Study identifies an expanded role for PKM2 in helping cancer cells survive

It has long been known that cancer cells use nutrients differently than normal cells. In recent years, the rapidly reemerging field of cancer metabolism has shed new light on the ways that cancers use glucose to grow and thrive, demonstrating that manipulation of an enzyme called PKM2 is important to this metabolic process. Now a new study led by a scientific team at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) has uncovered another key mechanism that cancer cells use as part of their survival strategy -- and once again it seems that they are using PKM2 to their advantage.
Reported in the Nov. 3 express online edition of Science, the new findings show that by keeping PKM2 activity at lower-than-normal levels, cancer cells are able to withstand damage caused by oxidative stress and the generation of potentially toxic reactive oxygen species (ROS). Importantly, the study shows that small-molecule PKM2 activator drugs could be a way to interfere with this process -- and thereby disrupt tumor growth .
"Many cancer cells take up glucose at higher rates than most normal cells, and then use the sugar in a distinct way to fuel their proliferation," explains senior author Lewis Cantley, PhD, Director of the Cancer Center at BIDMC and the William Bosworth Castle Professor of Medicine at HMS. "Several years ago, it was discovered that the M2 form of the pyruvate kinase enzyme [PKM2] plays a key role in this metabolic process. Now, these new findings demonstrate yet another way that cancer cells are able to manipulate PKM2 to their advantage, suggesting that by keeping PKM2 activity low, cancer cells channel incoming glucose to metabolic pathways that generate antioxidants, and thereby survive oxidative stress."
Glycolysis is a multi-step process in which glucose is broken down so that cells can make use of the sugar for energy and other essential functions, and the PKM2 enzyme is responsible for the final step of the process. Previous work from the Cantley lab had suggested that inhibition of PKM2 by growth factor signaling was providing a stall-point in the glycolytic process, functioning like a dam in a river to enable glucose breakdown products to accumulate and eventually spur cancer cell growth.

**Source: Beth Israel Deaconess Medical Center

Las enfermedades neurológicas aumentan con la edad

Las enfermedades neurológicas aumentan con la edad y van a representar "un enorme coste económico por su frecuencia, duración y repercusión social". Así lo afirmó en Sitges el dr Jorge Matías-Guiu( jefe del Servicio de Neurología del Hospital Clínico San Carlos de Madrid) durante el X Seminario Lundbeck centrado en el día a día de las patologías neurodegenerativas. Para el experto "son enfermedades sociales que repercuten no solo al paciente y su entorno, por lo que es fundamental avanzar en el diagnóstico precoz y en la búsqueda de biomarcadores más exactos". En las últimas décadas se ha pasado a investigar más en las causas que en las consecuencias de estas enfermedades.

Conforme pasen los años la demencia irá en aumento, existiendo una previsión de afectar a casi un 70% de la población anciana en el año 2030. Para ello es básico la investigación. Según Matías-Guiu "en España sólo es posible en ámbitos traslacionales y clínicos. Hemos estado investigando para los demás. Hay muchos grupos de investigación pero con pocos recursos y necesitamos investigar con continuidad para dirigir directamente los resultados al paciente".

Otro de los participantes en el Simposium, Pablo Martínez-Lage( neurólogo de la Fundación CITA de San Sebastián) insistió "que no están unidos los investigadores clínicos y básicos, aunque resulta clave en este tema la necesidad de equipo multidisciplinar para este tipo de enfermedad". También aseguró que el tiempo de media de comenzar a tratar a un enfermo neurológico es de casi tres años, comenzando en el médico de Atención Primaria, la consulta del especialista y el diagnóstico. Javier Pagonabarraga( neurológo del Hospital Sant Pau de Barcelona) aseveró "que en muchos casos no hay tratamientos para la causa de la enfermedad por desconocimiento. Aunque han mejorada su nivel es muy difícil que los médicos de AP estén preparados y formados específicamente. Por ello, lo mejor es derivar al especialista pero pronto. Para mí esta coordinación es mejorable en España hoy en día".

Los expertos insistieron en el prioritario reto de la investigación para este tipo de enfermedades. El doctor Matías-Guiu aseguró que "el estudio de los mecanismos causales es básico para intentar atender mejor a esta población". Aseguró, en el caso del Alzheimer, "que no hay ninguno en estos momentos que ofrezcan plena certitud, pero sí ayudan a conseguir un diagnóstico temprano. A ello se une el análisis del historial médico, las entrevistas con pacientes cercanos, las pruebas de imagen, etc". Pero reveló cómo "muchas personas tienen miedo a la enfermedad y a saber que la pueden sufrir a lo largo de la vida. Para esto la genética está avanzando a pasos agigantados".

En el Seminario Lundbeck de Sitges de abordaron en concreto las enfermedades de Alzheimer y Parkinson. En los primeros hasta un 90% de los pacientes desarrollan al menos un trastorno conductual a lo largo de su vida. Por frecuencia el 92% experimenta apatía en el estadio grave, el 85% agitación, el 84% actividad motor aberrante y el 62%, depresión. Los trastornos de la conducta y las dificultades en las actividades de la vida diaria son prevalentes en esta enfermedad, como aseguran los cuidadores, experimentando de forma frecuente en los síntomas cognitivos( 93%). Esto representa la mayor problemática para los cuidadores.

Estrategias del médico para mejorar el cumplimiento del tratamiento en enfermos de psoriasis

*Buscar y desarrollar una relación cordial y cómplica médico-paciente

*Buscar el contacto visual, interesarse por los detalles de la historia del paciente y escuchar con atención

*Tocar el paciente

*Explicar el tratamiento y el porqué de éste

*Facilitar que el paciente pregunte y manifieste sus dudas e inquietudes

*Realizar una demostración practica del tratamiento, cómo se aplica sobre la piel

*Facilitar fórmulas farmacéuticas más fáciles de aplicar, no grasas, que no huelan, o manchen y de una aplicación diaria

*No complicar innecesariamente un tratamiento

*Facilitar al paciente puntos de información donde dirigirse en caso de duda

*Proporcionar instrucciones escritas o audiovisuales para facilitar la comprensión del tratamiento

*Programar visitas de seguimiento para generar confianza y promover el cumplimiento

*Expresar positivamente al paciente su implicación cuando el tratamiento ha funcionado

Más información en:
www.psorinfo.es
www.accionpsoriasis.org

Gladstone scientists identify gene critical for cell responses to oxygen deprivation

Scientists at the Gladstone Institutes have identified a protein that kick-starts the response to low levels of oxygen, suggesting new lines of research relevant to a variety of potentially fatal disorders associated with diminished oxygen supply, including cancer, heart disease, stroke and other neurological conditions that affect millions of people worldwide. In a paper being published November 3 in Molecular Cell, the laboratory of Gladstone Associate Investigator Katerina Akassoglou, PhD, maps out the chain of events that take place during hypoxia. Hypoxia is a condition that can occur in people with diseases such as heart disease and stroke. It deprives tissues and organs of an adequate oxygen supply.
"This discovery provides a novel understanding of the steps by which cells normally respond to hypoxia, a fundamental biological process that is implicated in many medical conditions," said Dr. Akassoglou, whose research at Gladstone -- a leading and independent biomedical-research organization -- investigates the mechanisms of inflammation and tissue repair in the brain.
The paper details how Dr. Akassoglou's lab discovered the previously unknown biological function of a protein called p75NTR. When activated by hypoxia, p75NTR sets off the cascading series of events that results in increased blood-vessel production to replenish oxygen levels during disease.
Previous research had indicated that hypoxia triggers the activation of a protein called HIF1-alpha -- an activation that ultimately leads to more blood vessels and an ensuing improvement in oxygen flow. There has been much interest among researchers in modifying levels of the HIF1-alpha protein to spur blood-vessel production in individuals with hypoxic conditions. But Dr. Akassoglou decided to take a different approach in her research.
By monitoring the responses of mice under hypoxic conditions, Dr. Akassoglou found that hypoxia first activated the p75NTR protein, which then activated HIF1-alpha and set everything in motion.
"What was most striking to us was what happened when we removed the gene that makes p75NTR," said Natacha Le Moan, PhD, a Gladstone postdoctoral fellow and the first author of the paper. "By effectively silencing p75NTR, the mice's response to hypoxia was impaired and blood-vessel production decreased."
"Now that we've shown that p75NTR spurs the activation of HIF1-alpha and the production of blood vessels during hypoxia, we can move forward with exploring potential therapies," said Dr. Akassoglou, who is also an associate professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. In addition, Dr. Akassoglou is also an associate adjunct professor of pharmacology at the University of California, San Diego.
"Dr. Akassoglou's trailblazing discovery could enable the development of pharmaceutical therapies for conditions that are caused or exacerbated by reduced oxygen levels," added Lennart Mucke, MD, who directs neurological research at Gladstone. "This is important news for those who suffer from hypoxia-related illnesses such as heart disease, stroke and certain types of cancer."

**Source: Gladstone Institutes

Exercise provides clue to deadly ataxia

When Dr. John Fryer and Dr. Huda Zoghbi prescribed mild exercise for mice with a neurodegenerative disorder called spinocerebellar ataxia 1 (SCA1), they did not know what to expect. Fryer, then a postdoctoral associate in the lab of Zoghbi who co-discovered the gene for the disorder, was disappointed when the exercise did not affect the mice's gait or walking ability. However, he and Zoghbi decided to put them back in their cages and see what would happen. What they found was the mice that exercised lived longer than those that had not. A report on their research appears online in the journal Science.
The result was important because spinocerebellar ataxia 1 is a devastating inherited disorder with no cure. The disease occurs when a mutation in the gene for a protein called ataxin1 causes numerous repeats of the DNA sequence CAG (cytosine, adenine, guanine), the genetic code for an amino acid called glutamine. SCA1 first affects gait and motor skills, then swallowing, speech and cognition and eventually kills the person who has it.

-Brief period of exercise
"What surprised us was that a brief period of exercise in early life had a long-term effect on survival," said Zoghbi, professor of molecular and human genetics, pediatrics, neurology and neuroscience and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.
"That exercise extended the mice's survival surprised me," said Fryer, now an assistant professor of molecular neuroscience at the Mayo Clinic in Jacksonville, Fla. The finding sparked Fryer's interest and he then began to explore what happened within the neurons.

-Protein partner
Exercise increased a growth factor that in turn dampened a particular pathway that involves a protein partner of ataxin1 called capicua. When capicua levels are decreased in mice carrying mutant ataxin1, several symptoms were improved including motor coordination and memory deficits. In SCA1 mice, certain neurons of the cerebellum called Purkinje cells are usually destroyed, but many of these were spared when capicua was reduced. Additionally, SCA1 mice with reduced levels of capicua were less likely to lose weight and they lived longer -- just as the exercised mice did.
"This opens up the possibility for many more studies," said Zoghbi, who is also a Howard Hughes Medical Institute researcher. "Would more rigorous exercise be more helpful or would it hurt them?"

-Might translate to humans
"It might translate to humans," said Fryer. "What we don't know yet is what kind of exercise would we recommend? We are not sure what we should tell an ataxia patient at this point but know that with more research we will have answers."
"Having shown that decreasing capicua improves symptoms begs the question if separating mutant ataxin1 and capicua would also suppress symptoms," said Zoghbi. "This work got us to a molecular pathway that might help us subdue the disease. It's like an onion. We are peeling away the layers to get to the core that will help understand all the details that contribute to this disease."
Dr. Harry Orr, a long-time collaborator and co-discoverer of the SCA1 gene with Zoghbi and director of the Institute of Translational Neuroscience at the University of Minnesota, said, "This is the first time in our collaboration that we found something that will have a direct impact on patients sooner rather than later. This could open additional strategies for treatment. Exercise, however, may not help everyone, particularly those who are far into the disease."
"The path to this finding has been long," said Orr.
It started with finding the families and getting their help in finding the gene. They since developed mouse models that enabled them to study the disease and have looked at several molecular pathways involved.

-Turning the corner
"We are starting to turn the corner to go back to the patients," said Orr. "These people have been very courageous and understanding."
"When one is looking at a disease, one cannot look at just one aspect of it," said Zoghbi. "We had to look at many changes in the neurons and mice to reach the conclusion in this paper. It's almost like detective work."
Others who took part in this study include Peng Yu, Hyojin Kang, Caleigh Mandel-Brehm, Angela N. Carter, Juan Crespo-Barreto, Yan Gao, Adriano Flora and Chad Shaw, all of BCM.
Funding for this work came from the National Institutes of Health and the Howard Hughes Medical Institute.

*Source: Baylor College of Medicine

GP receptionists help safeguard patients in repeat prescribing, finds study

Receptionists and administrative staff in UK general practices make important 'hidden' contributions to repeat prescribing, concludes a study published on bmj.com. It finds that over-reliance on electronic health records can affect the quality and safety of repeat prescribing, but that reception staff often use "practical judgments" to help bridge the gap between formal prescribing protocols and the complex reality of the repeat prescribing process.
The findings highlight the need to ensure that training in repeat prescribing goes beyond technology to help safeguard patients, say the authors.
Repeat prescriptions account for up to three quarters of all medication prescribed and four fifths of medication costs in UK general practice and repeat prescribing has long been recognised as a significant quality and safety concern.
It is often assumed that electronic records make repeat prescribing safer by reducing human error. However, some suggest it may introduce technology-related errors.
So researchers at Queen Mary, University of London analysed how doctors, receptionists and other administrative staff contributed to, and collaborated on, repeat prescribing routines at four UK general practices.
The aim was to identify potential threats to patient safety and characteristics of good practice.
They found repeat prescribing to be a complex, technology-supported social practice, requiring collaboration between clinicians and administrative staff.
They also found that a "model-reality gap" exists between formal prescribing protocols and the real time activity of repeat prescribing, but that staff often bridge this gap by making "practical judgments" which helped to safeguard patients.
This work was creative and demanded both explicit and tacit knowledge, although clinicians were often unaware of this input, say the authors.
In conclusion, reception and administrative staff make important 'hidden' contributions to repeat prescribing in general practice, they write. Although not formally accountable for prescriptions signed by doctors, they consider themselves informally accountable to patients for the quality and safety of these contributions.
Studying technology-supported work routines opens up a relatively unexplored agenda for patient safety research, they add.
"It seems reasonable to encourage well trained receptionists to use their initiative in repeat prescribing, but practices need to ensure that members of staff do not step beyond their levels of knowledge and competence," writes Professor Anthony Avery from the University of Nottingham Medical School in an accompanying editorial.
There is little evidence that the high levels of autonomy and engagement shown by some receptionists is a cause for concern, he adds. Nevertheless errors do occur in the repeat prescribing process and he calls for further research to find out why.

**Source: BMJ-British Medical Journal

Pep Guardiola se solidariza con los enfermos mentales de Africa

La escena impacta. Son las cuatro de la tarde, en plena Rambla de Catalunya. Y un africano encadena a Pep Guardiola delante del cine Alexandra. El entrenador del Barça posó de esta guisa para apoyar el estreno del documental Los olvidados de los olvidados. La historia de miles de enfermos mentales africanos que son atados habitualmente a la intemperie, privados de comida y agua, y abandonados por sus familias. Una cruda realidad que denuncia e incluso es capaz de cambiar a Grégoire Ahongbonon, un reparador de neumáticos que un día decidió dedicarse por completo a una heroica misión: rescatarlos, curarlos y devolverlos a sus familias, una vez reinsertados en la sociedad.

Guardiola fue recibido por su amigo Tortell Poltrona, con quien protagonizó la portada de un libro de relatos de 40 periodistas y cuya recaudación fue para la oenegé de este último, Pallassos sense Fronteres. Y en una de las expediciones del clown al continente más pobre del mundo fue cuando conoció a Ahongbonon.
La cinta, dirigida por Carles Caparrós, revela cómo las familias recluyen a los enfermos mentales por vergüenza o superstición. Y lo hace narrando el día a día de Ahongbonon, que sin subvenciones ha construido centros de acogida y de trabajo que han albergado ya a más de 15.000 enfermos.
Otros de los que han querido solidarizarse por la causa son el actor Àlex Casanovas, el grupo teatral El Tricicle, el cantautor Quico Pi de la Serra y el siempre activo y combativo pare Manel.

**Publicado en "EL PERIODICO DE CATALUNYA"