Exame de sangue da mãe detecta síndrome de Down

Testando apenas o sangue da mãe, uma equipe de pesquisadores conseguiu detectar com precisão a síndrome de Down no feto, por meio do sequenciamento dos genes.

Isso evita procedimentos invasivos de diagnóstico pré-natal, como a punção de líquido amniótico, que podem causar risco à gravidez.

A equipe de 24 pesquisadores liderada por Dennis Lo Yuk Ming, da Universidade Chinesa de Hong Kong, demonstrou que a análise do material genético pode eliminar a necessidade desses procedimentos na gravidez de alto risco.

"A maioria das gestações estudadas estavam no primeiro trimestre, o que sugere que é possível implementar o teste mesmo no começo da gravidez", afirmam Lo e colegas sobre o sequenciamento genético.

O teste procura fragmentos do DNA fetal no sangue da mãe e determina se há cromossomo 21 triplo -causador da síndrome de Down.

Foram testadas 753 grávidas que já tinham feito os exames tradicionais. Dessas, 86 tinhas fetos com a doença.

Lo e colegas já tinham publicado outro artigo, em dezembro passado, também na "Science Translational Medicine", sobre a varredura genética do sangue.

GENE RECESSIVO

Outra pesquisa publicada ontem demostra o potencial do sequenciamento genômico para descobrir doenças hereditárias.

O artigo está na última edição da "Science Translational" e mostra um teste que analisa o genoma de futuros pais e mães para detectar 448 doenças.

A equipe de Stephen F. Kingsmore, do Centro Nacional para Recursos do Genoma, EUA, optou por vasculhar doenças com origem hereditária comprovada e baseada em genes ditos recessivos. A pesquisa foi feita com mais de cem amostras de DNA, não com pacientes.

Nesses casos de doenças causadas por genes recessivos, o problema é provocado por apenas um gene.

Para ser afetada, a criança precisa herdar a forma recessiva, não dominante, do pai e da mãe. Se pai e mãe têm ambos uma mutação no mesmo gene recessivo, então qualquer feto estará com 25% de chance de ter a doença, como é o caso da fibrose cística (que afeta o pulmão) ou a doença de Tay-Sachs.

Kingsmore e colegas lembram que já foram identificadas 1.139 dessas doenças com origem em genes recessivos. Doenças hereditárias provocam 20% das mortes de crianças no mundo.

Enquanto a pesquisa de Lo sobre síndrome de Down envolve fetos (é "pré-natal"), o objetivo do segundo estudo é testar se os pais são portadores dos genes que provocam a doença, um estudo "pré-concepção".

Graças a checagens pré-concepção e ao aconselhamento genético dos pais, foi possível, por exemplo, reduzir em 90% os casos da doença de Tay-Sachs, problema neurodegenerativo e incurável, entre os judeus asquenazes (da Europa central).

APLICAÇÃO

De acordo com Kinsgmore, a principal questão associada a esse tipo de teste, para que ele seja disseminado, é a educação dos médicos e do público sobre as informações genéticas: como interpretá-las e como aplicá-las.

"Isso vai requerer o treinamento de muitos conselheiros genéticos", disse o pesquisador à Folha.

Ele afirma que pretende começar a oferecer o teste nos EUA já no outono deste ano (em torno de setembro, no hemisfério Norte).

"Vai levar vários anos para informar e educar os médicos sobre o teste. Nós achamos que o ritmo da adoção vai se relacionar com o custo, que deve ser de cerca de US$ 500 (R$ 837)", afirma Kingsmore.

A próxima etapa da pesquisa vai envolver pacientes voluntários. A ideia é escanear até 580 doenças simultaneamente.

Comentando o futuro dos testes genéticos, também na "Science Translational Medicine", o pesquisador Laird Jackson, do Hospital da Criança de Filadélfia, EUA, disse que esses estudos jogam uma luz nova sobre velhas preocupações éticas, legais e sociais associadas com a tecnologia genética.

"A tecnologia está aqui, continuando a se desenvolver, e vai se tornar mais barata, mais rápida e, portanto, mais disponível."

A questão agora é educar consumidores e profissionais sobre o poder dos testes.

"Deve haver uma discussão aberta sobre suas qualidades e a respeito de sua implementação", declarou Jackson.

Nutricionista e farmacêutica falam sobre fitoterápicos usados em dietas

Karin Honorato e Ana Inácia explicam os efeitos de produtos populares. Para emagrecer, elas recomendam acompanhamento especializado.

Muito se tem falado de remédios fitoterápicos que agem, com sucesso, como emagrecedores. Mas o que a maioria das pessoas que faz uso desses medicamentos não sabe são os reais efeitos, contra-indicações e efeitos colaterais desses produtos. No dia 19 de dezembro de 2010, o Fantástico mostrou uma reportagem sobre dois desses medicamentos. Hoje, na coluna da nutricionista Karin Honorato, a especialista vai conversar com a farmacêutica Ana Inácia, sobre os reais efeitos e efeitos colaterais desses medicamentos que prometem quase um “milagre” do emagrecimento.

No vídeo, você vai entender a explicação das duas profissionais a respeito de substâncias populares, como a caralluma, hoodiagordoni, pholia magra, gymnena, entre outros, e de medicamentos, como Divine Shen e a sibutramina.

Abaixo, segue uma breve explicação de cada um dos produtos.

Divine Shen – é um medicamento à base de fibra de laranja, mas que tem em sua composição a sibutramina, substância com venda controlada. Entre os efeitos colaterais estão o aumento da pressão arterial, taquicardia e AVC.

Caralluma – muito na moda, a caralluma foi suspensa pela Anvisa por não ter efeitos comprovados. Não há estudos suficientes que comprovem o efeito divulgado.

Hoodiagordoni – fitoterápico proibido pela Anvisa.

Pholia magra – muito usado por pessoas que buscam um rápido emagrecimento. Ele atua como inibidor de apetite, mas não há estudo comprovando sua eficácia. Pode se tornar perigoso para a saúde se usado em grandes quantidades ou por tempo prolongado.

Chá verde – chá muito usado na desintoxicação do organismo. Usado em grandes quantidades, o chá pode provocar aumento da pressão arterial, além de favorecer a disfunção da tireóide e anemia.

Gymnena – a substância ajuda a controlar a vontade de comer doce, mas pode alterar a função da insulina, que regula o nível de açúcar no organismo, se tomada em quantidade inadequada.

Faseolamina – conhecida como “feijão-branco”, ela impede a absorção de amido pelo organismo. Pode alterar os níveis nutricionais necessários ao corpo.

Ayslim manga – atua no sistema nervoso central e pode desregular os níveis de colesterol e trigliérides.

Em todos os casos, tanto a nutricionista quanto a farmacêutica concorda que as pessoas que querem perder peso devem procurar a ajuda de especialistas, como nutricionistas, médicos, e fazer exercícios físicos corretamente, sempre acompanhados por profissionais da área, como educadores físicos e fisioterapeutas. Desta forma, será possível emagrecer de forma saudável.

Cientistas desenvolvem técnica que protege fígado em casos de câncer de cólon

Pamplona (Espanha), 13 jan (EFE).- Uma equipe de cientistas espanhóis desenvolveu uma técnica de tratamento genético que, com a combinação de imunoterapia e quimioterapia, ajuda a proteger o fígado de pacientes com câncer de cólon, já que é comum que a doença se expanda para esse órgão.

Por enquanto, os resultados foram obtidos apenas em testes com animais, informaram nesta quinta-feira os responsáveis pela pesquisa, Jesús Prieto e Rubén Hernández, da Universidade de Navarra, no norte da Espanha.

O câncer de cólon apresenta uma tendência de se expandir ao fígado, de modo que mais da metade dos pacientes apresenta metástases hepáticas, o que limita suas opções de cura, afirmam os pesquisadores.

Nos estágios iniciais, as metástases podem ser eliminadas por cirurgia, mas na maioria dos pacientes isso não é possível ou as metástases reaparecem depois de um tempo, por isso que a quimioterapia muitas vezes é a única alternativa, embora sua eficácia a longo prazo seja limitada.

Segundo os pesquisadores, "este tratamento combinado elimina metástases pré-existentes e protege o fígado contra possíveis recidivas".

De acordo com Prieto e Hernández, "os resultados obtidos em modelos animais confirmam que é uma modalidade terapêutica sumamente promissora que poderia ser eficaz em pacientes com tumores de cólon com metástase de fígado".

Na fase atual, o trabalho dos pesquisadores se centra em aperfeiçoar os mecanismos para produzir meios de tratamento genético com um rendimento compatível com sua aplicação clínica, enquanto se propõem a validar estes resultados em outros modelos experimentais para prever o possível efeito que teria em humanos. EFE

Pesquisa canadense descobre composto eficaz para aliviar a dor crônica

Substância atua direto no cérebro; testes in vitro e em animais têm resultados promissores

Um composto capaz de diminuir a dor crônica poderá melhorar as condições de vida de milhões de pessoas em todo o mundo. A nova substância - batizada de NB001 - é descrita em um trabalho publicado na última edição da Science Translational Medicine. Há poucos analgésicos no mercado voltados especificamente para a dor crônica. Quase todos atuam sobre a dor aguda.

Uma pesquisa divulgada no ano passado apontou que cerca de 29% dos habitantes de São Paulo sofrem com dor crônica. Calcula-se que, nos Estados Unidos, 65 milhões de pessoas também enfrentam o mal. Especialistas explicam que o processo neurofisiológico da dor crônica é diferente dos mecanismos que provocam o tipo agudo.

De um modo geral, quando o estímulo doloroso cessa, a dor aguda desaparece. Ela desempenha, assim, um importante papel: faz com que a pessoa proteja o órgão ou o tecido afetado e informa o corpo que há algo errado.

A dor crônica, no entanto, permanece quando o estímulo já desapareceu, como uma memória persistente - e incômoda - do evento que causou a dor. Ao contrário da forma aguda, não traz benefícios. Só sofrimento.

Estudos anteriores haviam comprovado as diferenças bioquímicas entre os dois processos, e cientistas procuravam um modo de interferir apenas na dor crônica. Descobriram então a enzima AC1, que comprovadamente participa da gênese da dor crônica em uma região do cérebro conhecida como córtex cingulado anterior. O próximo passo foi a busca de uma substância capaz de inibir a ação da AC1. Cientistas do Canadá chegaram a vários compostos. O mais eficaz foi o NB001, testado em colônias de células neuronais e em camundongos com dor crônica.

Em entrevista ao Estado, Min Zhuo, professor da Universidade de Toronto, afirmou que pretende iniciar os testes em humanos em cinco anos. Mas, para isso, precisa estabelecer parcerias com indústrias farmacêuticas.

A Science Translational Medicine também publicou uma análise crítica sobre a descoberta. Assinam dois pesquisadores da Universidade da Califórnia em São Francisco. Eles questionam se o NB001 não inibiria o funcionamento da enzima AC1 no hipocampo, prejudicando processos como a memorização. Ao Estado, Zhuo argumentou que, nos testes realizados com animais, não houve nenhum impacto na memória dos camundongos.

O problema

A dor crônica faz com que muitas pessoas permaneçam inativas, evitando exercícios físicos e o convívio social. O neurocirurgião Manoel Jacobsen Teixeira, da USP, destaca que é preciso lutar contra essa tendência. “Senão, forma-se um ciclo vicioso. A dor gera inatividade, e a inatividade prolonga a dor”, afirma Teixeira. “A pessoa precisa sair e praticar exercícios: isso alivia a dor crônica.”

A anestesiologista Fabiola Minson, diretora da Sociedade Brasileira para o Estudo da Dor (SBED), também aponta a conveniência de procurar um médico especialista em dor. O aposentado Sérgio Casarini, de 64 anos, passou por três profissionais de diferentes especialidades e reclamou da dor que sentia na planta dos pés, fruto de uma neuropatia causada pela diabete.

O problema só foi resolvido quando chegou a um quarto médico, especializado no alívio da dor. “Ia à praia e não conseguia pisar na areia, de tanta dor. Ficava com os pés levantados”, conta. “No mês passado, com o tratamento adequado, voltei à areia."

Pesquisa sobre vermes abre novas vias para tratamento de câncer de pele

Uma equipe de cientistas descobriu o mecanismo de renovação da pele presente do verme Caenorhabditis elegans, o que abre novas linhas de estudo na luta contra o envelhecimento da derme em humanos e a cura e cicatrização de ferimentos.

Publicado na revista "PNAS", o trabalho poderia ajudar no tratamento de câncer de pele e no desenvolvimento de tratamentos contra os nematódeos, doenças parasitárias causadas por nematódeos, um tipo de verme como o estudado nesta pesquisa, muito comum nos países em desenvolvimento.

Antonio Miranda-Vizuete, do centro de biologia do desenvolvimento andaluz, do CSIC (Conselho Superior de Pesquisas Científicas) da Espanha, diz que o envelhecimento nos seres vivos ocorre pela redução da capacidade das células para reparar o dano oxidativo que acumulam ao longo da vida.

Ao envelhecer, a qualidade da pele de um animal piora drasticamente, embora os mecanismos que geram o envelhecimento cutâneo ainda não tenham sido descobertos, detalhou o cientista espanhol.

O estudo constata que o processo de mudança no verme está associado às mudanças no estado de oxidação de proteínas presentes em sua pele.

Quando é bloqueada a atividade destas proteínas, a pele velha não se debilita o suficiente para que o animal rompa e passe à fase seguinte do estado larváceo, por isso que o nematódeo acaba morrendo preso dentro de sua própria pele.

Pelo contrário, a aplicação de glutationa, uma molécula presente em todos os organismos vivos e que regula o equilíbrio de oxidação celular, favorece a mudança e a passagem ao estado seguinte larváceo, já que ajuda ao verme a degradar a pele velha e separar-se dela.

Apesar de que, por enquanto, os resultados só foram demonstrados no verme Caenorhabditis elegans, as descobertas deste estudo poderiam servir de base para a pesquisa da renovação da pele humana e de outros animais, assim como no tratamento de cânceres cutâneos e outras afecções da pele, segundo o CSIC.

As nematodiases são doenças que afetam humanos, animais e plantas. A elefantíase, na qual as larvas obstruem os copos linfáticos, e a anisaquíase, que afeta os humanos após a ingestão de peixe cru contaminado por parasitas, são algumas das variantes deste mal, que atinge milhões de pessoas no mundo todo, principalmente nos países em vias de desenvolvimento.

Estas doenças acarretam importantes custos econômicos e comerciais quando surgem em criações de gado e plantações agrícolas.

"Como nem humanos, animais e plantas têm processo de mutação, a descoberta de qual é a proteína da pele que está envolvida no processo de oxidação, seria possível encontrar novas formas de tratar muitas doenças", concluiu Miranda.

New Research Aims to Shut Down Viral Assembly Line

ScienceDaily (Jan. 12, 2011) — Under the electron microscope, a coronavirus may resemble a spiny sea urchin or appear crownlike, (the shape from which this family of pathogens takes its name). Previously recognized as the second leading cause of the common cold in humans and for economically important diseases in many domesticated animals, a new disease form abruptly emerged as a major public health concern in 2002, when the SARS coronavirus (CoV) surfaced in Asia.

The rapid spread of the virus caused significant social and economic disruption worldwide , infecting over 8000 people with Sudden Acute Respiratory Syndrome or SARS and killing about 10 percent of them. While SARS-CoV was brought under control through decisive action by health officials, the sudden scourge underlined the threat posed by coronaviruses and spurred new research into the inner workings of these infectious agents.

Brenda Hogue and her colleagues at the Biodesign Institute at Arizona State University are studying the intricate formation of these viruses -- a process known as viral assembly. The research may offer fresh insight, leading to a new generation of antiviral agents that can disrupt the ability of coronaviruses like SARS to assemble viable infectious particles. Such strategies may prove applicable against other classes of virus as well.

The group's work recently appeared in the Journal of Virology.

Viruses, Hogue stresses, differ fundamentally from other common microscopic pathogens like bacteria, in that viruses are structurally primitive, lacking the means to independently replicate. Viruses are composed of genetic information (DNA or RNA), encased by proteins. They exist in a shadowy region between living and non-living entities.

In order for a virus to replicate, it must commandeer machinery of a host cell it has infected. Nevertheless, viruses have evolved to be highly adept at this sort of replication-by-proxy, and can infect virtually all types of organisms, from animals and plants to bacteria and even Archaea. Viruses -- of which millions of forms are known to exist -- are far and away the most numerous (and successful) parasitic invaders on earth.

"Coronaviruses are a very large family of RNA viruses," Hogue says. "They infect humans and a broad range of animals." While the symptoms produced by coronavirus infection in humans tend to be respiratory, in animals, such viruses can cause a range of severe problems, from neurological ailments to immunosuppressive effects. Various coronaviruses are responsible for common colds in humans, though the combined upper and lower respiratory symptoms and gastrointestinal complications seen in SARS patients are unusual.

In the study reported in Journal of Virology, Hogue and her team closely examined one of the major proteins found in the coronavirus that is crucial to the pathogen's process of assembly. Known as the M, it is one of four proteins, in addition to S, N and E, required to produce a fully assembled viral particle, capable of infecting a host.

The membrane (M) protein makes up the bulk of the outer shell or envelope of the virus, forming a lattice that surrounds and shields the viral genome. The spike protein (S) -- named for its spike-like or crown-like appearance under electron microscopy, is critical for allowing the coronavirus to attach to the host cell's receptors, prior to viral entry into the cell. The nucleocapsid (N) protein encapsidates the genomic RNA. The envelope or E protein is the least plentiful protein known to play a central role in virus assembly, though its presence is very important. In addition to assisting viral assembly, the E protein also appears to be involved in shuttling the newly assembled virions out of the cell, enabling these particles to escape and infect other host cells in the exponential process of viral infection.

The group wanted to determine the requirements for the M protein to function during assembly of the viral envelope. To establish this, coronaviruses were genetically manipulated to form mutant versions, exhibiting varying degrees of viability. Much of this manipulation focused on domains within the viral genome coding for a distinct structural and/or functional domain of the M protein. Conserved domains, as they are known, contain genetic sequence patterns or motifs that tend to recur across a number of different viruses or within a particular virus type, like catch phrases recurring in different books. These conserved domains are generally involved in functions essential to viral formation, survival or replication, making them an attractive target for therapeutic efforts designed to short-circuit viral assembly.

Viral pathogens like the SARS coronavirus, (along with hepatitis C and influenza), use RNA rather than DNA as their genetic material. In general, such RNA viruses mutate more rapidly than DNA viruses, posing particular challenges to virologists hoping to combat them. They can also acquire alterations that allow them to hop from one species to another. Something like this now appears to be at the root of the SARS outbreak.

"We think that the reservoir for this virus is bats, because a large number of SARS-like viruses have been isolated from bat populations around the world," Hogue says. SARS-CoV was subsequently able to infect a secondary animal host, now believed to be the civet cat -- a mongoose-like creature found in Asia and sometimes used as a food source, particularly in China, where the SARS outbreak originated. Contact with infected civets in the open markets may have caused the initial human cases of SARS, which then rapidly spread -- human to human -- from the Guangdong provinces in China to 37 countries.

Viruses that act as respiratory pathogens, including SARS, are highly transmissible from person to person through contact with respiratory droplets that become aerosolized from coughs or sneezes. Virions may also persist on surfaces that come in contact with an infected individual. Following transmission, virions initiate the infectious process of host cells, which transpires in several important phases.

First, viral proteins located on the virus' outer capsid bind to particular receptors on the host cell's surface. Next, virions enter the cell, either by fusing their membranes with those of the host cell or through the process of endocytosis, in which the host cell takes in the virion in a membrane-bound vesicle. The virion is now in a position to begin the replication cycle, releasing its genetic material into the cell. The viral genome encodes genes that when expressed, yield the protein components necessary to assemble new virus particles.

Hogue stresses the importance of in silico analysis, in which large libraries of proteins can be screened through analysis, in order to identify conserved and non-conserved protein regions, thus greatly accelerating the pace of discovery. "The more we learn about these particular regions of proteins that are critically important for the assembly process," she says, "the likelier it is we can design molecules that will be able to interfere with this process."

While some conserved domain alterations in the M protein proved lethal to coronaviruses, others undermined viral assembly without shutting it down completely, often causing compensatory efforts on the part of the virus, (known as second site changes) which may offer insights into the virus' adaptive capabilities. In the coming year, Hogue plans to examine the non-lethal changes introduced, studying these mutant viruses under high-resolution cryo-EM, to determine how alterations of specific domains affect overall coronaviral structure.

Additionally, Hogue's group is closely examining the under-represented envelope or E protein. "One reason we are excited about this is that a number of enveloped viruses, including hepatitis C, influenza and others, that are of real medical significance, have small ion channel proteins," Hogue says. "If we can develop ways to target and obliterate the ion channel activities of these proteins, we may be able to disable these viruses and prevent or reduce infections."

Brenda Hogue is a researcher in the Center for Infectious Diseases and Vaccinology at the Biodesign Institute and is also Associate Professor in the College of Liberal Arts and Sciences, School of Life Sciences at Arizona State University.

DNA Introduced Directly Into Cell Nucleus Using Protein Nanodisks

ScienceDaily (Jan. 12, 2011) — Researchers have discovered a novel gene therapy method using particles measuring only a few nanometers which encapsulate genetic material and introduce themselves directly into the cell nucleus. The nanodisks, as researchers have named the particles, travel rapidly to the interior of the cell until reaching the nucleus, thus increasing the efficiency of the gene transfer process.

One of the challenges of gene therapy -- a set of methodologies aimed at treating several nucleic acid diseases (DNA or RNA) -- is to assure that this material arrives directly to the nucleus of the cell without losing a substantial amount along the way and without producing any undesired side effects. With this aim, scientists experiment with the use of different types of vectors, molecules capable of transporting genetic material to the correct place. Presently, natural "deactivated" viruses are the most commonly used vectors in clinical trials, their side effects however often limit therapeutic application.

One of the most promising alternatives in this field is the use of artificial viruses. These viruses can be constructed through genetic engineering by assembling minute protein structures made up of peptides, the building blocks of proteins.

The team of scientists, led by Antonio Villaverde, lecturer of the Department of Genetics and Microbiology, researcher at the UAB Institute of Biotechnology and Biomedicine and of the Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), demonstrated that the peptide R9, formed by a specific type of amino-acid (arginine), can encapsulate genetic material, assemble itself with other identical molecules to form nanoparticles and enter directly into the cell nucleus to release the material it contains. The nanoparticles have the shape of a disk, with a diameter measuring 20 nanometres and a height of 3 nm.

The study was published recently in the journals Biomaterialsand Nanomedicine and describes how scientists studied the performance of R9 nanodisks in the interior of the cells using confocal microscopy techniques provided by the UAB Microscopy Service and applied by Dr Mònica Roldán. The images show that once the cell membrane is passed, particles travel directly to the nucleus at a rate of 0.0044 micrometres per second, ten times faster than if they dispersed passively in the interior. Nanoparticles accumulate in the interior of the nucleus and not in the cytoplasm -- the thick liquid between the cell membrane and nucleus -- and therefore increase their level of effectiveness. One of the photos was selected by the journal Biomaterials as one of the 12 images of the year 2010.

Participating in this discovery were researchers from the Institute of Material Science of Barcelona (ICMAB-CSIC), the Catalan Institute for Research and Advanced Studies (ICREA), and the Technical University of Catalonia. The discovery represents a new category of nanoparticles offering therapeutic benefits. According to Dr Esther Vázquez, director of the project, "nanodisks assemble automatically, move rapidly, remain stable and travel to the interior of the nucleus. This makes them a promising tool as a prototype for the safe administration of nucleic acids and functional proteins."

Scientists Discover Way to Stop Pancreatic Cancer in Early Stages, Study Suggests

ScienceDaily (Jan. 12, 2011) — Cancer researchers at the Peggy and Charles Stephenson Oklahoma Cancer Center have found a way to stop early stage pancreatic cancer in research models -- a result that has far-reaching implications in chemoprevention for high-risk patients.

The research already has sparked a clinical trial in California, and the FDA-approved drug, Gefitinib, should be in clinical trials at OU's cancer center and others nationwide in about a year. The research appears in the latest issue of Cancer Prevention Research, a journal of the American Association for Cancer Research.

C.V. Rao, Ph.D., and his team of researchers were able to show for the first time that a drug used in current chemotherapy for later stages of pancreatic cancer had a dramatic effect if used earlier.

With low doses of Gefitinib, which has no known side effects at this level, scientists were able to not only stop pancreatic cancer tumors from growing, but after 41 weeks of treatment, the cancer was gone.

"This is one of the most important studies in pancreatic cancer prevention," Rao said. "Pancreatic cancer is a poorly understood cancer and the focus has been on treatment in the end stages. But, we found if you start early, there will be a much greater benefit. Our goal is to block the spread of the cancer. That is our best chance at beating this disease."

The Oklahoma cancer center research team said the finding points to an effective way to stop pancreatic cancer before it reaches later stages of development where the survival rate drops below 6 percent.

Currently, most pancreatic cancer is not identified until the later stages. However, research is moving closer to the development of an early detection test for pancreatic cancer. When that is in place, Oklahoma cancer center researchers believe they now have a method to target the cancer before it spreads.

Rao said OU officials and researchers will meet with other centers, including M.D. Anderson, whose specialists called the research "provocative," to discuss a pilot study in early 2011. Researchers hope to begin a Phase II clinical trial at the centers within 18 months. A Phase I trial is not required since the drug already has approval for human use from the U.S. Food and Drug Administration.

The clinical trials will focus on at-risk patients, particularly those with an inflammation of the pancreas called pancreatitis. The drug also could help other high risk populations, including patients with a family history of pancreatic cancer and American Indian populations or others with Type 2 diabetes.

Gefitinib works by targeting signals of a gene that is among the first to mutate when pancreatic cancer is present. By targeting the signal for tumor growth expressed by the mutated gene, researchers were able to stop the cancer's procession.

"This gene is the key in 95 percent of cases of pancreatic cancer. It is our best target," Rao said. "By targeting this gene, we can activate or inactivate several other genes and processes down the line."

Rao said the drug also could be effective in lung and colorectal cancer, but it is not known if it would work as well as in pancreatic cancer. The OU College of Pharmacy is assisting in the development of drugs and imaging techniques needed to further test Gefitinib with patients.

Rao's research was funded by a grant from the National Cancer Institute.

MicroRNAs Could Increase the Risk of Amputation in Diabetics

ScienceDaily (Jan. 12, 2011) — New research has found one of the smallest entities in the human genome, micro-RNA, could increase the risk of limb amputation in diabetic patients who have poor blood flow.

The study by Dr Andrea Caporali and colleagues in Professor Costanza Emanueli's research group in the Regenerative Medicine Section of the School of Clinical Sciences at the University of Bristol was funded by the Medical Research Council and is published online in Circulation: Journal of the American Heart Association.

The research group have shown in an experimental cell study that conditions mimicking diabetes and a lack of blood supply to a tissue increased a particular miRNA (miRNA-503) and impaired the ability of endothelial cells, which line the interior surface of blood vessels. Micro-RNAs (miRNAs) are small sections of ribonucleic acid (RNA) that can inhibit many genes.

Alternatively, slowing down miRNA-503 improved the capability of endothelial cells to duplicate and form into networks of small blood vessels. The researchers showed that microRNA-503 reduces cell growth and prevents the formation of blood vessels by direct binding and inhibition of cyclin E1 and Cdc25 mRNA.

Costanza Emanueli, Professorial Research Fellow in Vascular Pathology & Regeneration, said: "Because each miRNA can regulate many genes, they represent an exciting new target to correct diseases that have complex underlying mechanisms, like diabetes, rather than trying to target one specific gene. Our study is the first to provide evidence for a role of miRNAs in diabetes-induced defects in reparative angiogenesis."

The team subsequently investigated miR-503 and target gene expression in muscular specimens from the amputated ischaemic legs of diabetic patients. As controls, calf biopsies of non-diabetic and non-ischemic patients undergoing saphenous vein stripping were used. In diabetic muscles, miR-503 expression was remarkably higher, and plasma miR-503 levels were also elevated in the diabetic subjects.

Finally, using mouse models of diabetes and limb ischaemia, the researchers found that inhibition of the miRNA-503 (using a "decoy miRNA") could restore-post-ischaemic blood flow recovery. The findings of this study highlight important clinical implications of miR-503 in diabetes-associated vascular complications.

In early diabetes, high blood glucose levels damage blood vessels leading to lack of blood flow (ischaemia). Such ischaemic complications are the leading cause of disease and death in diabetic patients. In limbs, lack of blood flow can result in non-healing ulcers and, in diabetic patients, the ischaemic disease follows an unalterable course and limb amputation is too often the eventual remedy.

Tissues can recover from lack of blood flow by new blood vessel growth (angiogenesis), which restores blood supply to the tissue (reperfusion). However, diabetes harms the restoration of the flow of blood to a previously ischemic tissue, by mechanisms that are not fully understood, and so a better understanding of the molecular mechanisms underpinning diabetes-associated vascular complications is urgently needed to improve therapeutic options.

Critical Link Between Down Syndrome and Alzheimer's Disease Discovered

ScienceDaily (Jan. 12, 2011) — Researchers at the University of British Columbia and Vancouver Coastal Health Research Institute have discovered that the genetic mechanism which destroys brain cells is responsible for early development of Alzheimer's Disease in people with Down Syndrome and for development of Alzheimer's Disease in general population -- providing a potential new target for drugs that could forestall dementia in people with either condition.

The research, led by Dr. Weihong Song, Canada Research Chair in Alzheimer's Disease and a professor of psychiatry in the UBC Faculty of Medicine, found that excessive production of a protein, called Regulator of Calcineurin 1 (RCAN1), sets in motion a chain reaction that kills neurons in the hippocampus and cortex in people with Down Syndrome and Alzheimer's Disease.

The findings were published online recently in the Journal of Biological Chemistry.

"Neuronal death is the primary reason for the memory loss and other cognitive impairments of Alzheimer's Disease, and it's the main reason people with Down Syndrome develop Alzheimer's Disease long before most people, usually in their 30s," says Song, a member of the Brain Research Centre at UBC and the Vancouver Coastal Health Research Institute (VCHRI), and Director of Townsend Family Laboratories at UBC. "By looking for the common elements of both conditions, we were able to pinpoint how and why the deterioration occurs."

Alzheimer's Disease (AD) is the most common form of dementia, which usually affects people over age 60. The Alzheimer Society of Canada estimates that the disease affects more than 238,000 Canadians, and that by 2031 about 750,000 Canadians will suffer from AD and related dementias.

Down Syndrome (DS) is a congenital anomaly that includes developmental delays and learning disabilities. A 2002 report by the Public Health Agency of Canada said that about one in 800 Canadian newborns have the condition; the average lifespan for those with Down Syndrome is 49 years. People with DS have an extra copy of the gene that produces RCAN1, thus leading to its excess production. The resulting neuronal death -- with symptoms that mirror those of AD patients -- is one of the prime reasons for the shortened lifespan of people with DS.

The research team discovered that some AD patients have similarly elevated levels of the RCAN1 protein, despite having two copies of the responsible gene. It's still unknown why, though Dr. Song speculates that the gene's overexpression might be triggered by stroke, hypertension or the presence of a neurotoxic protein, called beta amyloid, that typically collects into clumps in the brains of people with AD -- what he describes as a "vicious cycle" in which one destructive factor exacerbates another.

But now that the culprit gene and protein have been identified, "we can develop therapies that interfere with the gene's ability to produce that protein, and hopefully short-circuit the destruction of brain cells," Dr. Song says.

The research was supported by the Canadian Institutes of Health Research, the Jack Brown and Family Alzheimer's Research Foundation, the Michael Smith Foundation for Health Research and the National Natural Science Foundation of China.

MicroRNA-TP53 Circuit Connected to Chronic Lymphocytic Leukemia

ScienceDaily (Jan. 12, 2011) — The interplay between a major tumor-suppressing gene, a truncated chromosome and two sets of microRNAs provides a molecular basis for explaining the less aggressive form of chronic lymphocytic leukemia, an international team of researchers reports in the Jan. 4 edition of the Journal of the American Medical Association.

"Our findings could reveal new mechanisms of resistance to chemotherapy among leukemia patients as this feedback mechanism could help us differentiate between patients with poor or good prognosis," said co-senior author George Adrian Calin, M.D., Ph.D., associate professor in The University of Texas MD Anderson Cancer Center Department of Experimental Therapeutics and co-director of the Center for RNA Interference and Noncoding RNAs.

B cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults, with an estimated 14,990 new cases in 2010 in the United States. It's caused by aberrant versions of infection-fighting B cell lymphocytes, a white blood cell.

Deletion of the long arm of chromosome 13, called 13q, has been associated with less aggressive, or indolent, CLL. In a series of experiments, a team led by Calin and colleagues at MD Anderson and The Ohio State University uncovered the details of that relationship.

"This finding represents the most detailed pathogenetic mechanism involving microRNAs for any human disease," Calin said. MicroRNAs, or miRNAs, are short, single-stranded bits of RNA that regulate the messenger RNA expressed by genes to tell a cell's protein-making machinery which protein to make.

Deletion of 13q unleashes two proteins known to stymie programmed cell death, or apoptosis, a frontline defense against formation and growth of malignant cells, the researchers found. However, it also leads to increased expression of the tumor suppressor gene TP53, which indirectly reduced levels of another protein associated with poor survival among CLL patients. The first effect appears to cause CLL, while the combination of effects keeps it indolent, Calin said.

The team worked with three chromosomal deletions common to CLL:

Deletion 13q, causes the abolition or reduction of two miRNAs: miR-15a and miR-16-1. It's the most common form of deletion, occurring in about 55 percent of CLL cases.

Deletion 11q occurs in about 18 percent of CLL cases and affects two other miRNAs: miR-34b and miR-34c.

The short arm of chromosome 17, called 17p, is home to the tumor-suppressing gene tumor protein p53, or TP53. It is deleted in about 7 percent of CLL.

Patients with deletions at 11q and 17p experience the most aggressive form of the disease.

The researchers analyzed blood samples from 208 CLL patients, comparing the relative expression and activity of the miRNAs and TP53 depending on the type or types of deletions the patients had.

Normal Conditions, No CLL

With no chromosomal deletions, the microRNAs miR-15a and miR-16-1 inhibit expression of the tumor-suppressor TP53. However, TP53 in turn activates the two miRNAs, which then control expression of two other genes that prevent programmed cell death, or apoptosis. Apoptosis occurs at normal levels, preventing leukemia development.

TP53 also activates the miR34b and miR-34c microRNAs, which then inhibit the gene ZAP70, which is associated with shorter survival among CLL patients.

Why Indolent CLL Follows 13q Deletions

With 13q deletions, miR-15a and miR16-1 are reduced or absent, which allows for increased expression of TP53. This further activates miR-34b and miR-34a, resulting in greater inhibition of Zap70. That's the good part.

With miR-15a and 16-1 gone, expression of the two genes that suppress programmed cell death, BCL2 and MCL1, increases, which allows more aberrant cells to form and grow. While this effect causes slow-growing CLL, the counterweight of suppressed ZAP70 keeps it from getting worse, Calin said.

TP53 is, in effect, a link that joins the two different sets of microRNAs, the researchers noted.

Experiments in acute myeloid leukemia, lung and cervical cancer cell lines indicate the same mechanism may be at work in other cancer types, but more studies will be needed to validate that, Calin said.

This study clears the way for further translational research to identify microRNAs involved in resistance to CLL therapy and therefore poor outcomes for patients, as well as the identification of plasma miRNAs with predictive value for response to therapy. A team led by Calin and study co-author Michael Keating, M.D., professor in MD Anderson's Department of Leukemia, is investigating these topics.

Carlo Croce, M.D., Ph.D., professor and chairman of the Department of Molecular Virology, Immunology and Medical Genetics at the Comprehensive Cancer Center of The Ohio State University, was co-corresponding author.

Funding for this research was provided by grants from the National Cancer Institute, the U.S. Department of Defense, the NCI-funded MD Anderson Select Programs of Research Excellence in Leukemia and the CLL Global Research Foundation. Also, Muller Fabbri, M.D., is supported by a 2009 Kimmel Scholar Award, Amelia Cimmino, M.D., Ph.D., is supported by a fellowship from the Federazione Italiana Ricera sul Cancro, and Calin has fellowships from the MD Anderson Research Trust and The University of Texas System Regents Research Scholar Program.

Co-authors with Calin and Keating are Masayoshi Shimizu, Riccardo Spizzo, M.D., Ph.D., Milena Nicoloso, M.D., Simona Rossi, Ph.D., Elisa Barbarotto, Ph.D., and Deepa Sampath, Ph.D., all of MD Anderson's Department of Experimental Therapeutics and Center for RNA Interference and Noncoding RNAs; first author Muller Fabbri, M.D., Arianna Bottoni, Ph.D., Nicola Valeri, M.D., Federica Calore, Ph.D., Hansjuerg Alder, Ph.D.. Tatsuya Nakamura, Ph.D., Brett Adair, and Sylwia Wojcik, all of the Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University; Massimo Negrini, Ph.D., Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy; Amelia Cimmino, M.D., Ph.D., Institute of Genetics and Physics, National Research Council, Naples, Italy; Francesca Fanini, Ph.D., Ivan Vannini, Ph.D., Gerardo Musuraca, M.D., and Dina Amadori, M.D., of the Istituto Scientifico Romagnolo per lo Studio e la Cura del Tumori, Meldola, Italy; Marie Dell'Aquila, Ph.D., Laura Rassenti, Ph.D., and Thomas Kipps, M.D., Ph.D., of the Department of Medicine, University of California San Diego; Ramana Davuluri, Ph.D., of the Center for Systems and Computational Biology, Wistar Institute, Philadelphia; Neil Kay, M.D., Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn; and Kanti Rai, M.D., Long Island Jewish Medical Center, New Hyde Park, N.Y.