Blood Type A May Predispose to Some Rotavirus Infections

Whether you become infected by some strains of rotavirus may depend on your blood type. Some strains of rotavirus find their way into the cells of the gastrointestinal tract by recognizing antigens associated with the type A blood group, a finding that represents a new paradigm in understanding how this gut pathogen infects humans, said Baylor College of Medicine researchers in an online report in the journal Nature.

Intestinal pathogen
Rotavirus is a major intestinal pathogen that is the leading cause of severe dehydration and diarrhea in infants around the world. An estimated 500,000 people worldwide die from the infection annually.
The structure of a key part of a strain of the virus known as P[14] provides a clue to how the virus infects human cells, said Dr. B. V. Venkataram Prasad, professor of biochemistry and molecular biology at BCM and the report's corresponding author.
In strains of rotavirus that infect animals, the top of a spike on the virus attaches to the cell via a glycan (one of many sugars linked together to form complex branched-chain structures) with a terminal molecule of sialic acid. The same did not appear to be true of virus strains that infect humans, and scientists believed the human rotavirus strains were bound to glycans with an internal sialic acid molecule, but they did not know how this occurs.

Surprise finding
"We wondered how this genotype of rotavirus recognized a cellular glycan," said Prasad. "With colleagues at Emory (University School of Medicine), we did a glycan array analysis to see which glycans interacted with the top of the virus spike (called VP8*)."
The only type of glycan that interacted with VP8* was type A histo-blood group antigen, he said.
"That was surprising," he said. "We thought it had to be a glycan with sialic acid."
The histo-blood group antigen A does not have sialic acid.
However, when Dr. Liya Hu, a post-doctoral researcher in Prasad's laboratory, determined the structure of the VP8* domain, she found that the type A glycan bound to the rotavirus spike protein at the same place as the sialic acid would have in an animal rotavirus. Histo-blood group antigens are known to promote binding of norovirus and Helicobacter pylori cells to intestinal cells, but this had never been demonstrated in rotavirus.

VP8* domain
Hu's structural study, using crystallography, showed subtle changes in the structure of the VP8* domain of the virus that allowed it to use the histo-blood group antigen A as a receptor.
In collaboration with the laboratory of Dr. Mary Estes, professor of molecular virology and microbiology at BCM, Prasad and his colleagues found that laboratory cells modified to express the histo-blood group antigen A were easily infected by this rotavirus strain. Cells that lacked this antigen were not easily infected.
An antibody to the histo-blood group antigen A blocked infection by the virus into human intestinal cells in culture.
"No one expected this," said Prasad. "Is there an emerging theme here with these intestinal pathogens? Do other viruses use these blood group antigens as a door to enter the cell?"
Further studies identified a second rotavirus strain P[9] that uses the histo-blood group antigen as a receptor, he said.

Novel mechanism of transmission
"The question now is do different strains use other histo-blood group antigens in this way?" he said.
Estes said, "These studies are significant because they provide a novel mechanism of transmission for a rotavirus strain that jumps from ungulates (such as horses, zebras, pigs, sheep) into humans."
The authors found humans infected with the P[14] strain had type A blood, but more studies are needed to confirm the connection.
Larger populations of infected individuals need to be studied to determine if there is a clear association of these virus strains using histo-blood group antigens as a receptor," they said.
This finding raises questions about why humans developed different blood groups, Prasad said. It may be an evolutionary change that occurred after the pathogen first invaded human cells.

**Published in "SCIENCE DAILY"

Los médicos británicos piden que las marcas de comida rápida no puedan patrocinar ningún evento deportivo

Cirujanos, psiquiatras, pediatras y médicos de todas las especialidades del Reino Unido lanzaron ayer una campaña contra la obesidad muy beligerante con las marcas de la llamada comida rápida. La Academia de los Reales Colegios Médicos, que representa a 200.000 facultativos del país, pidió que se prohíba que firmas como McDonald's y Coca-Cola patrocinen grandes acontecimientos deportivos, incluso los Juegos Olímpicos, y que personajes famosos publiciten comida insana para niños. La Academia considera necesario, para luchar contra la obesidad, imponer “contundentes y duras” medidas para acabar con la publicidad irresponsable de las grandes compañías de alimentación.
Los médicos quieren que se empleen los mismos criterios que con el tabaco. Una directiva comunitaria prohíbe la publicidad de tabaco en prensa, radio e Internet. Las tabaqueras tampoco pueden patrocinar acontecimientos deportivos u otro tipo de actividades en las que participen Estados de la UE.
Los estudios revelan que 48% de los hombres y un 43% de las mujeres del Reino Unido serán obesos en 2030, lo que supondrá un incremento de infartos, enfermedades del corazón y cáncer, y, por tanto, un mayor gasto para la sanidad pública.
Considera la Academia que se debe exigir a los fabricantes de productos alimenticios que publiquen claramente los datos sobre calorías, azúcar, sal y grasa de sus productos. Además, propone al Gobierno británico que imponga el denominado impuesto sobre la grasa, que se ha aplicado en algunos países escandinavos.
Barbara Gallani, directora de salud y ciencia de la Federación de Alimentos y Bebidas, que representa los intereses de los fabricantes de comidas y bebidas no alcohólicas, considera que la petición de la organización médica se equivoca al despreciar la beneficiosa colaboración entre dichas empresas y los acontecimientos deportivos, aunque está de acuerdo en que algo hay que hacer, según informó The Guardian. Por su parte, un portavoz de Coca-Cola señaló: “Sin el apoyo de patrocinadores como nosotros, hasta 170 de los 200 comités olímpicos nacionales no podrían enviar a sus atletas a competir a los Juegos”.

*AGENCIAS

Nanoparticles Home in On Brain Tumors, Boost Accuracy of Surgical Removal

Like special-forces troops laser-tagging targets for a bomber pilot, tiny particles that can be imaged three different ways at once have enabled Stanford University School of Medicine scientists to remove brain tumors from mice with unprecedented accuracy.

In a study published online April 15 in Nature Medicine, a team led by Sam Gambhir, MD, PhD, professor and chair of radiology, showed that the minuscule nanoparticles engineered in his lab homed in on and highlighted brain tumors, precisely delineating their boundaries and greatly easing their complete removal. The new technique could someday help improve the prognosis of patients with deadly brain cancers.
About 14,000 people are diagnosed annually with brain cancer in the United States. Of those cases, about 3,000 are glioblastomas, the most aggressive form of brain tumor. The prognosis for glioblastoma is bleak: the median survival time without treatment is three months. Surgical removal of such tumors -- a virtual imperative whenever possible -- prolongs the typical patient's survival by less than a year. One big reason for this is that it is almost impossible for even the most skilled neurosurgeon to remove the entire tumor while sparing normal brain.
"With brain tumors, surgeons don't have the luxury of removing large amounts of surrounding normal brain tissue to be sure no cancer cells are left," said Gambhir, who is the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of the Molecular Imaging Program at Stanford. "You clearly have to leave as much of the healthy brain intact as you possibly can."
This is a real problem for glioblastomas, which are particularly rough-edged tumors. In these tumors, tiny fingerlike projections commonly infiltrate healthy tissues, following the paths of blood vessels and nerve tracts. An additional challenge is posed by micrometastases: minuscule tumor patches caused by the migration and replication of cells from the primary tumor. Micrometastases dotting otherwise healthy nearby tissue but invisible to the surgeon's naked eye can burgeon into new tumors.
Although brain surgery today tends to be guided by the surgeon's naked eye, new molecular imaging methods could change that, and this study demonstrates the potential of using high-technology nanoparticles to highlight tumor tissue before and during brain surgery.
The nanoparticles used in the study are essentially tiny gold balls coated with imaging reagents. Each nanoparticle measures less than five one-millionths of an inch in diameter -- about one-sixtieth that of a human red blood cell.
"We hypothesized that these particles, injected intravenously, would preferentially home in on tumors but not healthy brain tissue," said Gambhir, who is also a member of the Stanford Cancer Institute. "The tiny blood vessels that feed a brain tumor are leaky, so we hoped that the spheres would bleed out of these vessels and lodge in nearby tumor material." The particles' gold cores, enhanced as they are by specialized coatings, would then render the particles simultaneously visible to three distinct methods of imaging, each contributing uniquely to an improved surgical outcome.
One of those methods, magnetic resonance imaging, is already frequently used to give surgeons an idea of where in the brain the tumor resides before they operate. MRI is well-equipped to determine a tumor's boundaries, but when used preoperatively it can't perfectly describe an aggressively growing tumor's position within a subtly dynamic brain at the time the operation itself takes place.

**Published in "SCIENCE DAILY"

España: solo el 26% de los grandes dependientes están en residencias

Dos tercios de los dependientes más graves están atendidos en su domicilio y, de ellos, la inmensa mayoría al cuidado de sus familiares, cuando muchos necesitarían ayuda especializada. Se trata de enfermos de alzhéimer en su fase más aguda, por ejemplo, o ancianos encamados de escasa movilidad. Solamente el 26% de los grandes dependientes están en residencias, un servicio que se considera el adecuado para estas personas porque ahí recibirían ayuda profesional día y noche. Son, por primera vez, datos oficiales a los que ha tenido acceso este periódico. Datos que maneja el Gobierno antes de proceder a aligerar la burocracia que lastra el sistema de atención a la dependencia.
Porque otra de las conclusiones de este informe es que los dos niveles de gravedad en que se dividen los grandes dependientes (nivel II y nivel I) se atienden prácticamente con las mismas ayudas. Quizá por eso la ministra de Sanidad y Servicios Sociales, Ana Mato, recuerda siempre que es necesario simplificar los trámites, y ya desde su llegada al Gobierno se presume que los dos niveles en que se divide cada uno de los tres grados de dependencia (grandes dependientes, dependientes severos y dependientes moderados) puedan eliminarse.
Pero eso puede tener sus pros y sus contras. Desde luego la burocracia se simplificaría y posiblemente se ganaría en tiempo, porque los dependientes más graves normalmente empeoran pronto: el que se calificó como nivel I no tardará en pasar al nivel II. Revisar todos esos casos lleva su tiempo y, finalmente, las ayudas no son muy diferentes. Pero una reforma así no es ajena a ciertos riesgos. ¿Cuántos de los grandes dependientes en su nivel más bajo pasarían directamente al grado anterior, es decir, a ser solo dependientes severos, y cuántos de los severos se caerían al apartado de los moderados? La consecuencia de este desplazamiento tiene un final lógico: los más leves de los moderados (grado I, nivel I) ya no podrían pasar a ningún sitio, directamente se saldrían de la ley.
Los responsables de la dependencia en el Ministerio justifican esta posible reforma en que muchos de estos dependientes leves están ya atendidos por los servicios sociales básicos, puesto que su incorporación en el calendario de la ley está establecida para 2013, aunque esta fecha puede aplazarse, como ha ocurrido este año: el Gobierno ha suspendido la entrada al sistema de los moderados prevista para 2012. Pero no es lo mismo estar bajo el sistema de la dependencia, cuyas ayudas se garantizan por derecho, que quedar al albur de los servicios sociales básicos, muy mermados por la crisis (y por la propia Ley de Dependencia). En estos casos, si hay dinero habrá ayuda, si no lo hay...

-Cambiar la valoración puede traer ahorro, pero peligra la calidad
Por otro lado, la mudanza de los dependientes de un grado a otro inferior conllevaría ahorros puesto que el Gobierno no paga lo mismo por un usuario grave que por uno más leve. Todo ello será materia de debate entre las comunidades antes de que se tome una decisión, pero ninguna está en disposición de hacer ascos a un alivio económico. El asunto, en ese caso, sería la calidad de la asistencia, el peligro de que un gran dependiente sea atendido como correspondería a un caso más leve.
En este informe, el Gobierno lamenta la “infrautilización” de los servicios de la red pública. “No parece que se utilicen de forma prioritaria ni en función de una mayor necesidad de cuidados profesionales”, advierten. Solo un 26% de los grandes dependientes están en residencias, pero casi el 46% (y el 47% de los severos) están atendidos por sus familiares, “cuando la formación de estos cuidadores se realiza con posterioridad”. Cabría añadir que, en muchos casos, no hay ni siquiera una formación, ni periodos de respiro para las mujeres que pasan el día entero, y quizá la noche, al cuidado de dependientes. Situaciones así generan más dependencia y de forma prematura, como advierten siempre los expertos. El Gobierno plantea para estos cuidadores una formación adecuada.
Sorprende también el porcentaje (10%) de grandes dependientes atendidos con teleasistencia, que no es más que un botón para avisar de una caída, por ejemplo. Podría decirse que esta ayuda no es única, puesto que es compatible con otras, pero también es cierto que la ratio de ayudas por cada dependiente es de 1,24 como media, así que puede que algunos de los más afectados solo reciban esa. No está aclarado en los datos.

-El Ministerio de Servicios Sociales prevé reformar también el copago
A la vista de todo esto, el Ministerio propone simplificar el “entramado de grados y niveles” con que se clasifican las situaciones de dependencia, dado que no encuentran muchas diferencias ni en las valoraciones que se les hacen ni en el tipo de ayuda que conceden para cada nivel dentro de un mismo grado. Proponen también ajustar las prestaciones a las necesidades verdaderas del dependiente. La paga para el cuidador familiar, que se preveía como algo excepcional en la ley, se ha convertido en norma, en parte porque así lo solicitaban los usuarios —aunque su opinión no es determinante—, en parte porque no había servicios suficientes para atenderlos. Revertir esa situación requerirá llevar los servicios (residencias, centros de día) allá donde no los haya. Pero en estos tiempos será difícil convencer a los empresarios de que acojan a los dependientes en sus geriátricos cuando algunas comunidades, como Castilla-La Mancha, ya han advertido que recortarán las subvenciones públicas que les dan. A menos que el dinero que resta salga del bolsillo del ciudadano. No es descabellado, puesto que el Ministerio tiene previsto reformar también el copago, es decir, determinar la situación económica del usuario y su aportación, muy dispar entre las comunidades.
La dependencia experimentará grandes cambios, en la valoración de los usuarios, en la financiación del sistema y, posiblemente, en las prestaciones que se reciban. La música parece acertada, pero la letra pequeña está por ver.

**Publicado en "EL PAIS"

Memory in Adults Impacted by Versions of Four Genes

Two research studies, co-led by UC Davis neurologist Charles DeCarli and conducted by an international team that included more than 80 scientists at 71 institutions in eight countries, has advanced understanding of the genetic components of Alzheimer's disease and of brain development. Both studies appear in the April 15 edition of the journal Nature Genetics.

The first study, based on a genetic analysis of more than 9,000 people, has found that certain versions of four genes may speed shrinkage of a brain region involved in making new memories. The brain area, known as the hippocampus, normally shrinks with age, but if the process speeds up, it could increase vulnerability to Alzheimer's disease, the research suggests.
The second paper identifies two genes associated with intracranial volume -- the space within the skull occupied by the brain when the brain is fully developed in a person's lifespan, usually around age 20.
DeCarli is a pioneer in the field of neuroimaging of the aging brain who has been at the forefront of developing and using quantifiable imaging techniques to define the relationship between structure and function in the healthy aging brain and to characterize the changes associated with vascular and Alzheimer's dementias. He is professor of neurology and director of the UC Davis Alzheimer's Disease Center and the UC Davis Imaging of Dementia and Aging Laboratory.

Genetic variants of hippocampus study
The gene variants identified in the first study do not cause Alzheimer's, but they may rob the hippocampus of a kind of "reserve" against the disease, which is known to cause cell destruction and dramatic shrinkage of this key brain site. The result is severe loss of memory and cognitive ability.
Scientists calculated that hippocampus shrinkage in people with these gene variants accelerates by about four years on average. The risk of Alzheimer's doubles every five years beginning at age 65, so a person of that age would face almost twice the Alzheimer's risk if he or she had these versions of the gene.
Looked at another way, if a person with one of these variants did get Alzheimer's, the disease would attack an already compromised hippocampus and so would lead to a more severe condition at a younger age than otherwise, the research suggests.
"This is definitely a case of 'bigger is better,'" said DeCarli. "We already know that Alzheimer's disease causes much of its damage by shrinking hippocampus volume. If someone loses a greater-than-average amount of volume due to the gene variants we've identified, the hippocampus is more vulnerable to Alzheimer's."
Why the aging hippocampus normally decreases in volume is unclear. The new research shows that the genes most strongly linked to shrinkage are involved in maturation of the hippocampus and in apoptosis, or programmed cell death -- a continual process by which older cells are removed from active duty.
The scientists suggest that if the gene variants they identified do affect either maturation or the rate at which cells die, this could underlie at least some of the increased rates of hippocampus shrinkage.
"Either by making more or healthier hippocampal neurons or preventing them from dying with advancing age, the healthy versions of these genes influence how people remember as they get older," said DeCarli. "The alternate versions of the genes may not fully provide these benefits."
The researchers hope that they can find ways to protect the hippocampus from premature shrinkage or slow its decline by studying the normal regulation of the proteins coded by these genes.
The genetic analysis draws on what is known as a genome-wide association study -- research aimed at finding the common genetic variants associated with specific diseases or other conditions. Different versions of a gene usually come down to changes in just one of the tens of thousands of DNA "letters" that make up genes. These one-letter differences are known as single-nucleotide polymorphisms, or SNPs.
The research involved more than 80 scientists at 71 institutions in 8 countries. Many researchers are needed for such a study in order to put together the large samples, or cohorts, of people whose genetic makeup is to be investigated, to measure the hippocampus from magnetic resonance pictures of the brain and for the labor-intensive statistical analysis of the findings.
The study used a very large assemblage of genetic and disease data called the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, or CHARGE. The consortium brings together several population-based cohorts in the United States and Europe.
The cohort was made up of 9,232 dementia-free volunteers with an average age of 67. The study identified four different gene variants associated with hippocampus volume decline. One, known as rs7294919, showed a particularly strong link to a reduced hippocampus volume, suggesting that this gene is very important to hippocampus development or health.
The findings were then assessed in two other cohorts. One, including both normal and cognitively compromised people with an average age of 40, showed that three of the suspect SNPs were linked to reduced hippocampus volume. Analysis of results from the third group, comprised primarily of older people, showed a significant association between one of the SNPs and accelerated memory loss.
"With this study, we have new evidence that aging, the hippocampus and memory are influenced by specific genes," DeCarli said. "Understanding how these genes affect the development and aging of the hippocampus may give us new tools to delay memory loss with advanced age and possibly reduce the impact of such diseases as Alzheimer's disease."

Genetic variants of Intracranial-volume study
While the first study deals with the genetic associations with brain shrinkage, the second deals with associations impacting intracranial volume, which is an indirect measure of the size of the brain at full development.
Though brain volume and intracranial volume are both highly heritable, the genetic influences on these measures may differ. To assess the genetic influence on these two measures, researchers in the second study performed a genome-wide association study on cross-sectional measures of intracranial volume and brain volume in 8,175 elderly in the CHARGE consortium.
They found no associations for brain volume, but they did discover that intracranial volume was significantly associated with two loci: rs4273712, a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21.
"Since geneticists are already familiar with the other functions of these same genes, associating these particular genes with intracranial volume may help us better understand brain development in general," said DeCarli. "For instance, we know that one of these genes has played a unique evolutionary role in human development, and perhaps we as a species are selecting this gene as a way of providing further advances in brain development."
Both studies involved international teams representing scores of institutions, funded by a variety of NIH grants as well as grants from agencies around the world.

**Published in "SCIENCE DAILY"

Cada vez más pacientes acceden a la pastilla única contra el VIH

La mitad de los pacientes españoles con VIH recibe tratamiento con la pastilla única, que sustituye el clásico cóctel de fármacos con el que se ha tratado el virus del sida en las últimas décadas.
"Se trata del tercer gran avance fundamental en el tratamiento del sida", explica a ELMUNDO.es Josep María Gatell, jefe del Servicio de Enfermedades Infecciosas del Hospital Clínic de Barcelona. "Primero fue la aparición del primer antirretroviral, el 1986. Diez años después, empezamos a usar combinaciones de estos fármacos, lo que disminuyó mucho la mortalidad. En 2006, apareció la pastilla única, mucho más cómoda y mejor tolerada", señala este experto.
Gatell, que ha participado en la presentación del Congreso Estándares de tratamiento en VIH: avanzando hacia el futuro, promovido por Gilead, cree que este tratamiento se consolidará en los próximos años como el de elección "porque cada vez habrá más pastillas únicas entre las que elegir". Según sus cálculos, en dos o tres años el fármaco único -aprobado en 2006- alcanzará al 70% de pacientes.
"Los pacientes nuevos, salvo raras excepciones, pueden tratarse con este fármaco, que contiene tres principios químicos", señala el experto catalán. "Aquellos que empezaron la terapia hacer años o décadas no siempre pueden porque en el pasado tuvieron problemas con algunos compuestos o porque han desarrollado resistencias".
Tanto Gatell como Santiago Moreno, jefe del Servicio Enfermedades Infecciosas del Hospital Ramón y Cajal de Madrid y presente también en la presentación, han subrayado los beneficios del fármaco único desde el punto de vista de la adherencia y la efectividad.
"La pastilla única es la aspiración de todas las áreas de la medicina", ha exclamado Moreno, para quien la terapia antirretroviral está tocando techo, tras las grandes avances alcanzados para aumentar la tolerancia y minimizar al máximo la toxicidad y efectos secundarios como la pancreatitis y la lipoatrofia.

'Pagaremos un precio muy alto por los recortes'

Mientras el tratamiento contra el virus del sida avanza, en España "el número de nuevos casos permanece estable desde hace años (unos 3.500-4.000 al año) y las nuevas infecciones se producen en su mayoría por transmisión sexual, en contra de lo que ocurría hace unos años, cuando la vía más frecuente era la parenteral", explica Gatell.
"Lejos de disminuir estas cifras, éstas permanecen estables e, incluso, con una cifra discreta al alza", ha puntualizado Moreno. Uno de los principales problemas, como ha destacado este experto, es que entre un 50% y un 60% de los casos se diagnostica tarde.
"Son necesarias nuevas medidas para frenar tanto los nuevos contagios como los diagnósticos tardíos", subraya Gatell. "Hay que luchar para resolver este tema y desmantelar el Plan Nacional del Sida no es una medida adecuada. Asignar menos recursos ahora nos hará pagar un precio muy alto en unos años", denuncia.

**Publicado en "EL MUNDO"

Gene Mutations Play Critically Important Role in Acute Myeloid Leukemia; Promising Development for New Treatments

 The key to treating one of the most common types of human leukemia may lie within mutations in a gene called FLT3, according to new research led by physician-scientists at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.

Published this week in the journal Nature, the work validates certain activating mutations in the FLT3 gene as targets for acute myeloid leukemia therapy -- a critically important finding for developing drugs.
"These mutations are critically important for the survival of leukemia cells that harbor them," said Neil Shah, MD, PhD, who led the research, and is co-leader of the Hematopoietic Malignancies Program at the Helen Diller Family Comprehensive Cancer Center at UCSF and the Edward S. Ageno Distinguished Professor of Hematology/Oncology. "Our results also identify drug-resistant mutations in FLT3 that represent high-value targets for future drug development, and will hopefully rekindle interest in developing potent FLT3 inhibitors for the treatment of acute myeloid leukemia."
The new work also suggests why a handful of older drugs developed to treat acute myeloid leukemia by targeting FTL3 have previously failed in clinical trials. The problem with these drugs was not lack of precision but of power -- they were aimed at the right target needed to stop the cancer, but most likely did not hit this target hard enough.
Patients in the future may be better served by therapies that involve combinations of multiple, more potent drugs that can suppress all drug-resistant forms of FLT3, said Shah, whose lab is working to identify such compounds and bring them to the clinic as quickly as possible.

Common and deadly form of cancer
Acute myeloid leukemia occurs when the precursors of our own blood cells become corrupted by mutations in their DNA. The mutant precursors then fail to produce several critical components of blood: white cells, which fight infections; red cells, which carry the blood's oxygen supply; and platelets, which clog vessels when they are cut and help minimize blood loss.
Instead, the mutant precursors give rise to leukemia cells, which accumulate in the bone marrow and bloodstream, crowding out the healthy blood components, and commonly lead to life-threatening infections, anemia, and bleeding.
Over the last several decades, the five-year survival for acute myeloid leukemia has not improved, even as better diagnostic tests, imaging techniques and treatments have driven down mortality for other forms of cancer. According to the National Cancer Institute, 1 in 256 Americans will be diagnosed with acute myeloid leukemia in their lifetime and today nearly four out of five people with the disease die within five years of their diagnosis.
The goal of therapy is to eliminate cancerous cells altogether from the bone marrow, and the discovery several years ago that many people with acute myeloid leukemia have activating mutations in the FTL3 gene, coupled with the relationship of these mutations to poor prognosis, led scientists to speculate that targeting this mutated gene might be an effective way to fight the cancer -- but only if the gene was critically important for the survival of leukemia cells.
Several drugs were tested in the clinic, but failed to put the disease into deep remission. The cause for these failures came down to one of two possible reasons: either the FTL3 gene mutations were not central "drivers" critical for cancer to develop and leukemia cells to survive, or the drugs themselves could not achieve the necessary degree of inhibition of FLT3.
The new work by Shah and his colleagues demonstrates the latter. They worked with eight leukemia patients who participated in a clinical trial involving a compound known as AC220, the first clinically-active FLT3 inhibitor. All eight relapsed after first achieving deep remissions with AC220.
In collaboration with Pacific Biosciences, a Menlo Park, Calif. company, a new sequencing technology was adapted to more sensitively and precisely detect drug-resistant mutations. The team showed that in all eight cases, one or more of these mutations evolved at the time AC220-resistant disease developed.
They are now searching for compounds that can specifically target these mutated, AC220-resistant forms of FTL3, and have identified several promising candidates, one of which is currently being evaluated in a clinical trial at UCSF by Catherine Smith MD, who works in Shah's laboratory and is the first author of the article.

**Published in "SCIENCE DAILY"