quarta-feira, 31 de agosto de 2011

escola em tempo integral

Governo quer ter 32 mil escolas com ensino em período integral até 2013
Camila Campanerut*
Enviada do UOL Educação
Em Mata de São João (BA)

COMENTE
O ministro da Educação, Fernando Haddad, afirmou na noite desta terça-feira (30), na Bahia que, a pedido da presidente da República, Dilma Rousseff, a pasta estuda como viabilizar a antecipação da meta de aumentar a rede pública de ensino para atender os alunos em período integral.
 
“Com o [programa] Mais Educação, já estamos com 15 mil escolas [atendidas], a presidente pediu um estudo para anteciparmos as metas de 2014, nós pretendíamos chegar em 32 mil escolas até 2014. A presidente está ansiosa para que nós atinjamos esta meta em 2013 e liberamos verba para chegar a 40 mil, 45 mil escolas em 2014”, declarou o ministro durante sua exposição no 4º Fórum Nacional Extraordinário de Dirigentes Municipais de Educação.
 
A idéia do programa é oferecer atividades fora do horário de aula, permitindo que os estudantes permaneçam na unidade educacional por período integral fazendo outras atividades de cunho cultural, esportivo, entre outras.
Segundo dados do MEC, o programa teve início em 2008, com a participação de 1.380 escolas em 55 municípios em todos os Estados do país, e beneficiava 386 mil estudantes. Em 2009, houve a ampliação para 5.000 escolas em 126 municípios, e em 2010, a meta era atender 10.000 escolas. Ampliar o ensino integral foi uma das bandeiras levantadas durante a campanha presidencial de Dilma.
 
Em seu discurso, Haddad destacou ainda que a criação deste programa foi resultado das reivindicações dos municípios e ressaltou que as famílias têm o papel fundamental para permitir que as crianças e os adolescentes possam estudar.  
 
Diante da campanha dos dirigentes municipais de pedir que 10% do PIB seja destinado à educação, Haddad comentou que “será uma pena que não vou estar no MEC para investir este dinheiro todo”, uma vez que ao final do primeiro trimestre do ano que vem ele será obrigado a deixar o cargo caso se lance como candidato - o ministro postula a candidatura à Prefeitura de São Paulo.
 
A participação do petista encerrou o primeiro dia do evento que reúne mais de 1.500 dirigentes e secretários municipais de educação de todo o país, organizado pela Undime (União Nacional dos Dirigentes Municipais de Educação).
 
A presença de Haddad, no entanto, testou sua popularidade. Em vários momentos ele foi ovacionado ao citar o aumento em três vezes do orçamento da pasta durante o goveno Lula. Depois de sua fala, por mais de meia hora, ele foi obrigado a tirar fotos com os presentes que se amontoaram para cumprimentá-lo pessoalmente.
 
*A jornalista viajou a convite da Undime (União Nacional dos Dirigentes Municipais de Educação).

terça-feira, 30 de agosto de 2011

CNPq - Program sem fronteiras e cooperação com Universidades da Coréia

Ciência sem Fronteiras: CNPq estabelece parceria com universidades da Coreia do Sul



O Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/MCTI) acaba de estabelecer acordos com quatro das melhores universidades da Coreia do Sul. O principal objetivo é promover o intercâmbio de estudantes e pesquisadores entre os dois países, no âmbito do Programa Ciência sem Fronteiras. Um edital específico para as instituições coreanas será lançado em breve. Entre as instituições conveniadas está a 29ª na classificação do Times Higher Education, Pohang Science and Technology University (POSTECH), focada nas áreas de Engenharias e Ciências Exatas.
A Korean Advanced Institute for Science and Technology (KAIST), é conceituada nas áreas de Engenharias e Ciência e Tecnologia. A University of Science and Technology (UST) possui um interessante modelo de educação, os estudantes da universidade são alocados nos institutos de tecnologia coreanos, desde o início do curso. Já a Yoinsei University, a mais antiga da Coreia, é muito forte nas áreas biológica e da saúde.

Histórico

Na última quarta-feira (24), uma Carta de Entendimento com o National Institute for International Education, representado no ato pelo seu diretor Nam Jo Chung, foi assinada na Coreia. Também participaram do encontro o secretário de Pesquisa e Desenvolvimento do Ministério da Ciência, Tecnologia e Inovação (MCTI), Carlos Nobre, representando o ministro Aloizio Mercadante, e Dong-Geum Seol, vice-ministro de Educação e Ciência e Tecnologia, da Coreia.
Na sessão final da primeira reunião do Comitê Conjunto de Cooperação em Ciência e Tecnologia entre o Brasil e a Coreia, foi assinada a Carta de Intenções entre o CNPq e a National Research Foundation da República da Coreia.

domingo, 28 de agosto de 2011

Não é assim mesmo - Fabio Barbosa Folha de São Paulo

FÁBIO BARBOSA

Não é assim mesmo...


Nossa pior atitude é aceitar que "é assim mesmo" e que nada podemos fazer para melhorar as coisas no país


Por muito tempo achei, assim como muitos, que a questão de cidadania se resolveria por meio de um melhor nível médio de educação. Entretanto, temos muitas evidências indicando que isso não é suficiente.
O reforço que teve de ser dado recentemente na questão do respeito dos motoristas à faixa de pedestres na cidade de São Paulo mostra como ainda temos de lidar com noções muito básicas de cidadania.
Note-se que essa falta de respeito à faixa de pedestres acontece de forma generalizada pela cidade, não importa se estamos falando de um bairro de maior ou de menor nível de educação ou de renda.
Isso indica que não será suficiente um amplo investimento em educação, mas precisaremos também buscar uma forma de darmos foco ao que o jornalista Gilberto Dimenstein, na sua coluna nesta Folha, há um mês, chamou de Educação para a Cidadania.
Observar as leis de trânsito, cuidar da limpeza das ruas, respeitar a fila, não estimular o comércio ilegal ou "pirata", evitar o desperdício de água, entre outras, são condutas básicas para que possamos melhorar a qualidade de vida de todos. Mesmo em zonas da cidade onde o nível médio de educação é certamente bastante elevado, esses desvios são cometidos a todo instante.
Ao comentar esses problemas com colegas, e especialmente com jovens, noto uma grande receptividade para que busquemos formas de mobilizar a sociedade, não apenas conscientizando, mas também punindo e expondo aqueles que negligenciam esses comportamentos.
Algumas iniciativas poderão vir das autoridades, como é o caso da Lei Cidade Limpa na cidade de São Paulo, que, na minha opinião, já poderia ser estendido para além dos outdoors, chegando às ruas e às calçadas da nossa cidade.
Os currículos escolares precisam certamente ser ajustados, incorporando essa visão de cidadania, do papel que cabe a cada um de nós, e a valorização da interdependência, que existe entre tudo e todos.
Ninguém vive sozinho, e nossas atitudes (boas e más) impactam o todo, que deve ser construído junto.
A sociedade civil tem ferramentas tradicionais e modernas para se organizar: as redes sociais, o Twitter, as associações de bairros, as empresas etc.
Não precisa ser nada grandioso, nada que abranja toda a cidade, mas, se cada um conseguir impactar o seu "ao redor", o seu grupo de relacionamento mais próximo, a somatória será grandiosa. E assim um importante passo terá sido dado na mudança de atitude e na abertura de melhores perspectivas.
Recentemente, o jornalista espanhol José Arias, do jornal "El País", escreveu um artigo que causou grande repercussão. Lá, ele pergunta por que não nos indignamos. O foco era a questão dos casos de corrupção no Brasil, e o assunto repercutiu em vários jornais e artigos.
A mesma questão, porém, pode também ser estendida para o aspecto da cidadania. Por que não nos indignamos? A resposta para ambos os aspectos (apatia diante da corrupção e das questões de cidadania), parece ser que muitos acham que esse não é um problema nosso, ou que é grande demais para resolvermos ou influenciarmos. Decorre daí a pior das atitudes, que é a de aceitar que "é assim mesmo", e nada fazer...
Felizmente, há outro movimento, positivo e com um número cada vez maior de pessoas, especialmente jovens, se indignando, se mobilizando, procurando acender a luz e mostrar as coisas como elas são.
Esse é um primeiro e importante passo para que tenhamos a dimensão do problema e possamos tratá-lo de forma adequada. A imprensa e a opinião pública têm importante papel nessa jornada, mantendo a chama acesa e apontando novos caminhos.
Empunhar a bandeira da cidadania, e agir de forma coerente, são maneiras de sedimentar a base para a construção de cidades melhores, e, portanto, de um país melhor.
P.S.: Com esta coluna me despeço deste espaço onde escrevi textos durante pouco mais de um ano.
A partir do final de setembro assumirei novas responsabilidades, em outro grupo de mídia.
Agradeço à Folha pela oportunidade e aos leitores pelas tantas manifestações de apoio.


FÁBIO COLLETTI BARBOSA, 56, administrador de empresas, é presidente do conselho de administração do Banco Santander e presidente do conselho da Febraban.
colletti.barbosa@gmail.com

Nova droga experimental anti inflamatória


redirecionando os linfócito T - New England J of Medicine

figura ilustrativa. Não é a original do artigo


Tem havido progressos consideráveis no entendimento da resposta imune contra tumores. Neste artigo os autores mostram que redierecionando as células T in vitro contra alvos tumorais resulta em remissão de linfoma e melanoma.


Redirecting T Cells

Walter J. Urba, M.D., Ph.D., Dan L. Longo, M.D.

N Engl J Med 365:754-757 | August 25, 2011

The pursuit of tumor-reactive T cells as a cancer therapy has continued unabated since the discovery of the graft-versus-leukemia effect in patients undergoing allogeneic hematopoietic stem-cell transplantation.1 Some successes have been noted: the adoptive transfer of Epstein–Barr virus (EBV)–specific T cells can prevent and treat post-transplantation lymphomas,2 and the adoptive transfer of in vitro activated and expanded autologous tumor-infiltrating lymphocytes after systemic depletion of lymphocytes induces durable complete remissions in some heavily pretreated patients with metastatic melanoma.3 Therapy with tumor-infiltrating lymphocytes is difficult and expensive, and it has benefited only patients with melanoma. Redirecting T cells by gene transfer of T-cell receptors with predefined antigen specificity, which could overcome some of the problems with tumor-infiltrating lymphocytes, has not been very successful clinically as yet.

A parallel strategy has been to redirect T cells with chimeric antigen receptors, which include a targeting moiety, usually a single-chain Fv variable fragment from a monoclonal antibody, a transmembrane hinge region, and a signaling domain (typically the zeta chain from the T-cell signaling complex) (Figure 1). Chimeric antigen receptors have theoretical advantages over other T-cell–based therapies. They use the patient's own cells, which avoids the risk of graft-versus-host disease. They can be created quickly, and the same chimeric antigen receptor can be used for multiple patients. Since chimeric antigen receptors recognize cell-surface molecules, they broaden the repertoire of potential targets to include cell-surface proteins, sugars, and lipids.4 They also eliminate the requirement for restriction of the major histocompatibility complex (MHC) and overcome some of the evasion strategies used by tumors to escape recognition by the immune system (such as MHC loss or altered antigen presentation). First-generation chimeric antigen receptors had limited clinical activity, primarily because in vivo activation of the chimeric antigen receptor T cells induced only transient cell division and suboptimal cytokine production, which failed to produce prolonged T-cell expansion and sustained antitumor effects. These deficiencies were overcome by the addition of a costimulatory signaling domain in second-generation chimeric antigen receptors, which enhanced the proliferation, survival, and development of memory cells — features that appeared to be the hallmarks of successful therapy with EBV-specific T cells and tumor-infiltrating lymphocytes. The CD28 signaling domain has been used most commonly, but CD137 (4-1BB) and CD134 (OX40) domains can also be effective.

Figure 1


T-Cell Activation.

In this issue of the Journal, Porter and colleagues5 describe a heavily pretreated patient with chronic lymphocytic leukemia (CLL) who had a complete remission associated with the tumor lysis syndrome after adoptive immunotherapy with second-generation anti-CD19 chimeric antigen receptor–modified T cells. Four days after receiving chemotherapy with pentostatin and cyclophosphamide for depletion of lymphocytes, the patient received 1.42×107 transduced T cells over 3 days with no additional cytokines. Unselected peripheral-blood T cells were infected with a self-inactivating lentiviral vector carrying genes for the chimeric antigen receptor. These genes included the single-chain Fv from the hypervariable region of a human CD19-specific murine antibody, a hinge region, and human 4-1BB and CD3-zeta signaling domains. The tumor lysis syndrome was diagnosed 22 days after treatment and correlated temporally with the induction of high levels of cytokines (interferon-? and interleukin-6) and with an increase in the number of circulating chimeric antigen receptor–positive T cells to a level that was nearly 1000 times as high as the level detected the day after infusion. Eight months after therapy, chimeric antigen receptor–positive T cells persisted, and the patient had no evidence of disease on physical examination or on computed tomographic, flow-cytometric, or cytogenetic analysis.

The expansion, persistence, and development of the memory phenotype, not to mention antitumor effects, of these T cells were impressive.6 The apparent superiority to CART19 T cells with only a CD28 domain7 may be explained by the interaction of the CD28 ligands CD80 and CD86, which are present on CLL cells, with CD28 in addition to the 4-1BB signaling through the chimeric antigen receptor. In this respect, the chimeric antigen receptor may have functioned more like a third-generation construct that includes a combination of costimulatory domains. In addition to the tumor lysis syndrome, the patient had B-cell depletion and hypogammaglobulinemia. These conditions may not be major problems in patients with CLL, but in other tumor types, the persistence of activated T cells, memory T cells, or both could pose substantial problems. Both toxic effects to the target organ and also “on-target but off-organ” toxic effects have been observed because of unappreciated cross-reactive target antigens.8 Toxicity may become more of a problem as more potent second- and third-generation chimeric antigen receptors are used in patients with different tumor types. Safety measures include the infusion of lower numbers of T cells, the use of immunosuppressive agents, and the introduction of an inducible “suicide signal” to kill the cells when they are creating mischief; a novel, nonimmunogenic, inducible caspase 9 suicide gene has been developed for this purpose.9 The only deaths from toxic effects reported thus far have been acute and occurred within hours after administration of the gene-transfected cells,7,10 — a situation in which the suicide strategy would not have had time to work.

Only with the more widespread clinical use of chimeric antigen–receptor T cells will we learn whether the results reported by Porter et al. reflect an authentic advance toward a clinically applicable and effective therapy or yet another promising lead that runs into a barrier that cannot be easily overcome.

This article (10.1056/NEJMe1106965) was published on August 10, 2011, at NEJM.org.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

References

PL Weiden, KM Sullivan, N Flournoy, R Storb, ED ThomasAntileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.N Engl J Med1981;304:1529-1533
CM Rooney, CA Smith, CYC Ng, Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.Blood1998;92:1549-1555
SA Rosenberg, JC Yang, RM Sherry, Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.Clin Cancer Res2011;17:4550-4557
M Cartellieri, M Bachmann, A Feldmann, Chimeric antigen receptor-engineered T cells for immunotherapy of cancer.J Biomed Biotech2010;2010:956304 (Epub 2010 May 5)-956304 (Epub 2010 May 5)
DL Porter, BL Levine, M Kalos, A Bagg, CH JuneChimeric antigen receptor-modified T cells in chronic lymphoid leukemia.N Engl J Med2011;365:725-733
M Kalos, BL Levine, DL Porter, T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med2011;3:95ra73-95ra73
R Brentjens, R Yeh, Y Bernal, I Riviere, M SadelainTreatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial.Mol Ther2010;18:666-668
HE HeslopSafer CARS.Mol Ther2010;18:661-662
V Hoyos, B Savoldo, C Quintarelli, Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.Leukemia2010;24:1160-1170
RA Morgan, JC Yang, M Kitano, ME Dudley, CM Laurencot, SA RosenbergCase report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.Mol Ther2010;18:843-851
Source Information

From the Providence Cancer Center and the Earle A. Chiles Research Institute, Portland, OR (W.J.U.).

sábado, 27 de agosto de 2011

Homenagem a Baruf Benacerraf - 1921-2011- Immunity


Mutos de nós que gostamos de imunologia, leu e aprendeu um pouco de imunologia lendo no livro do Prof . Benacerraf. Veja abaixo a homenagem da immunity sobre a vida de Benacerraf

Obituary

Baruj Benacerraf (1921–2011)
Norman L. Letvin1Corresponding Author Contact InformationE-mail The Corresponding Author
1 Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

Available online 25 August 2011.

Article Outline

Main Text

Main Text

With the recent passing of Baruj Benacerraf at the age of 90, the immunology community has lost one of its pioneering leaders. He was a corecipient of the Nobel Prize in Medicine in 1980 for his demonstration of the genetic control of immune responses. Baruj also made important contributions to our understanding of numerous other immunologic phenomena. In addition, he was a supremely gifted scientific administrator and a devoted mentor for generations of immunologists.
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Baruj Benacerraf on the day he was notified that he had been awarded the Nobel Prize in 1980. Photograph by Joe Wrinn, with permission from Harvard Medical School.

Perhaps his most important scientific contribution was his description in the early 1960s of the genetic control of immune responses to administered foreign antigens. Observing that some guinea pigs responded to an antigenic challenge whereas others did not, he showed through inbreeding experiments that this responder versus nonresponder status was genetically determined. He postulated that the responder versus nonresponder status was under the control of what he called immune response or Ir genes—what we now know are genes encoding the major histocompatibilty complex (MHC). The importance of these observations was recognized in 1980 with a Nobel Prize, which he shared with George Snell and Jean Dausset.
Baruj's background was a colorful one. A member of a Sephardic Jewish family involved in the international textile trade (his father was Moroccan and his mother Algerian), he was born in Venezuela and raised in France. He received his undergraduate degree at Columbia University in New York City and medical degree from the Medical College of Virginia in Richmond. After a brief period of U.S. military service as a physician in Germany and France immediately following World War II, Baruj did a fellowship in immunology at Columbia University with Elvin Kabat and then moved to France, where he began his career in immunology while overseeing his ailing father's business holdings.
In 1956, Baruj returned to the U.S. to accept a faculty position at New York University. He became Chief of Immunology at the National Institute of Allergy and Infectious Disease in 1968 and then moved to Harvard Medical School in 1970, where he became Chairman of the Department of Pathology. In 1980, he became President of the Harvard Medical School-affiliated Dana-Farber Cancer Institute.
As his career evolved, Baruj's efficiency and administrative prowess became legendary. He launched his career as an independent investigator while overseeing a substantial family business enterprise. At the height of his active professional life, he simultaneously led the Department of Pathology at Harvard Medical School, the Dana-Farber Cancer Institute during an unprecedented period of growth in its clinical and research operations, and his own very active and productive basic immunology laboratory. One of Baruj's life-long friends and professional colleagues, Sheldon Wolff, urged me to spend time working with Baruj after I finished my clinical training in medicine, saying that even if I eventually chose to pursue a career outside of science, I would learn invaluable lessons from Baruj on how to be a successful administrator.
While Baruj's many achievements were impressive, he claimed that his greatest satisfaction came from mentoring young immunologists. He cared deeply about the professional success and personal happiness of his fellows. In spite of his many pressing administrative obligations, he always found time to walk through the laboratory every day and speak individually with each of his fellows about the progress of his or her experiments. He often called me at home in the evening to discuss the outcome of an experiment if the results were not apparent by the end of the usual work day. Perhaps most importantly, his mentoring did not end when a fellow left the laboratory to embark on an independent career. As he did with many others who trained with him, Baruj continued to provide me with invaluable advice on scientific and professional issues as my career progressed. It is not surprising that Baruj's fellows have gone on to make major contributions to our understanding of the immune system and have played major leadership roles in the field of immunology.
Central to his success as a mentor was his genuine feeling that each of his fellows was a member of his family. During his time at Harvard Medical School, he often had members of his laboratory join him, his wife Annette, and his daughter Beryl for dinners at their apartment or weekends at their summer home on Cape Cod. This sense of family carried over to his many fellows who grew to feel an intergenerational bond as members of Baruj's extended family. It is, therefore, only natural that Baruj's passing leaves all of us in the community of immunologists with a deep feeling of personal loss, the loss of a member of our family.

quarta-feira, 24 de agosto de 2011

célula come célula - The Scientist


It’s a Cell-Eat-Cell World

For more than 100 years, pathologists have observed cancer cells engulfing other live cells, but scientists are only now beginning to understand how it happens and what it means for tumorigenesis.
By Jef Akst | August 1, 2011
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CORBIS, LAUGHING STOCK
It was a late night in 1984, and graduate student Xiaoning Wang was all alone in the lab. At First Military Medical University (now Southern Medical University) in Guangzhou, China, he was working at the lab’s only camera-equipped microscope, under a wooden hood constructed by his advisor, using a hair dryer to keep a cell culture of murine sarcoma cells at 37°C—mouse (and human) body temperature. He’d been doing the same thing nearly every night for the past month, hoping to capture on film what he had witnessed just a few weeks earlier—a tumor cell engulfing a live natural killer (NK) cell, a lymphocyte of the innate immune system and a major player in tumor suppression. After many sleepless nights, he had started to worry that perhaps he’d be unable to repeat the results.

“I watched day by day, night by night,” he recalls. He often saw the two cell types interact, but “most of the time, the lymphocyte killed the tumor cell.” But that fateful night it happened again. “I watched the whole process,” he says, “one cell entering another cell.” Controlling his excitement, Wang snapped pictures repeatedly as the two cell types came together, attached—and then the NK cell moved completely within the tumor cell. After another nerve-racking few hours of developing the film, Wang surveyed his pictures with pride. “I see success. I got the whole process from the beginning to the end. I think, I can graduate!”

Not having easy access to scientific literature in post-revolution China, Wang didn’t realize that he wasn’t the first to observe these so-called cell-in-cell structures (though he was one of the first to photograph the engulfment process). In fact, sporadic reports of live cells inside tumor cells date back to the beginning of the 20th century. With an internalized cell housed in a large vacuole, the strange cellular event was typically recognized by the crescent shape of the host-cell nucleus, squished along the cell’s perimeter by the intracellular structure. Over the last 100 years, lymphocytes, neutrophils, NK cells, and even other tumor cells have been found living temporarily within the cells of a variety of human cancers, including those of the skin, lung, breast, brain, pancreas, kidney, and blood. But until recently, little research has been devoted to how the cells got there and what consequences their engulfment has for tumor growth and survival. “For a long time, the cell-in-cell phenomenon had been overlooked in research,” Wang says.

Over the last 100 years, lymphocytes, neutrophils, NK cells, and even other tumor cells have been found living temporarily within the cells of a variety of human cancers.
In the last few years, however, a handful of labs have begun to detail the process, documenting cell-in-cell structures in as many as 12 percent of tumor cells in vivo and 30 percent or more in vitro, depending on cancer type. In 2006, a group in Italy described metastatic melanoma cells that internalized T cells.1 The following year, another group analyzed breast tumor cells ingesting other tumor cells.2 And in 2009, Wang, now with his own lab complete with a proper hood, confirmed and added to his results from the 1980s, demonstrating that a variety of tumor cell lines harbor NK cells.3

The names given to the process include cell cannibalism, entosis, and emperipolesis. The molecular details of the engulfment seem to vary depending on cell type—as do the fate of internalized cells and, most likely, the consequences of the phenomenon, which have been proposed to range from tumor promotion to tumor suppression. But there is one thing most researchers tend to believe: cell engulfment is biologically important in tumor pathogenesis, and may hold potential for both the diagnosis and the treatment of cancer.

“Cannibalism is a very important discovery,” says Stefano Fais, an oncologist at the Istituto Superiore di Sanità in Italy, who led the study on T-cell-eating melanoma cells. “Cannibalism is a feature common probably to all malignant cancers.”

Who’s eating whom?
In the summer of 2006, a small group of researchers gathered in Guangzhou, China, to discuss recent developments in stem cell research. One evening, after hosting a social event alongside the picturesque Pearl River for the meeting attendees, Wang—by then the dean of the School of Bioscience and Bioengineering at South China University of Technology in Guangzhou—decided to take the opportunity to share his work from grad school (which had been published in English in 1987, along with more detailed electron micrograph images of the cell engulfment activity4). In the dim light of a local pub that overlooked the river and the city, Wang showed the researchers the photos. At this time, Wang says, few people had ever heard of such cell-in-cell structures, and “they were very excited about this phenomenon.”


Infographic: Cell-In-Cell-Action
View full size JPG | PDF
LUCY READING-IKKANDA

The images caught the eye of one researcher in particular, cell biologist Xuebiao Yao of the University of Science and Technology of China in Hefei. “I was surprised,” Yao recalls. “Seeing Dr. Wang’s early electronic micrographs reminded me of the technology used for hybridoma cell making, chemically putting two different kinds of cells together”—but Wang had not chemically induced this phenomenon. “I [wanted] to investigate whether this cell-in-cell process occurs in regular physiology or pathophysiology in [the] human body,” Yao says.

So the two arranged a collaboration to reignite Wang’s graduate work on tumor-cell engulfment. But among many other ongoing projects, the work got pushed to the side until the following year, when a group at Harvard Medical School published a paper detailing the engulfment of breast cancer cells by other breast cancer cells. Led by Michael Overholtzer and Joan Brugge, the group found that approximately one-quarter of breast cancer cells in a suspension culture contained internalized sibling tumor cells. The researchers detailed the engulfment process, which they termed entosis, noting that it required many elements of cytoskeleton regulation and cell-cell junctions, including actin, myosin II, cadherins and Rho signaling. Inhibiting any of these factors suppressed cell engulfment. Unexpectedly, when the researchers inhibited components of the Rho pathway in only a subset of tumor cells, they found that those cells were unable to enter other tumor cells, but they were still able to host internalized cells.2

“The mechanism really took us by surprise,” says Overholtzer, now at Memorial Sloan-Kettering Cancer Center in New York City. Unlike phagocytosis, the process by which macrophages take up dead cells and other extracellular materials for digestion and disposal, the cell that was being internalized seemed to take an active role in its own engulfment. “The data suggested that the cells were not being eaten at all,” he says. “They were invading.”

The researchers proposed that engulfment may be initiated after the cells detach from the extracellular matrix. This is a common occurrence among tumor cells in vivo, Overholtzer says, as cells proliferate from a single epithelial sheet to form a three-dimensional mass. Once they are freed from the forces attaching them in place, the dynamics holding cells together at cell-cell junctions take over. If there is an imbalance in these forces between two cells, with one cell pulling more strongly than the other, engulfment may result.

Indeed, anecdotal reports of cell-in-cell structures in tumors are documented in fluid samples. “We have noted that most of the malignant tumors [have] significant numbers of cell cannibalism, particularly in body fluids where the cells are floating, such as effusion fluids and urine samples, and also in breast carcinomas,” says cytopathologist Pranab Dey of the Postgraduate Institute of Medical Education and Research in India.

Though Overholtzer’s work clearly differs in some experimental details from Wang’s grad-school observations—Overholtzer’s group found that cancer cells engulf other cancer cells, while Wang observed the engulfment of immune cells—the results spurred Wang and Yao into action. They and their colleagues were able to re-document the phenomenon, finding internalized NK cells in up to 10 percent of tumor cells, depending on cancer type. Further characterizing a cell line from an epidermoid, or squamous cell, carcinoma, the researchers identified a role for E-cadherin in forming the connections between the NK and tumor cells prior to engulfment. They also identified a role for ezrin, a protein that links the plasma membrane with the actin cytoskeleton, in the internalization process.3


Entosis in Human Breast Tumors: Cells undergoing entosis illustrate some of the possible fates of internalized cells. The red stain highlights beta-catenin, a cell-cell adhesion protein found along the cells’ perimeters, and the blue labels the nuclei of both the host and internalized cells.
1. Cell within a another cell, squishing the host cell nucleus into a crescent shape.
2. An internalized cell undergoing cell death.
3. An internalized cell undergoing cell division.
4. A 3-cell structure—a cell within another cell, within a another cell.
COURTESY OF MICHAEL OVERHOLTZER

Like Overholtzer, Wang suspects that the internalized NK cells may play an active role in the process. The tumor cells he studied did not engulf dead lymphocytes, distinguishing the process from phagocytosis and suggesting that the tumor cells may respond to a signal produced by living NK cells. Furthermore, the knockdown of ezrin appeared to affect the fluidity and flexibility of the tumor cells’ plasma membranes, Wang explains, making them more rigid, potentially hindering NK cells from pushing into tumor cells. While siRNA-mediated knockdown of ezrin had no effect on the conjugation of the two cells, it inhibited NK cells from fully entering the tumor cells. Conversely, when the tumor cells were treated with reagents to activate the phosphorylation of ezrin, NK cell engulfment became more efficient.

Just a few years earlier, Fais’s group had similarly documented a role for ezrin in the engulfment of T cells by melanoma cells.1 Those researchers also identified another key player—a protein called caveolin-1, a main component of invaginations in the plasma membrane called caveolae, which research has suggested participate in the uptake of bacteria and viruses. “My idea is that ezrin binds to caveolin-1, thus connecting caveolae to actin and allowing the endocytic process [to proceed],” says Fais, who believes that T cells do not have an active role in engulfment. In the highly acidic tumor microenvironment, he says, “T cell activities are virtually abolished, [yet] T cells are equally cannibalized in both buffered and acidic media.” For this reason, Fais distinguishes this phenomenon as true cell cannibalism, with the host cell actively engulfing its victims, in contrast with the invasive aspect of entosis.

Despite this difference and the suspected role of caveolae in certain endocytic processes, Fais still argues that the cannibalistic activity he observed in melanoma cells is distinct from phagocytosis. His group documented T cells resting close to the cannibalistic melanoma cells before the tumor cells began to invaginate to capture the live lymphocytes. In contrast, phagocytosis is characterized by the formation of cellular extensions that embrace and engulf the external material. “Cannibalism looks to me like a swallowing of the external body,” says Fais, who proposes that it functions to provide nutrition to tumors. “Phagocytosis is to scavenge, not to feed. It’s really different.”

Hungry tumors or kamikazes?
Though the mechanisms of engulfment may differ among cell and cancer types, the end result is nearly indistinguishable—a whole, living cell is housed within a large vacuole inside a tumor cell. Internalized cells usually follow one of three paths. They can continue living, at least temporarily, within the host cell, even dividing within their vacuole homes. Occasionally, they escape from the host cell to once again become a single, individual cell in the extracellular space. By and large, however, death is the most common fate for cells engulfed by tumor cells. Wang and colleagues demonstrated evidence of the apoptotic death of NK cells following their uptake by tumor cells. Nearly 90 percent of the internalized lymphocytes underwent traditional, programmed cell death, as evidenced by the activation of caspase 3. Work by Overholtzer’s group, on the other hand, suggests that cell engulfment between tumor cells represents a different type of cell death altogether—one mediated by lysosomes. The vacuoles housing the internalized tumor cells, his group observed, became acidic and surrounded by lysosomal membranes, indicative of fusion with lysosomes. Furthermore, when the researchers overexpressed B-cell lymphoma 2 (Bcl-2) to inhibit apoptosis, it had little effect on the death of internalized cells. On the other hand, inhibiting lysosomal acidification of the vacuoles could rescue the captured cells, when it was combined with apoptotic inhibitors. Interestingly, when only the lysosomal inhibitors were introduced, more cells appeared to undergo an apoptotic death, suggesting that apoptosis serves as a backup mechanism to the more common lysosomal death of the internalized cells.

Fais suggests it is simply the acidic environment of the tumor-cell vacuoles in metastatic melanoma cells that kills the internalized lymphocytes, though lytic enzymes may help to further digest the cell, he says. He argues that the engulfment and subsequent killing of cells such as lymphocytes is cell cannibalism in the most literal sense—one cell eating another. Once the victim is digested, the tumor cell can theoretically derive nutrients from it, promoting cancer survival and growth.

“We know that nutritional stress is a common feature of tumors,” says Eileen White, a cancer biologist at The Cancer Institute of New Jersey and Rutgers University. “We know they’ll undergo this process of autophagy where they’ll eat themselves. If they have the capability of eating each other or other cells—that would open a whole new door for tumors to sustain themselves.”

As evidence for this hypothesis, Fais showed in vitro that cell cannibalism increased under starvation conditions, and that the ingestion of T cells promoted the survival of melanoma cells. “The T cell is great because it has all these wonderful complex carbohydrates on the surface,” says cancer biologist Thomas Seyfried of Boston College. “They can all be degraded to glucose and other fuels [that tumor cells] could be using.”

But even if cells are deriving nourishment from their cannibalistic activities, it’s likely not the only benefit of the behavior, says immunologist Yufang Shi, who studies apoptosis at the Chinese Academy of Sciences and the Child Health Institute of New Jersey. “For one cell to digest another cell and to get energy . . . this is very uneconomical,” Shi explains. “You have to really make the cell into amino acids and polysaccharides. It’s very hard to use that as energy.” The fact that cell cannibalism increased when the cells were starving may simply be due to the fact that nutrient deprivation can cause cells to become detached from the extracellular matrix, Shi added—an event that Overholtzer’s group suggests could promote cell engulfment as a result of imbalanced cell-cell adhesion forces.

Another possibility is that the engulfed cells are driving the process. Internalized immune cells, for example, may have the potential to suppress tumor growth. During his initial graduate studies in the 1980s and again when he resumed this work more recently, Wang observed that some NK cells internalized by tumor cells can actually kill their host cells from the inside out. “After they enter into the tumor cells, they make the tumor cells erupt,” Wang says. “When [these NK cells] die, they also release a lot of enzymes,” Shi explains. “They are cytotoxic cells, so they can kill by releasing directly into the target cell, like the suicide bombers.”

But whether the internalized NK cells are initiating the engulfment is still unclear. If, on the other hand, the tumor cells are actively consuming the lymphocytes, it could provide a way for cancer to evade attack by the immune system. “I have a suspicion that maybe tumor [cells] in some conditions can kill the NK cells as a way to escape the surveillance of the immune system,” Wang says. This may become particularly important as the cancer metastasizes, Yao adds. “One of the physical challenges for those tumor cells will be how to survive in the new sites. One way is by taking [up] those NK cells and other immune cells to damage the immune response of cancer [patients].”

The bizarre phenomenon may also contribute to the genetic instability of cells, perhaps contributing to the formation of cancer early on. This March, Overholtzer and colleagues published the finding that cell-in-cell structures can act as cleavage barriers that disrupt cell division, leading to changes in ploidy—the number of sets of chromosomes in the cell—which are known to drive tumor progression.5 Conversely, cell engulfment may act to suppress tumor growth, such as when tumor cells eat other tumor cells. “Entosis has a dual nature,” says Overholtzer. “It clearly can kill [tumor] cells, but also, it can disrupt ploidy—one is predicted to be tumor suppressive, one is tumor promoting.”

For now, the question of function remains “a puzzle,” Fais says, and “I don’t have all the pieces.” But with evidence growing for significance of cell engulfment in tumor pathogenesis, researchers are now considering whether the phenomenon could serve to aid in diagnosis or in the development of new cancer treatments. “I think in the next few years this will be a very active field,” Shi says.

Exploiting Engulfment for Diagnosis and Treatment
Despite the uncertainty surrounding the implications of cell engulfment in tumor pathogenesis, the fact that tumor cells take up other living cells provides an intriguing starting point for both diagnostic and therapeutic developments.

Marker of malignancy
Cell engulfment tends to be more common in, if not exclusive to, metastatic tumors. While oncologist Stefano Fais of the Istituto Superiore di Sanità in Italy found evidence of cell-in-cell structures in 100 percent of the metastatic tissues he examined, he found no primary melanoma cells containing lymphocytes and only rarely observed engulfment of sibling tumor cells.1 Similarly, Pranab Dey of the Postgraduate Institute of Medical Education and Research in India found that cell-in-cell formation correlated with the different grades of breast carcinomas, with more aggressive cancers showing higher rates of cannibalism.6 “It is a marker of malignancy, there is absolutely no doubt,” Dey says.

Starve your cancer
If engulfment is beneficial to tumor growth, it stands to reason that strategies to inhibit the behavior may effectively treat cancer. Currently, a handful of cancer clinical trials are investigating the use of chloroquine, a drug that alters the pH of lysosomes and thus disrupts autophagy, the process by which tumor cells eat themselves when resources are scarce. If such a process is involved in the digestion of internalized cells, similar therapies may also serve to cut off engulfment as a potential food supply. These therapies may be most effective when combined with dietary restriction to further limit the cancer’s access to food. “The cancer cells only need to [digest themselves and other cells] if they’re hungry,” says Thomas Seyfried, a cancer biologist at Boston College. “If you take glutamine and glucose away from them, that’s when you hit them with the chloroquine.”

Pick your poison
Cancer researcher Mamdooh Ghoneum of Charles Drew University of Medicine and Science in South Los Angeles, California, is investigating the use of baker’s yeast as a natural cancer therapy, and has shown that after engulfing yeast cells in vitro, breast, tongue, colon, and skin cancer cells undergo apoptosis. The results were later confirmed in mice suffering from cancer that had metastasized to the lung. “When we injected mice with yeast, we can see 80 percent of the tumor disappear,” Ghoneum says. But unlike most cell engulfment researchers, he believes that the process is equivalent to phagocytosis, and noted that both living and dead yeast cells have the ability to kill cancer.

terça-feira, 23 de agosto de 2011

India e inovação em tuberculose -Nature

Conference aims to spur interest in creating better diagnostic tests.

Gozde Zorlu


Madhukar Pai.
Madhukar Pai, an epidemiologist and tuberculosis (TB) researcher based at McGill University in Montreal, Canada, is co-chairman of the Stop TB Partnership's New Diagnostics Working Group and a consultant to the Bill & Melinda Gates Foundation, headquartered in Seattle, Washington.

He has helped to organize the first ever conference to get the Indian pharmaceutical industry interested in TB innovation: 'TB Diagnostics in India: From Importation and Imitation to Innovation', to be held on 25 and 26 August in Bangalore, India. Nature caught up with him to find out how he thinks emerging economies, such as India, can help to combat the TB epidemic with improved diagnostics.

Is there a good test for TB?

No, there is an urgent need for a simple, cheap and rapid test for TB, like we have for malaria and HIV. Despite all the efforts made by the World Health Organization's (WHO's) Stop TB Partnership and national programmes, TB continues to be a huge problem, with more than 9.4 million cases and 1.3 million deaths a year.

The United Nations' Millennium Development Goal of eliminating the disease by 2050 looks impossible at the current rate of decline. Diagnosis is a key challenge. We are barely detecting 60% of cases, so undiagnosed TB continues to fuel transmission. Misdiagnosis is another concern — there are dozens of inaccurate blood tests for active TB. Earlier this month, the WHO published a policy recommendation against the use of such tests, based partly on my work.

What tests are available?

The WHO currently endorses three diagnostic approaches. These are: visual detection, such as by smear microscopy; growing bacteria in cultures; and molecular DNA tests. Smear microscopy is the main technology used in developing countries, but it misses a large number of cases and does not pick up multi-drug-resistant strains. Culture and molecular tests are more accurate, but their cost and need for sophisticated laboratories is an issue in developing countries.

What's in the pipeline?

Several teams are working on a variety of technologies, from tests for antigens and antibodies, to hand-held molecular tests and non-invasive breath tests.

This kind of development depends on basic research into TB. The Bill & Melinda Gates Foundation is investing a lot of money into this field, as are other groups, such as the Foundation for Innovative New Diagnostics in Geneva, Switzerland, the US National Institutes of Health in Bethesda, Maryland, academics and industry. The hope is that we will have a cheap, accurate and rapid test in about five years.

But one area of concern is the funding gap. An analysis by the Treatment Action Group, a think tank based in New York, estimated that in 2009, just US$41 million was spent on research and development for TB diagnostics — way off the Global Plan to Stop TB's estimate that $740 million will be required each year to the end of 2015.

What part can India play?

There is a lot of buzz about the potential of Brazil, Russia, India, China and South Africa in the development of affordable health-care technologies. This is especially exciting for diseases of poverty, such as TB, that may not be of great interest to rich countries or to industry, which do not see a market to justify investments.

Although these countries have a large TB burden, they also have the technical resources to invest in solutions and are capable of addressing the funding gap by infusing more resources into research and development for diseases such as TB. There is also potential for philanthropic initiatives from high-net-worth individuals and companies in these growing economies.

India is a key player in the emerging power structure. It has a large scientific resource and its success in the information-technology area has inspired entrepreneurship in several areas, including biotechnology.

What are the main challenges?

ADVERTISEMENT

The Indian industry has done well with generic products but the transition to innovation is not an easy one. In fact, I think easy success with generics has actually made it harder for Indian industry to innovate. Real innovation will require changes such as progressive policies by the government to increase funding and partnership opportunities between government, donors, researchers and the private industry.

What do you hope the Bangalore conference will achieve?

We hope that the meeting will result in partnerships among Indian groups who can work together to solve a big public-health problem for India, but also come up with viable business models that are sustainable for industry.

We have 70 companies participating, plus venture capitalists, donors, funding agencies, government officials and academics. Getting this many groups together has not been easy – many companies are just not interested in TB. Even if a handful of companies and stakeholders make a serious effort at developing innovative products for TB, I would consider that a big success! 

sexta-feira, 19 de agosto de 2011

folha de São Paulo- Intolerável -Marina Silva







MARINA SILVA

Intolerável

Corrupção mata. Entender isso é fundamental para atacar um dos males que mais empatam o desenvolvimento socioeconômico e político do Brasil. Ainda há quem não veja a conexão entre corrupção e violência, mas elas estão intimamente ligadas.
Da mesma forma, devemos entender que a baixa eficiência e o mau funcionamento dos serviços do Estado estão tremendamente relacionados à cultura da corrupção, ao patrimonialismo, à falta de transparência e à baixa capacidade de mobilização social.
A morte da juíza Patrícia Acioli, no Rio, não é apenas um crime brutal. A execução de uma servidora pública correta e rigorosa com os crimes, principalmente os cometidos por agentes públicos, revela a força que as máfias têm no país. E o tamanho que elas adquiriram, graças à corrupção.
Quando a propina chancela e incentiva o desvio de conduta, torna-o cada vez maior. E chega a um ponto em que vê na lei um obstáculo que precisa ser removido, tirando do caminho quem a faz cumprir.
É na má política que se choca o ovo da serpente da violência policial e das relações espúrias entre poder de Estado e delinquência. Quem assistiu aos filmes de José Padilha "Tropa de Elite" e "Tropa de Elite 2" pode ver como a propina de todo dia fortalece a mão que aperta o gatilho contra os inocentes.
A morte de Patrícia Acioli é uma afronta ao Estado democrático de Direito. Ela não é apenas mais uma vítima. Era alguém que, no desempenho de suas funções, buscava combater a barbárie de grupos que querem controlar a vida de quem mora na periferia e, claro, o próprio Estado.
Matar uma juíza revela enorme convicção da própria impunidade. É uma declaração de guerra às leis, à democracia e à sociedade. Assim como é inaceitável que o Brasil conviva com a execução de uma juíza, também não é mais tolerável convivermos com o nível de corrupção que tem marcado o nosso país.
Vemos, na mídia, como a Índia, país com problemas maiores do que os nossos, desperta vigorosamente para o combate à corrupção. E o que falta para o Brasil? Quanto mais indignada for a resposta da sociedade aos escândalos e aos homicídios de cada dia, maior será o poder de reação contra essas mazelas no âmbito do próprio Estado.
A autoridade pública da menor à maior se sentirá fortalecida e incentivada a agir contra a corrupção, que é, em si, uma forma de violência contra a coletividade.
A faxina, então, deixa de ser rápida, como se faz quando chega uma visita inesperada, e passa a ser permanente, vigorosa, profunda. É desse nível de exigência que precisamos. Se nos acostumarmos a deixar barato, perderemos o controle do que é público, do que é de todos nós.
MARINA SILVA escreve às sextas-feiras nesta coluna.




Anticorpos neutralizantes do HIV



NATURE | LETTERprevious article next article
Broad neutralization coverage of HIV by multiple highly potent antibodies

Laura M. Walker, Michael Huber, Katie J. Doores, Emilia Falkowska, Robert Pejchal, Jean-Philippe Julien, Sheng-Kai Wang, Alejandra Ramos, Po-Ying Chan-Hui, Matthew Moyle, Jennifer L. Mitcham, Phillip W. Hammond, Ole A. Olsen, Pham Phung, Steven Fling, Chi-Huey Wong, Sanjay Phogat, Terri Wrin, Melissa D. Simek, Protocol G. Principal Investigators, Wayne C. Koff, Ian A. Wilson, Dennis R. Burton & Pascal Poignard
AffiliationsContributionsCorresponding authors
Nature (2011) doi:10.1038/nature10373
Received 20 April 2011 Accepted 14 July 2011 Published online 17 August 2011


Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies1, 2, 3. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.
Artigo completo
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10373.html#/f1

quinta-feira, 18 de agosto de 2011

A morte do Instituto de Patologia das Forças Armadas - AFIP

da Nature


55 milhões de lâminas e 33 milhões de blocos de parafina.
Este instituto ajudou em muito na formação de patologistas e nos diagnósticos de doenças tropicais. É lamentável seu fechamento


Death of a pathology centre: Shelved
ALISON MCCOOK
For decades, the Armed Forces Institute of Pathology has been a leader in disease diagnosis. Now it is closing, and its legacy is in jeopardy.

The news took William Travis's breath away. The e-mail he had just opened revealed that the organization where he had worked for nearly 15 years — the Armed Forces Institute of Pathology (AFIP) in Washington DC — was to close. "I had cold chills," recalls Travis, now a thoracic pathologist at the Memorial Sloan-Kettering Cancer Center in New York City. "I was shocked. I thought, 'How could an institution like this be allowed to go away?' I had trouble breathing."

That was in the spring of 2005, just five months after Travis had left the institute. The storied medical centre had become a casualty in a wave of cost-cutting closures and consolidations at the US Department of Defense. And on 15 September, less than a year shy of its 150th birthday, the AFIP will shut its doors for good.

In its long history, the AFIP has become a stalwart of the international biomedical community. With its vast library of tissue samples and expertise at analysing tissues for the diagnosis of disease, it has been a valuable resource for researchers and clinicians alike. Every year, the AFIP received at least 50,000 requests for second opinions on difficult cases from external pathologists. The nearly 800 employees — including experts in many areas of human and animal pathology — made major or minor changes to roughly half of the cases they acted on.

The military has yet to decide whether academic scientists will continue to have access to the AFIP's unique tissue repository. The largest in the world, it holds 55 million glass slides, 31 million paraffin blocks and more than 500,000 wet tissue samples. Scientists had only just begun to apply modern molecular techniques, such as DNA and RNA sequencing, to the collection. "That repository is an international treasury. And that has got to be available to the community at large," says John Madewell, a former AFIP radiologist now based at the M. D. Anderson Cancer Center in Houston, Texas. So even as scientists mourn the loss of the institution, many are wondering what will become of the fruits of its labours. "I am very concerned," says Madewell.

Humble beginnings

Click here for a slideshow on the AFIP’s history.
Credit: Reeve 69429/NMHM
From the start, the AFIP had a mission that extended beyond military strategy. In the spring of 1862, three dried and varnished tissue specimens were placed on a shelf in the Washington DC office of Brigadier General William Hammond, the Army surgeon-general. It was the beginning of the Army Medical Museum (see slideshow 'A diary of death & disease'). Hammond wanted to collect and catalogue the specimens that had been accumulating from men fighting in the American Civil War. He wanted a collection that would "embrace all forms of injuries and diseases, so that eventually it would become a general pathological museum, accessible for study to all medical men who are prosecuting original inquiries".

The museum became increasingly important to the military during the two world wars, says Michael Rhode, an archivist and one of the few remaining AFIP employees, as soldiers came back with strange new diseases such as gas gangrene, in which bacteria produce tissue-killing toxins inside the body. The army decided it needed a central location to collect and learn from unique cases and in 1944, the museum established the Army Institute of Pathology. Five years later, the institute became the central laboratory of pathology for all branches of the armed forces, and adopted its current name.

Rhode says that "there was a strong tradition of involving civilians". It was in the military's interests to collect difficult cases from around the world, to learn more about the diseases troops could face. As the AFIP didn't initially charge for second opinions on difficult cases, the samples flooded in.

The institute's final home, on 16th Street in Washington DC, was built in the 1950s to accommodate the growing repository and the pathologists who wanted to work at the AFIP, drawn to the collection and the stream of unusual cases. Within the first five years in the new building, AFIP scientists conducted more than 200 investigations of misunderstood diseases.

AFIP pathologists also began producing the Atlas of Tumor Pathology, a set of frequently updated volumes that are considered "bibles" of the field, says Chris Kelly, a former spokesperson for the AFIP. "There is probably not a bookshelf in a pathology office that does not contain at least one of these."

But many clinicians would say that the AFIP had the most impact with its consultation service, in which resident experts provided a second opinion on cases submitted by external pathologists in which, for whatever reason, the original diagnosis was uncertain. For instance, says former AFIP pathologist Susan Abbondanzo, two high-grade lymphomas — lymphoblastic and Burkitt's lymphoma — can be difficult to distinguish using the typical tissue-staining method used by most pathologists. But each has a very different treatment, so an incorrect diagnosis could kill the patient. The AFIP could routinely diagnose these cases, relying on experts in conjunction with a molecular and immunohistochemical laboratory, which many small hospitals lack. "I'm not going to say every diagnosis is life-saving," says Abbondanzo. "But many of the things you see there are, potentially."

A pathologist's goldmine
When pathologists extol the value of the AFIP, the conversation always returns to the tissue repository — all told nearly 90 million tissue samples, including some of the most rare and difficult cases ever encountered in the history of the field. A general pathologist might see one or a few cases of a rare tissue abnormality during a career. The repository often contains many, enabling researchers to categorize the diseased tissues and standardize diagnosis.


With nearly 90 million samples, the AFIP's tissue repository is the world's largest.
Credit: K. KASMAUSKI/CORBIS
Abbondanzo joined the AFIP's department of haematopathology in 1990, and the first research project she collaborated on was investigating whether the anti-seizure drug Dilantin caused tumours in lymph nodes. "It was a huge concern," she says. Abbondanzo had been a pathologist for six years, but had never seen a case of enlarged lymph nodes in people taking Dilantin. When she arrived at the AFIP, there were 25, which allowed Abbondanzo and her colleagues to determine that the vast majority of cases were benign, not cancerous — showing there was no association between the drug and the cancer 1.

And in the 1990s, Jeffery Taubenberger (then chair of the AFIP's department of molecular pathology) and his colleagues began applying molecular techniques to the repository's paraffin-embedded tissue blocks containing lung samples from soldiers killed by Spanish flu during the 1918 pandemic 2. From these samples, among others, they were able to analyse the genome of the virus and investigate why it was so deadly. They traced its virulence to multiple genes, and found that it triggers a dramatic inflammatory response.

Out of favour
Abbondanzo, who became the chair of the haematopathology department in 1994, began to suspect that the AFIP was in trouble during the first US war with Iraq in the early 1990s, when the Department of Defense began to take a closer look at its budget. Suddenly, research projects that would have been approved and encouraged in the past were being questioned. Abbondanzo and her colleagues had submitted a proposal to study follicular lymphoma, a type of cancer that is rare in children. The AFIP repository contained at least 20 childhood cases, providing an unprecedented opportunity to characterize the condition. But the board that approved proposals rejected the project, saying it had "no military relevancy", Abbondanzo says. During this same period, she attended a meeting at which someone from the department referred to the AFIP as an "obscure little agency".

Travis, too, was worried about the AFIP's future. In 2003, he and others asked pathologists from overseas to write letters urging the military to continue supporting the AFIP, and he worked with the office of Senator Edward Kennedy (Democrat, Massachusetts), a long-time supporter of the institute, which tried to get financial support from other agencies. "I spent countless hours," Travis says. "All those efforts were not going anywhere. It was very clear I had to look out for myself and my family." When a position opened at Memorial Sloan-Kettering, he applied.

Despite rumours that some services might be cut, the closure announcement in 2005 came as a shock. "We learned of it when everyone else did," says Kelly. Rhode, who has worked at the AFIP since the 1980s, heard the news in an auditorium full of other staff. "I don't remember people talking much. It seemed like we kind of just spilled out and went back to our offices in silence."

The AFIP was on a list of base closures and changes designed to save more than US$30 billion over 20 years. But the institute's budget in fiscal year 2004 was only $93 million — slightly more than 0.02% of the defence department's budget request for 2004 of $380 billion. The military had welcomed civilian pathology cases for decades. Clearly, something had changed. A spokesperson for the Department of Defense said the decision to "disestablish" the AFIP was "based on capacity, military value and scenario development after analysis of military and non-military workload, services available in the civilian sector and cost savings".

What really caused the demise of the AFIP, speculates Abbondanzo, is that the vast majority of its work had limited direct benefit to the military. "It's been a long time coming," she says.

Life after death
Not everything will disappear. A new entity, the Joint Pathology Center, has been created in Silver Spring, Maryland, to carry on the AFIP's military duties, including consulting on pathology cases for the military and other federal agencies.

The AFIP's museum, the National Museum of Health and Medicine, which includes such exhibits as the bullet that killed US President Abraham Lincoln, is being packed up and moved to Fort Detrick's Forest Glen Annex in Silver Spring — a "stressful" process, says Rhode. And Madewell has helped to move the radiological pathology training that the AFIP provided for the majority of US radiology residents to the American College of Radiology based in Reston, Virginia.

A 2007 report by the US Government Accountability Office concluded that the change in the AFIP's consultation and other services would have "minimal impact", because there are alternative sources of pathology expertise. In recent decades, some centres — such as the Mayo Clinic in Rochester, Minnesota, and Johns Hopkins University in Baltimore, Maryland — have developed strengths in particular fields of pathology, and have become sources for second opinions in difficult cases, says Colonel Vernon Armbrustmacher, one of the AFIP's former directors. "The world of pathology will survive without the AFIP," says Armbrustmacher. "I hate to say that, but it will."

Even so, these services could be more expensive than those of the AFIP, which charged from around $20 to just over $2,000 for consultations, depending on the procedure. Some pathologists will feel the hit more than others — especially those in developing countries, who frequently lack local services to diagnose emerging tropical diseases and can't afford to pay high fees. These were a minority of cases — perhaps between 5% and 10% of consultations, estimates Armbrustmacher. But "they were unbelievable cases", Travis recalls. "Really challenging, difficult problems."

And even when pathologists can afford second opinions from academic centres, what they receive may not be of the same calibre as what they would have got from the AFIP, says Timothy O'Leary, director of Clinical Science Research and Development at the US Veterans Health Administration in Washington DC, and a pathologist at the AFIP until 2004. "There are cases that are just not common. And at the AFIP, we saw a lot of those unusual cases, far more than you do at academic centres." It may only be "a few hundred, a thousand people each year" whose diagnoses might be significantly affected, he estimates. "But for those people, it can be a matter of life and death."

The fate of the tissue repository, which is now under the control of the Joint Pathology Center, remains unknown. It has been moved to two renovated buildings at Forest Glen Annex, one of which used to serve as the laundry facility for the AFIP and the Walter Reed Army Medical Center, which is also being relocated this year. Officials have asked the Institute of Medicine to recommend how best to use the repository, including who should have access to it, says the Joint Pathology Center's interim director Colonel Thomas Baker. Those recommendations are due in June 2012.

What's most important, many say, is that civilian pathologists continue to have access to the repository. New techniques in high-throughput genomics and proteomics could "now or soon" reveal even more clues about the deadly diseases preserved there, says Taubenberger, now at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. The repository "is only of value to people who know what's in it", says Travis. If the top pathologists can't access the material, an untold amount of valuable knowledge will never be uncovered, he says.

Inside the AFIP, the mood is decidedly sombre as people watch the lights go out, says Rhode. "Every day, you see a little bit more furniture moving down the hallway." Little by little, more offices are emptied, cleaned, locked and fitted with 'do not enter' signs.

Florabel Mullick, the last director of the institute, declined to be interviewed for this article. But in the AFIP's final newsletter last winter, she lamented watching the institution become a "shell of its former self" and wrote that closing the AFIP "has been one of the most painful experiences of my life … How does one, after all, watch missions that have benefitted so many people fade away?"

"It is the passing of one of the greatest institutions in the entire history of medicine," agrees Travis. "And it is very painful to see that happen. But we all have to move on."

References

Ref. Author / Title Source Year
1
Abbondanzo, S. L., Irey, N. S., Frizzera, G.
[view on publisher's website]
Am. J. Surg. Pathol.
19675-686
1995
2
Taubenberger, J. K., Reid, A. H., Krafft, A. E., Bijwaard, K. E., Fanning, T. G.
[view on publisher's website]
Science
2751793-1796
1997
Affiliations


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terça-feira, 16 de agosto de 2011

34 anos após a morte de Elvis Presley

We're caught in a trap
I can't walk out
Because I love you too much baby
Why can't you see
What you're doing to me
When you don't believe a word I say
We can't go on together
With suspicious minds (suspicious minds)
And we can't build our dreams
On suspicious minds
So, if an old friend I know
Drops by to say hello
Would I still see suspicion in your eyes
Here we go again
Asking where I've been
You can't see these tears are real
I'm crying (these crying)
We can't go on together
With suspicious minds (suspicious minds)
And we can't build our dreams
On suspicious minds
Oh, let our love survive
Or dry the tears from your eyes
Let's don't let a good thing die
When honey, you know
I've never lied to you
Yeah, yeah
We're caught in a trap
I can't walk out
Because I love you too much baby
Why can't you see
What you're doing to me
When you don't believe a word I say
Don't you know
We're caught in a trap
I can't walk out
Because I love you too much baby
Don't you know
We're caught in a trap
I can't walk out
Because I love you too much baby


Bridge Over Troubled Water

When you're weary, feeling small
When tears are in your eyes,
I will dry them all
I'm on your side
When times get rough
And friends just can't be found


Like a bridge over troubled water
I will lay me down
Like a bridge over troubled water
I will lay me down


When you're down and out
When you're on the street
When evening falls so hard
I will comfort you
I'll take your part
When darkness comes
And pain is all around


Like a bridge over troubled water
I will lay me down
Like a bridge over troubled water
I will lay me down


Sail on silver girl
Sail on by
Your time has come to shine
All your dreams are on their way
See how they shine
If you need a friend
I'm sailing right behind


Like a bridge over troubled water
I will ease your mind
Like a bridge over troubled water
I will ease your mind

Ponte Sobre Águas Turbulentas

Quando você está enfraquecida, sentindo-se pequena
Quando as lágrimas estiverem em seus olhos
Eu enxugarei todas elas
Estou ao seu lado
Quando os tempos se tornarem tempestuosos
E os amigos simplesmente não podem ser encontrados


Como uma ponte sobre águas turbulentas
Eu me estenderei
Oh, como uma ponte sobre águas turbulentas
Eu me estenderei


Quando você está pra baixo e desligada,
Quando você está nas ruas
Quando a noite cair, de forma tão dura,
Eu te confortarei
Eu assumirei sua parte
Quando a escuridão vier
E a dor está toda ao redor...


Sim, como uma ponte sobre águas turbulentas
Eu me deitarei
Oh, como uma ponte sobre águas turbulentas
Eu me deitarei


Navegue, garota prateada,
Navegue o seu caminho
Seu tempo de brilhar chegou
Todos os seus sonhos estão a caminho
Veja como eles brilham
Oh, se você precisar de um amigo?
Eu estou navegando bem atrás de você


Sim, como uma ponte sobre águas turbulentas,
Eu aliviarei sua mente
Como uma ponte sobre águas turbulentas,
Eu aliviarei sua mente....



mais detalhes sobre a vida e obra de Elvis Presley

http://pt.wikipedia.org/wiki/Elvis_Presley