04 April 2012

Former Pro Pitcher Now Keeps 'Strike Zone' in Proteins

Perhaps no other biochemist in the world has his own baseball card, but University of Massachusetts Amherst doctoral student Elih M. Velázquez-Delgado, who gave up a pitching career for science, does. Now the only stats he cares about are experimental data, because, he says, "I fell in love with the fact that I can see a molecule. I can actually see an enzyme and watch how it functions. That captured me."

A native of Puerto Rico who pitched for five seasons in the minors, the Arizona and California Leagues, for the Oakland A's and San Francisco Giants' organizations, Velázquez-Delgado says his fast ball was hot enough but he lacked the "killer instinct" required to make it in the majors. He reflects, "I may have the ability but not the mindset."
While pursuing an undergraduate degree in chemistry from the Universidad del Turabo in Puerto Rico, Velázquez-Delgado came to UMass Amherst in 2006 as an under-represented minority student summer intern with the help of the Northeast Alliance for Graduate Education and the Professoriate. He says, "I fell in love with what we do here. So I came back after I graduated to pursue a PhD degree."
Now he is working on his doctorate in the chemistry laboratory of Professor Jeanne Hardy and is about to publish his first academic paper with her. They report discoveries about an enzyme that's causally involved in Alzheimer's and Huntington's diseases in the current issue of the journal, Structure.
Though now a biochemistry researcher, Velázquez-Delgado still measures success in baseball terms. "The difference between being a good hitter and a bad one comes down to only 3 hits in 10 at-bats," he explains. "If you bat .300 or miss about 7 of 10 opportunities, you'll get somewhere. But if you bat .200 or miss 8 of 10 at bats, you're not going far."
"In research I feel it's the same. If you can get the same 30 percent success rate you'll be awesome. So not being depressed about the seven misses is a skill. If you work hours and hours, devoting your life to it, you'll shave that edge down until you succeed."
Hardy, his advisor, says Velázquez-Delgado has solved "a very difficult problem" in a remarkably short time. The goal was to use her lab's expertise in X-ray crystallography to find a way to allosterically inhibit, that is block the action of, the disease-related enzyme caspase-6. In practical terms, she points out, "if you can understand how nature inactivates caspase-6, you can perhaps make a drug that uses the same mechanism and find a treatment for the disease."
Caspase-6 is one of a family of enzymes that "chew up" or cut other proteins and are sometimes depicted as miniature Pac-man characters, all mouth, the chemists explain. One technique that has been used to inhibit their disease-causing cuts in biologically important proteins is to target the "mouth" location, figuratively shoving something in to stop it from chewing.
But the biochemists also know that nature uses another technique, exploiting a different site on the enzyme and inhibiting it there through a natural process called phosphorylation. Velázquez-Delgado proposed to use X-ray crystallography to see, with molecular precision, how nature inactivates caspase-6 and perhaps imitate that approach.
"Phosphorylation adds two electrical charges, so most people have assumed that they're critical to the inhibitory action," Hardy explains. "But in fact, in this whole class of enzymes nobody had ever studied how this kind of inhibition works. We suspected it was allosteric, that is not based on the "mouth" or active site, but on the position of an "ear" on the protein, but we had no idea of the molecular mechanism."
Caspases' active sites are composed of four mobile loops that can take a variety of positions. When the protein is phosphorylated at a position outside the active site, one of the four active site loops is forced in the wrong conformation for substrate binding, which means it can't cut substrate and lead to the disease state. Through a series of experiments that Hardy calls "clean and beautiful," Velázquez-Delgado discovered how to induce this non-binding state and reverse it again. His structural detective work suggested that by cutting off just one amino acid, the caspase would again be inhibited even in the phosphorylated state. He did the experiment, and it turned out to be correct.
"He found that of more than 5,000 atoms in the protein, if we delete three of those atoms, we reverse the effect and inhibition by phosphorylation doesn't happen. Those three atoms control this function. It's a completely new way to inhibit caspase-6, and it opens the door to developing a drug that works by the same mechanism," Hardy says.

**published in "SCIENCE DAILY"

Añadir un fármaco no mejora los beneficios de la quimioterapia en tumores de colon operables

En estos tiempos de estrecheces, más de un gestor sanitario va a llevarse una alegría al leer esta noticia. Añadir un anticuerpo monoclonal a la quimioterapia después de operar a los pacientes con cáncer de colon en fase III no añade ningún beneficio. Aunque el medicamento -cetuximab- sí ha demostrado su utilidad en pacientes con metástasis, no es así cuando la enfermedad está menos avanzada.
Erbitux (el nombre comercial de cetuximab) es un anticuerpo monoclonal que ya se emplea en combinación con un regimen de quimioterapia para tratar a pacientes con cáncer de colon metastásico. Por unos 3.000 euros al mes este medicamento, que bloquea los factores de crecimiento (EGFR), beneficia sobre todo a pacientes con el llamado gen KRAS no mutado.
Sin embargo, como ahora se pone de manifiesto en las páginas de 'The Journal of the American Medical Association' (JAMA), estos mismos beneficios no son extensibles cuando se trata de pacientes con cáncer de colon aún sin metástasis.
Este escenario es lo que los oncólogos denominan adyuvancia: se opera al paciente para extirpar el tumor y a continuación se le administra quimioterapia para reducir el riesgo de que el cáncer reaparezca en el futuro. Y aunque cetuximab parecía un buen candidato para complementar a la 'quimio', la realidad ha demostrado que no añade ningún beneficio.
"Es un estudio realmente importante, porque existía la duda de si añadir o no cetuximab en pacientes con cirugía curativa", explica el doctor Antoni Castells, del Hospital Clínic de Barcelona y coordinador de la Alianza para la Prevención del Cáncer de Colon. "Y lo que se ve es que no incrementa los beneficios y sí las complicaciones", apunta.
Lo ha confirmado un ensayo con 2.686 pacientes tratados entre 2004 y 2010 en la Clínica Mayo y otros centros estadounidenses (cuyos resultados ya se adelantaron en la conferencia de cáncer ASCO). Lo resume así el principal artífice del trabajo, Steven Alberts: "En pacientes operados de cáncer de colon en fase III -con la versión no mutada de KRAS-, añadir cetuximab a la quimioterapia no mejora el tiempo libre de enfermedad ni la supervivencia global del paciente".
De hecho, el grupo de pacientes tratados con el anticuerpo monoclonal mostró más efectos secundarios y toxicidad asociada al fármaco (especialmente en los mayores de 70 años).
En un comentario que publican en la misma revista Neil Segal y Leonard Saltz, del Memorial Sloan Kettering y del Weill Cornell Medical College (ambos en Nueva York, EEUU), se pone sobre la mesa el verdadero significado de este trabajo: "La inevitable conclusión es que lo que vale para las metástasis no sirve en adyuvancia".
Es decir, cetuximab, que sí funciona cuando las células del tumor ya han escapado de su localización original y se han asentado en otras partes del organismo, no parece útil en una fase más temprana del cáncer. "El objetivo de dar quimioterapia después de la cirugía no es tratar el tumor que el cirujano ya ha extirpado", añaden los editorialistas, "sino intentar erradicar cualquier micrometástasis oculta que haya podido quedar oculta en el organismo".
Y como concluye Alberts en su estudio, las características de estas micrometástasis son diferentes de las de las metástasis ya 'ancladas' en otras partes del organismo lejos del tumor primario. Para encontrar un fármaco que mejore a la quimioterapia en adyuvancia, añaden, todavía habrá que seguir estudiando para conocer mejor cómo son y cómo funcionan estas micrometástasis ocultas, de las que depende que un paciente con cáncer ya operado recaiga en el futuro.

**Publicado en "EL MUNDO"

Eating Cruciferous Vegetables May Improve Breast Cancer Survival

A study by Vanderbilt-Ingram Cancer Center and Shanghai Center for Disease Control and Prevention investigators reveals that breast cancer survivors who eat more cruciferous vegetables may have improved survival. The study of women in China was presented by postdoctoral fellow Sarah J. Nechuta, Ph.D., M.P.H., at the American Association for Cancer Research Annual Meeting in Chicago, Ill.

"Breast cancer survivors can follow the general nutritional guidelines of eating vegetables daily and may consider increasing intake of cruciferous vegetables, such as greens, cabbage, cauliflower and broccoli, as part of a healthy diet," said Nechuta.
Nechuta, Xiao Ou Shu, M.D., Ph.D., and colleagues investigated the role of cruciferous vegetables in breast cancer survival among women in the Shanghai Breast Cancer Survival Study, a prospective study of 4,886 Chinese breast cancer survivors who were diagnosed with stage 1 to stage 4 breast cancer from 2002 to 2006. Shu, Ingram Professor of Cancer Research, is the principal investigator of the Shanghai Breast Cancer Survival Study.
After adjusting for demographics, clinical characteristics and lifestyle factors, the researchers found cruciferous vegetable intake during the first 36 months after breast cancer diagnosis was associated with a reduced risk for total mortality, breast cancer-specific mortality and disease recurrence.
Survival rates were influenced by vegetable consumption in a dose-response pattern. As women ate more of these vegetables, their risk of death or cancer recurrence decreased.
Women who were in the highest quartiles of intake of vegetables per day had a 62 percent reduced risk of total mortality, 62 percent reduced risk of breast cancer mortality, and 35 percent reduced risk of breast cancer recurrence, compared to women with the lowest quartile of intake."
Nechuta noted that cruciferous vegetable consumption habits differ between China and the United States and suggested this fact be considered when generalizing these results to U.S. breast cancer survivors.
"Commonly consumed cruciferous vegetables in China include turnips, Chinese cabbage/bok choy and greens, while broccoli and Brussels sprouts are the more commonly consumed cruciferous vegetables in the United States and other Western countries," she said. "The amount of intake among Chinese women is also much higher than that of U.S. women."
Cruciferous vegetables contain phytochemicals known as isothiocyanates and indoles which appear to have a protective effect against some types of cancer.
Nechuta said the level of these bioactive compounds, proposed to play a role in the anticancer effects of cruciferous vegetables, depends on both the amount and type of cruciferous vegetables consumed.
She said there is a need for future studies that measure the bioactive compounds in these vegetables and the host factors that may influence the effects of these compounds to improve the understanding of the association between cruciferous vegetable consumption and breast cancer outcomes.

**published in "SCIENCE DAILY"

‘Positive Stress’ Helps Protect Eye from Glaucoma

Working in mice, scientists at Washington University School of Medicine in St. Louis have devised a treatment that prevents the optic nerve injury that occurs in glaucoma, a neurodegenerative disease that is a leading cause of blindness.

Researchers increased the resistance of optic nerve cells to damage by repeatedly exposing the mice to low levels of oxygen similar to those found at high altitudes. The stress of the intermittent low-oxygen environment induces a protective response called tolerance that makes nerve cells -- including those in the eye -- less vulnerable to harm.
The study, published online in Molecular Medicine, is the first to show that tolerance induced by preconditioning can protect against a neurodegenerative disease.
Stress is typically thought of as a negative phenomenon, but senior author Jeffrey M. Gidday, PhD, associate professor of neurological surgery and ophthalmology, and others have previously shown that the right kinds of stress, such as exercise and low-oxygen environments, can precondition cells and induce changes that make them more resistant to injury and disease.
Scientists previously thought tolerance in the central nervous system only lasted for a few days. But last year Gidday developed a preconditioning protocol that extended the effects of tolerance from days to months. By exposing mice to hypoxia, or low oxygen concentrations, several times over a two-week period, Gidday and colleagues triggered an extended period of tolerance. After preconditioning ended, the brain was protected from stroke damage for at least 8 weeks.
"Once we discovered tolerance could be extended, we wondered whether this protracted period of injury resistance could also protect against the slow, progressive loss of neurons that characterizes neurodegenerative diseases," Gidday says.
To find out, Gidday turned to an animal model of glaucoma, a condition linked to increases in the pressure of the fluid that fills the eye. The only treatments for glaucoma are drugs that reduce this pressure; there are no therapies designed to protect the retina and optic nerves from harm.
Scientists classify glaucoma as a neurodegenerative disease based on how slowly and progressively it kills retinal ganglion cells. The bodies of these cells are located in the retina of the eye; their branches or axons come together in bundles and form the optic nerves. Scientists don't know if damage begins in the bodies or axons of the cells, but as more and more retinal ganglion cells die, patients experience peripheral vision loss and eventually become blind.
For the new study, Yanli Zhu, MD, research instructor in neurosurgery, induced glaucoma in mice by tying off vessels that normally allow fluid to drain from the eye. This causes pressure in the eye to increase. Zhu then assessed how many cell bodies and axons of retinal ganglion cells were intact after three or 10 weeks.
The investigators found that normal mice lost an average of 30 percent of their retinal ganglion cell bodies after 10 weeks of glaucoma. But mice that received the preconditioning before glaucoma-inducing surgery lost only 3 percent of retinal ganglion cell bodies.
"We also showed that preconditioned mice lost significantly fewer retinal ganglion cell axons," Zhu says.
Gidday is currently investigating which genes are activated or repressed by preconditioning. He hopes to identify the changes in gene activity that make cells resistant to damage.
"Previous research has shown that there are literally hundreds of survival genes built into our DNA that are normally inactive," Gidday says. "When these genes are activated, the proteins they encode can make cells much less vulnerable to a variety of injuries."
Identifying specific survival genes should help scientists develop drugs that can activate them, according to Gidday.
Neurologists are currently conducting clinical trials to see if stress-induced tolerance can reduce brain damage after acute injuries like stroke, subarachnoid hemorrhage or trauma.
Gidday hopes his new finding will promote studies of tolerance's potential usefulness in animal models of Parkinson's disease, Alzheimer's disease and other neurodegenerative conditions.
"Neurons in the central nervous system appear to be hard-wired for survival," Gidday says. "This is one of the first steps in establishing a framework for how we can take advantage of that metaphorical wiring and use positive stress to help treat a variety of neurological diseases."

La salud sexual de los mayores

Un nuevo estudio, publicado en una de las revistas de mayor impacto mundial sobre sexualidad, The Journal of Sexual Medicine, analiza los factores que influyen en la actividad sexual de las personas mayores en España. «Esta investigación permite conocer una realidad social no suficientemente tratada en España: la sexualidad y las personas mayores», explica a SINC Domingo Palacios, investigador de la Universidad Rey Juan Carlos de Madrid y autor principal de este trabajo.

Los resultados, basados en la Encuesta Nacional de Salud y Sexualidad realizada en 1.939 ancianos heterosexuales durante el año 2009, revelan que el 62,3% de los hombres y el 37,4% de las mujeres son sexualmente activos.

Impedimentos
Además, existen otros factores que limitan la actividad sexual en ambos sexos: ser mayor de 75 años, no tener pareja, poseer un bajo nivel educativo, una mala percepción de la propia salud y la sexualidad, padecer dos o más enfermedades crónicas y tomar dos o más medicamentos. «Esto tiene su aplicación en la prevención de enfermedades y en la promoción de la salud y las prácticas sexuales saludables», afirma Palacios, quien subraya que entre las razones por las que la población mayor española no tiene relaciones sexuales destacan la viudedad y la enfermedad física de la pareja.

Los autores apuntan diferencias de género entre los mayores de 65 años, con una menor actividad sexual de las mujeres respecto a los hombres, y de edad, con mejores resultados entre los 65 y los 74 años que en los mayores de 75 años.

Esta no es la primera vez que se mide la salud sexual en la tercera edad. Ya en 2006, un estudio que se hizo público durante el XXVI Congreso de la Sociedad Española de Medicina de Familia y Comunitaria (SEMFYC) mostró que el 60% de las personas mayores de 65 años decía tener relaciones sexuales con una frecuencia media de cuatro veces al mes. En aquel trabajo, realizado en más de un centenar de personas por médicos de familia de Cataluña, la mayoría reconocía que aunque sus relaciones habían sufrido cambios a causa de la edad, no por ello eran «menos satisfactorias».

Asimismo, los datos coinciden con los de una encuesta realizada en EE UU y publicada en el New England Journal of Medicine en 2008, en la que el 73% de los estadounidenses entre 57 y 64 años practicaban sexo. La cifra bajaba al 53% entre los 65 y los 75 años y caía hasta el 26% a los 85.

**pùblicado en "ABC SALUD"

Repollo para el cáncer de mama según un estudio en China

El consumo de crucíferas está vinculado a las mejores tasas de supervivencia en cáncer de mama.

Comer repollo o col brócoli, la coliflor o nabos puede ser de gran ayuda para aquellas mujeres con cáncer de mama. Según un estudio presentado en la Reunión Anual de la Asociación Americana de Cáncer, el consumo de crucíferas en mujeres diagnosticadas de cáncer de mama se asocia con una mejora en la supervivencia en un grupo de mujeres de raza china.

De acuerdo con el trabajo, coordinado por Sarah J. Nechuta, de la Universidad de Vanderbilt en Nashville (EE.UU.), las mujeres supervivientes a cáncer de mama deben seguir las directrices dietéticas nutricionales, que subrayan el consumo diario de verduras al día.

Su equipo ha analizado ahora el papel de las crucíferas en la supervivencia del cáncer de mama. Así, evaluaron su efecto en Shanghai Breast Cancer Survival Study, un análisis prospectivo realizado sobre 4.886 mujeres supervivientes de un cáncer de mama.

Menos mortalidad
Los resultados mostraron que la ingesta de crucíferas durante los primeros 36 meses después del diagnóstico de cáncer de mama se asociaba con un menor riesgo de mortalidad global, de mortalidad por cáncer de mama y de recaídas.

Las investigadoras reconocen el sesgo del estudio, al haberse realizado en mujeres chinas donde se consumen muchas más verduras, pero subrayan que el consumo de estos alimentos, ricos en compuesto bioactivos, como isotiocianatos e indoles, poseen un papel en los efectos anticancerígenos de las crucíferas.

**Publicado en "ABC SALUD"

Early Warning System for Seizures Could Cut False Alarms

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Epilepsy affects 50 million people worldwide, but in a third of these cases, medication cannot keep seizures from occurring. One solution is to shoot a short pulse of electricity to the brain to stamp out the seizure just as it begins to erupt. But brain implants designed to do this have run into a stubborn problem: too many false alarms, triggering unneeded treatment. To solve this, Johns Hopkins biomedical engineers have devised new seizure detection software that, in early testing, significantly cuts the number of unneeded pulses of current that an epilepsy patient would receive.

Sridevi V. Sarma, an assistant professor of biomedical engineering, is leading this effort to improve anti-seizure technology that sends small amounts of current into the brain to control seizures.
"These devices use algorithms -- a series of mathematical steps --to figure out when to administer the treatment," Sarma said. "They're very good at detecting when a seizure is about to happen, but they also produce lots of false positives, sometimes hundreds in one day. If you introduce electric current to the brain too often, we don't know what the health impacts might be. Also, too many false alarms can shorten the life of the battery that powers the device, which must be replaced surgically."
Her new software was tested on real-time brain activity recordings collected from four patients with drug-resistant epilepsy who experienced seizures while being monitored. In a study published recently in the journal Epilepsy & Behavior, Sarma's team reported that its system yielded superior results, including flawless detection of actual seizures and up to 80 percent fewer alarms when a seizure was not occurring. Although the testing was not conducted on patients in a clinical setting, the results were promising.
"We're making great progress in developing software that is sensitive enough to detect imminent seizures without setting off a large number of false alarms," Sarma said. Further fine-tuning is under way, using brain recordings from more than 100 epilepsy patients at The Johns Hopkins Hospital, where several epilepsy physicians have joined in the research. Sarma said that within two to four years she hopes to see her system incorporated into a brain implant that can be tested on people with drug-resistant epilepsy.
"There is growing interest in applying responsive, or closed-loop, therapy for the treatment of epileptic seizures," said Gregory K. Bergey, M.D., professor of neurology and director of the Johns Hopkins Epilepsy Center. "Devices to do this have been tested in humans, but for this therapy to be useful for the patient with epilepsy requires early detection of abnormal brain activity that is destined to become a seizure. Detection has to be within seconds of seizure onset, before the seizure spreads to cause disabling symptoms such as alteration of consciousness."
He added, "Developing detection methods that can both provide this early detection and yet not be triggered by brain activity that will not become a clinical seizure has been a real challenge. Dr. Sarma's group appreciates how important this is. The application of their detection algorithms has produced promising preliminary results that warrant further study of more seizures in more patients."
In trying to solve the seizure false-alarm problem, Sarma drew on her training in electrical engineering, particularly a discipline called control theory. "We decided to start with the origin of the signal in the brain," she said.
Sarma's team compared electrical data from the brains of epilepsy patients before, during and after seizures. The researchers looked at how this activity changed over time, particularly when a seizure began. "We wanted to figure out when would be the optimal time to step in with treatment to stop the seizure," she said. The team members "trained" their system to look for that moment without setting off false alarms.
Ideally, Sarma would someday like to see her software embedded in a microchip that would continually check electrical activity in the brain and launch electrical stimulation whenever a seizure is just beginning to form. The device would operate as a closed loop system, resembling a thermostat that keeps a room's temperature at a constant, comfortable level.
Sarma's interest in brain disorders developed relatively late in her education. She earned a bachelor's degree from Cornell University in electrical engineering, then master's and doctoral degrees at MIT, both in electrical engineering and computer science. During her doctoral studies, however, she pursued a minor in neuroscience. For a class, she conducted a case study of her aunt, who had developed Parkinson's disease at age 29 and had trouble managing it with medication. Watching her aunt's condition was an emotionally draining experience, Sarma said, and she wondered if anything in her own training could help. "I really wanted to understand the neurobiological circuitry of this disease," she said.
That led Sarma to learn more about deep brain stimulation, the use of electric pulses to treat brain disorders such as Parkinson's and epilepsy. She completed a postdoctoral fellowship in MIT's Brain and Cognitive Sciences Department and became a neuroscience research associate affiliated with Massachusetts General Hospital and Harvard Medical School.
In 2009, Sarma joined the faculty of Johns Hopkins' Department of Biomedical Engineering, which is shared by the School of Medicine and the Whiting School of Engineering. She also is a core faculty member in the university's Institute for Computational Medicine. In 2011, Sarma was named a recipient of a Faculty Early Career Development Award from the National Science Foundation.
Her team's new system for seizure detection with reduced false alarms is protected by a patent obtained through the Johns Hopkins Technology Transfer office.