nos ratos diariamente, várias vezes por dia. Segundo os pesquisadores, ela age por cerca de 12 horas. Como camundongos geralmente não se contaminam pelo HIV, os pesquisadores os deixaram totalmente imunodeprimidos e, em seguida, injetaram células humanas saudáveis e depois o HIV.

Os cientistas perceberam que, ao aplicar essa substância no sangue dos animais, houve uma forte queda nas concentrações de HIV, o que demonstra que aconteceu um bloqueio da multiplicação viral e uma proteção dos níveis de CD4 (células de defesa).

“Há muito tempo a ciência desenvolveu essa técnica de interferência de RNA, mas apenas em laboratório, com cultura de células. É a primeira vez que um grupo consegue realizar essa experiência em células vivas de um modelo animal”, afirma o infectologista Esper Kallás, professor e pesquisador da USP.

Para Kallás, os resultados são importantes não apenas para combater o HIV, mas também outras doenças. “Teoricamente, você pode aplicar a mesma técnica para qualquer outro vírus, até mesmo para algo relacionado ao câncer. Ainda há muitas respostas a serem esclarecidas, mas, se for comprovado que a técnica não traz riscos e funciona em humanos, com certeza será uma aliada ao tratamento", avalia.

Malaria Parasite Caught Red-Handed Invading Blood Cells

ScienceDaily (Jan. 19, 2011) — Australian scientists using new image and cell technologies have for the first time caught malaria parasites in the act of invading red blood cells. The researchers, from the Walter and Eliza Hall Institute in Melbourne, Australia, and the University of Technology, Sydney (UTS), achieved this long-held aim using a combination of electron, light and super resolution microscopy, a technology platform new to Australia.

This image is a composite showing the behavior of different parts of the malaria parasite as it invades a red blood cell, at nanometer scales. The three components of the malaria parasite are labeled with fluorescent proteins (blue = parasite nucleus, red = secretory organelle, green = tight junction). The red blood cell is superimposed on the image for context. Image 1 (Attachment): The parasite is about to invade the red blood cell (unseen to the right of the picture). The tight junction (green) is like a window that the parasite brings with it and inserts into the red blood cell to gain entry. Image 2 (Invasion): This image is mid-invasion, the first time this step has even been visualized. The parasite "opens" the window it has inserted into the cell, and walks through. The secretory organelle (red) secretes its contents through the tight junction (green) and creates a vacuole which the parasite lives within in the red blood cell. In this image we see the parasite nucleus (blue) moving through the ‘window’ into the cell. Image 3 (Sealing): The parasite has completed invasion and is within a vacuole inside the host red blood cell. The window has been closed again, and will break down at a later stage. The parasite is now enclosed within its vacuole (red), the nucleus (blue) showing the parasite safely inside. (Credit: David Riglar and Jacob Baum (Walter and Eliza Hall Institute) with support from Cynthia Whitchurch and Lynne Turnbull (University of Technology, Sydney).)

The detailed look at what occurs as the parasite burrows through the walls of red blood cells provides new insights into the molecular and cellular events that drive cell invasion and may pave the way for developing new treatments for malaria. Institute researchers Dr Jake Baum, Mr David Riglar, Dr Dave Richard and colleagues from the institute's Infection and Immunity division led the research with colleagues from the i3 institute at UTS.

Dr Baum said the real breakthrough for the research team had been the ability to capture high-resolution images of the parasite at each and every stage of invasion, and to do so reliably and repeatedly. Their findings are published in today's issue of the journal Cell Host & Microbe.

"It is the first time we've been able to actually visualise this process in all its molecular glory, combining new advances developed at the institute for isolating viable parasites with innovative imaging technologies," Dr Baum said.

"Super resolution microscopy has opened up a new realm of understanding into how malaria parasites actually invade the human red blood cell. Whilst we have observed this miniature parasite drive its way into the cell before, the beauty of the new imaging technology is that it provides a quantum leap in the amount of detail we can see, revealing key molecular and cellular events required for each stage of the invasion process."

The imaging technology, called OMX 3D SIM super resolution microscopy, is a powerful new 3D tool that captures cellular processes unfolding at nanometer scales. The team worked closely with Associate Professor Cynthia Whitchurch and Dr Lynne Turnbull from the i3 institute at UTS to capture these images.

"This is just the beginning of an exciting new era of discoveries enabled by this technology that will lead to a better understanding of how microbes such as malaria, bacteria and viruses cause infectious disease," Associate Professor Whitchurch said.

Dr Baum said the methodology would be integral to the development of new malaria drugs and vaccines. "If, for example, you wanted to test a particular drug or vaccine, or investigate how a particular human antibody works to protect you from malaria, this imaging approach now gives us a window to see the actual effects that each reagent or antibody has on the precise steps of invasion," he said.

Malaria is caused by the Plasmodium parasite, which is transmitted by the bite of infected mosquitoes. Each year more than 400 million people contract malaria, and as many as a million, mostly children, die.

"Historically it has been very difficult to both isolate live and viable parasites for infection of red blood cells and to employ imaging technologies sensitive enough to capture snapshots of the invasion process with these parasites, which are only one micron (one millionth of a metre) in diameter," Dr Baum said.

He said one of the most interesting discoveries the imaging approach revealed was that once the parasite has attached to the red blood cell and formed a tight bond with the cell, a master switch for invasion is initiated and invasion will continue unabated without any further checkpoints.

"The parasite actually inserts its own window into the cell, which it then opens and uses to walk into the cell, which is quite extraordinary," Dr Baum said. "Visually tracking the invasion of Plasmodium falciparum into a red blood cell is something I've been aiming at ever since I began at the Walter and Eliza Hall Institute in 2003; it's really thrilling to have reached that goal. This technology enables us to look at individual proteins that we always knew were involved in invasion, but we never knew what they did or where they were, and that, we believe, is a real leap for malaria researchers worldwide."

This work was supported by the National Health and Medical Research Council, The University of Melbourne, Canadian Institutes of Health, the University of Technology, Sydney, and the Australian Research Council.

New Leads in the Case Against Drug-Resistant Biofilms

ScienceDaily (Jan. 19, 2011) — Films of bacteria that form around foreign materials in the body can be very difficult to defeat with drugs, but research led by Brown University biologists has identified a couple proteins that play a key role in building these "biofilms." This pair could prove to be a very important target for developing new antibiotics to fight infections.

Bird of Prey: Wings of the MqsA, each stabilized by zinc on the wing tip, may control the growth of cells that support biofilms, which are resistant to antibiotics. (Credit: Page Lab/Brown University)

When a foreign object such as a catheter enters the body, bacteria may not only invade it but also organize into a slick coating -- a biofilm -- that is highly resistant to antibiotics. Like sophisticated organized crime rings, biofilms cannot be defeated by a basic approach of conventional means. Instead doctors and drug developers need sophisticated new intelligence that reveals the key players in the network and how they operate. New research led by biologists at Brown University provides exactly that dossier on some key proteins in the iconic bacterium E. coli.

In a paper published this week in theJournal of Biological Chemistry, the researchers describe a couple of prime suspect genes and the "toxin-antitoxin" protein pair they produce. By analyzing the structure and binding of the proteins in the exquisite detail of atomic-scale X-ray crystallography, the team at Brown and Texas A&M University makes the case that "MqsR" and "MqsA" proteins are important operators worth targeting in hopes of disrupting the formation of biofilms.

"Developing new antibiotics has been very difficult, and they all pretty much target the same few proteins," said corresponding author Rebecca Page, assistant professor of molecular biology, cell biology and biochemistry at Brown. "Our proteins belong to a family of proteins that have never been investigated for their ability to lead to novel sets of antibiotics. This really provides a new avenue."

The main role of the combination, or complex, of MqsA and MqsR is that they appear to control the transcription of many genes, including ones that govern the growth of "persister" cells, which provide biofilms with a mesh of antibiotic-resistant constituents. In normal populations, persisters are one in a million. In biofilms, they are one in a hundred.

"The MqsR:MqsA complex not only binds its own genetic promoter, but also binds and regulates the promoters of other genes that are important for biofilm formation," Page said. "This is the only known toxin-antitoxin system that is capable of doing this."

An odd bird

The MqsA antitoxin is as unusual as it is influential, Page's team reports. For one thing, the protein, which resembles a bird with wide flapping wings -- Page likens it to a Klingon "Bird of Prey" ship from Star Trek -- needs the metal zinc on each wing tip to keep it stable. When it's bound to its partner toxin and DNA, the antitoxin also keeps a very tight lid on the toxin's ability to operate on mRNA, squeezing key parts, or active sites, so close together (about 1 billionth of a meter) that the mRNA simply can't enter.

Because the toxin's activity is key to the health and welfare of persister and biofilm cells, the properties of the toxin-antitoxin binding that regulate them give rise to some potential drug development strategies, Page said. For most of the time, the toxin is bound by the antitoxin, allowing cells to grow. Under other conditions, the antitoxin is destroyed and the toxin is free to cleave, or disable, mRNA. That shuts off existing persister and biofilm cells from further growth, and instead keeps them in a dormant state well-protected from things like antibiotics. If that cleaving goes on too long, however, the cells will die.

So two approaches for drug development, Page said, might be to find compounds that can either keep the toxin-antitoxin pair associated all the time (so that the toxin is inactive and thus that no cleaving occurs), or keep them separated all the time (so that the toxin is active and cleaving always occurs). The zinc on the antitoxin may also prove to be a target.

The investigation is ongoing, but the word is now out on the street that for MqsA and MqsR, the heat is on.

In addition to Page, the paper's other authors are graduate student Breann Brown and Associate Professor Wolfgang Peti in Brown's Department of Molecular Pharmacology, Physiology, and Biotechnology, and Thomas Wood, professor of chemical engineering at Texas A&M.

Cancer-Fighting Role for Cells Discovered

ScienceDaily (Jan. 19, 2011) — MIT scientists have discovered that cells lining the blood vessels secrete molecules that suppress tumor growth and keep cancer cells from invading other tissues, a finding that could lead to a new way to treat cancer.

Elazer Edelman, professor in the MIT-Harvard Division of Health Sciences and Technology (HST), says that implanting such cells adjacent to a patient's tumor could shrink a tumor or prevent it from growing back or spreading further after surgery or chemotherapy. He has already tested such an implant in mice, and MIT has licensed the technology to Pervasis Therapeutics, Inc., which plans to test it in humans.

Edelman describes the work, which appears in the Jan. 19 issue of the journal Science Translational Medicine, as a "paradigm shift" that could fundamentally change how cancer is understood and treated. "This is a cancer therapy that could be used alone or with chemotherapy radiation or surgery, but without adding any devastating side effects," he says.

Cells that line the blood vessels, known as endothelial cells, were once thought to serve primarily as structural gates, regulating delivery of blood to and from tissues. However, they are now known to be much more active. In the 1980s, scientists discovered that endothelial cells control the constriction and dilation of blood vessels, and in the early 1990s, Edelman and his postdoctoral advisor, Morris Karnovsky, and others, discovered an even more important role for endothelial cells: They regulate blood clotting, tissue repair, inflammation and scarring, by releasing molecules such as cytokines (small proteins that carry messages between cells) and large sugar-protein complexes.

Many vascular diseases, notably atherosclerosis, originate with endothelial cells. For example, when a blood vessel is injured by cholesterol, inappropriately high blood sugar, or even physical stimuli, endothelial cells may overreact and provoke uncontrolled inflammation, which can further damage the surrounding tissue.

Edelman and HST graduate student Joseph Franses hypothesized that endothelial cells might also play a role in controlling cancer behavior, because blood vessels are so closely entwined with tumors. It was already known that other types of cells within tumors, known collectively as the tumor stromal microenvironment, influence cancer cell growth and metastasis, but little was known about how endothelial cells might be similarly involved.

In the new study, Edelman, Franses and former MIT postdoctoral fellows Aaron Baker and Vipul Chitalia showed that secretions from endothelial cells inhibit the growth and invasiveness of tumor cells, both in cells grown in the lab and in mice. Endothelial cells secrete hundreds of biochemicals, many of which may be involved in this process, but the researchers identified two that are particularly important: a large sugar-protein complex called perlecan, and a cytokine called interleukin-6. When endothelial cells secrete large amounts of perlecan but little IL-6 they are effective at suppressing cancer cell invasion, whereas they are ineffective in the opposite proportions.

The researchers theorize that there is a constant struggle between cancer cells and endothelial cells, and most of the time, the endothelial cells triumph. "All of us, every day, are exposed to factors that cause cancer, but relatively few of us exhibit disease," says Edelman. "We believe that the body's control mechanism wins out the bulk of the time, but when the balance of power is reversed cancer dominates."

The struggle also depends on a third player, the endothelial cells' extracellular matrix -- structural proteins that pave blood vessels and on which the endothelial cells reside. Endothelial cells only function properly when their extracellular matrix is stable and of the correct biochemical composition. Under normal conditions, if a cell becomes cancerous, the endothelial cell may then keep it in check. However, the cancer cell fights back by trying to destroy the extracellular matrix or change the endothelial cell directly, both of which hinder the endothelial cell's efforts to control the cancer.

"There is this three-way balance that needs to be achieved," says Edelman. The more aggressive a cancer cell, the more likely it is to overcome the endothelial cells and extracellular matrix, allowing it to spread to other tissues.

Several years ago, Edelman began using endothelial cells, grown within a scaffold made of denatured, compressed collagen (a protein that makes up much of human connective tissue), as an implantable device. The "matrix-embedded endothelial cells" served as a convenient unit that could be produced in bulk, tested for quality control, retained intact for months and implanted immediately when needed. This way, the healthiest cells could be selected to secrete all of the chemicals normally released by endothelial cells and placed in multiple locations in the body to control disease.

In clinical trials these implants were placed around blood vessels after vascular surgery and controlled local clotting and infection better than devices without cells. Significantly, because the endothelial cells were associated with a matrix mimicking their natural state, even cells from other people could be implanted without being rejected by the patients' immune systems. No major side effects were seen in the clinical trials,

"Blood vessels and endothelial cells are the perfect regulatory units and our synthetic device recapitulated these control units perfectly," says Franses. Blood vessels penetrate to the deepest recesses of tumors, and in doing so carry the powerful regulatory endothelial cells as close to cancer cells as possible. The extracellular matrix backbone of the vessels can keep the endothelial cells healthy and the healthy endothelial cells control nearby cancer cells. "This is what we mimicked with our devices," he says. "In a sense it is like putting a cellular policeman on the corner of every tumor neighborhood."

In one mouse experiment reported in the new paper, endothelial cell implants significantly slowed tumor growth and prevented gross destructive change in tumor structure. Another experiment showed that cancer cells that had been grown in the secretions of endothelial cells were less able than standard cancer cells to metastasize and colonize the lungs of mice.

The new findings could also explain why drugs that suppress angiogenesis -- growth of new blood vessels -- have shown only transient and moderate benefit for cancer patients thus far. "You starve the tumor of its blood supply, but you also damage tumor blood vessel endothelial cells, so when the tumor comes back, there's nothing to keep it in check. The vessels feed the tumor but their endothelial cells control the cancer cells within. Giving the endothelial cells without the blood vessels provides the best of both worlds and perhaps one day could provide new means of cancer therapy," says Edelman.

Funding: NIH, NIH Medical Scientist Training Program, American Heart Association Scientist Development, and NIH-National Institute of Diabetes and Digestive and Kidney Diseases and National Kidney Foundation Young Investigator Grant.

Genetic Diversity Found in Leukemic Propagating Cells

ScienceDaily (Jan. 19, 2011) — Cancer scientists led by Dr. John Dick at the Ontario Cancer Institute (OCI) and collaborators at St Jude Children's Research Hospital (Memphis) have found that defective genes and the individual leukemia cells that carry them are organized in a more complex way than previously thought.

The findings, recently published inNature, challenge the conventional scientific view that cancer progresses as a linear series of genetic events and that all the cells in a tumour share the same genetic abnormalities and the same growth properties.

"Our results show this is not the case and open the way to discover how genetic abnormalities transform normal cells into leukemic cells and the steps that have to happen to make the leukemic cells increasingly abnormal and aggressive, how leukemic cells at different steps of genetic evolution (or progression) respond to therapy, or contribute to relapse," says Dr. Dick, Senior Scientist at OCI's Campbell Family Institute for Cancer Research, the research arm of Princess Margaret Hospital, and the McEwen Centre for Regenerative Medicine at University Health Network. Dr. Dick is also a Professor in the Department of Molecular Genetics, University of Toronto, and Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research.

The research team found that the leukemia cells taken from patients with acute lymphoblastic leukemia (ALL) are actually composed of multiple families of genetically distinct leukemia cells. They looked at how these families developed and retraced the ALL "family tree" back to its origins. They discovered that the so-called black sheep -- the cells that propagate the disease and potentially survive therapy -- persist through generations, and even branch off and evolve to form genetically distinct cancer families. Some of these genetic families dominate, making it appear that the leukemia cells only have one set of genetic abnormalities while other families are very rare, explaining why they had never been seen before.

The study results provide data linking genetic events in ALL taken from patients when first diagnosed to their future clinical survival. In the lab, the researchers reproduced human ALL in mice transplanted with patient leukemia samples. Sometimes the dominant genetic family would grow in the mice while in other mice the rarer families would grow.

"By looking at the genetic signatures of the leukemia cells in the different mice we were able to figure out their genetic ancestry and the evolutionary trajectory that that particular leukemia took. We found that if a particular gene family was mutated, the tumours were aggressive when grown in the mice. The patients with the corresponding tumours had poorer survival showing that the human-mouse transplant system could be very useful in predicting patient outcome."

This insight into genetic diversity has positive implications for cancer treatment, says Dr. Dick. "Understanding the complexity of cellular relationships and the existence of distinct genetic families of leukemia cells will shed light on why some cells of the cancer are not killed by the therapy and eventually regrow resulting in disease relapse, and help accelerate the development of tailored therapies to wipe out all the unwanted branches in the genetic tree."

Research collaborator Dr. Charles Mullighan, a hematologist at St. Jude Children's Research Hospital, adds: "Overall, the study proved that many leukemias comprise multiple subpopulations with different genetic alterations, and that these genetic alterations may evolve over time. The main clinical implication is that we now need to extend this work to identify genetic changes at low levels at diagnosis that confer a high risk of treatment failure and relapse and find ways of targeting them."

The current research builds from earlier findings published in 2007 when the Dick team developed a method to convert normal human blood cells into "human" leukemia stem cells. The converted cells, when transplanted into special mice that permit the growth of human cells, can replicate the entire disease process from the very moment it begins.

Gene Mutated in One in Three Patients With Common Form of Renal Cancer

ScienceDaily (Jan. 19, 2011) — In a collaborative project involving scientists from three continents, researchers have identified a gene that is mutated in one in three patients with the most common form of renal cancer. The gene -- called PBRM1 -- was found to be mutated in 88 cases out of 257 clear cell renal cell carcinomas (ccRCC) analysed, making it the most prevalent to be identified in renal cancer in 20 years.

The identification of a frequently mutated gene provides new insights into the biology of the disease, which will be critical in the continued effort to improve treatment for renal cancer. The study, published January 19 in the journal Nature, was carried out by researchers from the Wellcome Trust Sanger Institute (UK), the National Cancer Centre of Singapore, and Van Andel Research Institute (VARI) of Grand Rapids, Michigan.

Renal cancer is among the 10 most common cancers in both men and women in the United States, striking nearly 60,000 Americans in 2010, and killing more than 13,000, according to the National Cancer Institute.

Renal cell carcinoma (RCC) accounts for 9 out of 10 kidney cancers, and ccRCC is the most common subtype, accounting for 8 out of 10 RCC cases. Survival rates for early-detected ccRCC tumors can be as high as 95 percent, but that prognosis falls over time as tumors develop. Diagnosis is complicated by the fact that tumors can grow in the kidney for some time without presenting symptoms.

For many years, the main genetic determinant known to be involved in the development of renal carcinoma was mutation of the VHL gene on chromosome 3.

"Until recently, when we talked about the genetics of renal carcinoma we would inevitably be talking about VHL -- a gene mutated in eight out of ten patients," said Dr. Andy Futreal, Head of Cancer Genetics and Genomics and co-Head of the Cancer Genome Project at the Wellcome Trust Sanger Institute. "But we knew this was likely not to be the full story -- so the question we have sought to answer is which genes are conspiring with VHL to cause the disease we see in patients?"

"Over the last year or so, we have started to assemble that puzzle -- this research provides a new and critical piece."

The team's recent work had previously identified three mutated genes associated with renal cancer. These genes are all involved in altering part of the scaffold -- known as chromatin -- that holds the DNA together in our cells and can influence gene activity.

"Our understanding of how kidney cancer develops had already markedly improved through identification of three new mutated cancer genes, each of which makes a small contribution to the disease" said Professor Mike Stratton, Director of the Sanger Institute and co-Head of the Cancer Genome Project. "Now, our discovery of PBRM1 mutations in one in three kidney cancers is a major advance. We think we may have an almost complete understanding of the set of abnormal genes that drive this cancer and our understanding of the disease has been transformed by the realisation that most of these genes are involved in providing the structure that encases DNA in the cell and that regulates its function. This insight will provide us with many new therapeutic directions for this cancer."

Much of the story, the researchers suggest, seems to be locked into a small region of chromosome 3. The study finds that PBRM1(also known as Baf180) is tied together with two previously identified renal cancer genes -- including the well-established VHL cancer gene and the recently identified gene SETD2 -- on a small region of chromosome 3.

The team suggests that the fact that the genes are linked in their location allows cancer to exploit our biology -- by reducing the number of genetic events needed to hit and inactivate all three genes. The team found a significant level of overlap, with many patients carrying mutations in two, if not all three of the genes in this region.

"This study has begun to unlock the way these latest gene discoveries contribute to cancer," said Professor Bin Tean Teh, M.D., Ph.D., Head of the Van Andel Research Institute Laboratory for Cancer Genetics and the NCSS-VARI Translational Research Laboratory at the National Cancer Centre of Singapore. "And it is to the cancer's advantage that they sit together. The challenge for the future will be to build a picture of the processes the genes control. That will mean looking beyond the linear DNA code to the chemical interactions that take place at the structural level -- at the level of the chromosome."

Importantly, the newly discovered gene, PBRM1, functions as part of a protein complex called SWI-SNF, which also acts to alter the structure of chromatin -- further pointing to the importance of genome regulation in renal cancer.

"Our work provides evidence that PBRM1 may affect the processes of cell division in renal cells. Therefore, a defect in this gene could lead to abnormal cellular growth," said Kyle Furge, Ph.D., Head of VARI's Laboratory of Computational Biology. "For researchers, this discovery is exciting because PBRM1 is a protein that modifies the DNA in the cell. This study is one of the first to show that proteins that modify DNA are frequently mutated in cancer."

The mutations all appear to inactivate a protein that plays a role in remodelling the structure of the genetic material, allowing access of the DNA code to other proteins that can repair damage, control cell growth and turn other genes on and off.

In addition to the PBRM1 mutations, the team also found mutations in a gene called ARID1A in some ccRCC cases. The same gene was identified just weeks ago in clear cell ovarian cancer. The researchers suggest that further larger-scale research will be needed to understand what role this second gene plays in renal cancer.

This work was supported by the Wellcome Trust, the Van Andel Research Institute, the Lee Foundation, Cancer Research UK, the University of Cambridge and a fellowship from The International Human Frontier Science Program Organization.