Archive | March 2012

The next international conference on computational molecular biology, in April in Barcelona

RECOMB 2012, the 16th Annual International Conference on Research in Computational Molecular Biology, will take place in Barcelona on April 21-24, 2012. It is being organised by Roderic Guigó, from the CRG. Check out this video where he presents the meeting.

The meeting will focus on the computational challenges arising from the extraordinary developments in high throughput technologies. You can check the updates on the speakers and the program on the conference website.

As the organisers point out, the meeting overlaps with Sant Jordi (Saint George), on April 23, the patron of Catalonia, and one of the most important civic holidays in the country. The city fills with the smell of red roses, and there are books sold in every corner.

So, make sure you don’t miss this opportunity to enjoy the best mix of science and culture. Register now to Recomb 2012!

Breast cancer, osteoporosis and vitamin D

Aromatase inhibitors (AIs) are used in the treatment of estrogen–dependent breast and ovarian cancer in postmenopausal women, since the enzyme aromatase synthesizes estrogen. However, their use implies risk of osteoporosis and bone loss, and is associated with increased fracture rates. It is thought that vitamin D might play a role in minimising this effect.

To test this, Xavier Nogués and colleagues from the Genetic Study of Osteoporosis research group at the IMIM-Hospital del Mar have recently undergone a study in which they followed up a cohort of 232 women under AI treatment for early breast cancer. These women were ineligible for bisphosphonate therapy (usually used to reduce the risk of osteoporosis) and stayed on treatment for 1 year. They were supplemented with daily calcium (1 g) and vitamin D, as well as additional oral vitamin D every 2 weeks if their baseline vitamin D concentration was lower than 30 ng/ml.

Serum vitamin D was measured at baseline and 3 months, and lumbar spine (LS) bone mineral density at baseline and 1 year. The results, published in the journal Breast Cancer Research Treatment show that after a year on AI therapy, the participants experienced a significant 1.68 % bone loss at the lumbar spine (LS). High vitamin D at 3 months protected against LS bone loss, and those who reached the highest levels (≥40 ng/ml) had reduced bone loss by 1.70 % compared to those with low vitamin D levels (<30 ng/ml).

Nogués and colleagues conclude that improved vitamin D status using supplementation can indeed decrease the AI-associated bone loss. And they warn that, according to their results, the current Institute of Medicine target recommendation of 20 ng/ml might be too low to ensure good bone health.

Reference:
Prieto-Alhambra D, Servitja S, Javaid MK, Garrigós L, Arden NK, Cooper C, Albanell J, Tusquets I, Diez-Perez A, Nogues X. Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study. Breast Cancer Res Treat. 2012 Mar 21;

The Jennifer Aniston neuron

Rodrigo Quian Quiroga

No, we don’t mean to say that Rachel from “Friends” has only one nerve cell… This was the title of the talk Rodrigo Quian Quiroga, from the University of Leicester, gave at the PRBB a couple of weeks ago. This physicist did a PhD in maths and then turned to neuroscience, something that fascinates him. “I can see you. Isn’t this amazing?”, he said to start the talk. As the Chilean researcher said, we can all remember and have emotions. How do neurons do that? This is what Quian Quiroga has been trying to understand for the last 10 years, and he was invited by the Pasqual Maragall Foundation (FPM) to the PRBB to tell us about his latest research into a particular type of neurons at the hippocampus, which he calls ‘concept cells’.

He discovered them by doing single cell recordings in epilepsy patients who were subject to surgery to remove a specific area of the hippocampus. During 1 or 2h, the researcher had time to do some tests, with the patient awake. He showed them hundreds of unrelated pictures, and checked if the sight of these images was activating some neurons. In a specific patient, he found a neuron that fired every time the patient saw an image of Jennifer Aniston. Also, it wasn’t a specific image of Jennifer Aniston, but any picture of her. Or the sound of her voice, or her name written or spoken. Basically, this neuron responded to the ‘concept’ of Jennifer Aniston!

Jennifer Aniston

But the American actress isn’t the only one who has a neuron just for herself. In different patients, Quiroga found neurons responding to different concepts, always concepts that were familiar to the patient: mostly he discovered other celebrities, such as Maradona or Hally Berry, but he even found a patient with ‘concept neurons’ firing at pictures of himself. He found only one person who didn’t seem to have these neurons, and the patient turned out to be autistic – someone who cannot think abstract.

He then discovered that these neurons don’t fire to a single concept, but are able to make associations and fire to related concepts. Thus, the Jennifer Aniston neuron could also fire, although less strongly, to images of her friend Phoebe in the popular TV series.

How durable is the ‘memory’ of these cells? Will a neuron that fires for Brad Pitt today still do so in 10 years? The scientist thinks this depends on how familiar the person is with the concept and his relation to it. In any case, these cells are, he thinks, the building blocks for explicit memory functions, and the neural substrate to make associations. We probably all have thousands of these cells in the hippocampus, and the most familiar a concept is, the more neurons we will have encoding for it. If one of these neurons fires to 3 or 4 different concepts, and another one fires to one of those plus 5 new ones, the neurons might activate each other and create networks of related concepts, which would build our memory.

A fascinating story that will surely bring more surprises. Stay tuned for Quian Quiroga’s research!

Extracellular fibrinogen: the bad and the ugly in DMD

Having been for a long time in the radar of Pura Muñoz Cánoves from the CEXS-UPF, she could now demonstrate that the severity in muscular dystrophy is fibrinogen dependent. This fibrin precursor, which is never located outside of the vascular compartment in healthy muscle, is deposited in the extracellular matrix in mdx mice, the animal model for Duchenne muscular dystrophy (DMD). In their paper published in Human Molecular Genetics the researchers could furthermore show that the mechanisms supporting disease progression depend on the αMß2-binding motif of fibrinogen. Once this motif was experimentally eliminated from the fibrinogen gamma chain, this was sufficient to alleviate disease severity in mdx dystrophic muscle.

DMD is still a fatal degenerative muscle disorder. With the discovery of fibrinogen being a critical factor for inflammation-mediated DMD progression, new strategies for treatment could be developed. The counterproductive inflammatory environment established through the αMß2-mediated leukocyte activation could be stopped by selectively targeting this motif leaving its pro-coagulant properties unaltered. The authors also suggest looking into neurodegenerative diseases like Alzheimer’s and multiple sclerosis, because evidence was recently found that interference with the fibrinogen/macrophage axis improves neurodegeneration and stops demyelination in mouse models.

Reference:

Vidal B, Ardite E, Suelves M, Ruiz-Bonilla V, Janué A, Flick MJ, Degen JL, Serrano AL, Muñoz-Cánoves P
Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMß2 leukocyte integrin receptor.
Hum Mol Genet. 2012 Mar 1;

Studying two very particular ethnic groups: from Pygmies to Basques

Pygmies, everyone knows, present the lowest height among humans – adult men grow to less than 150 cm. One can find pygmy populations not only in Africa, but also in Australia, Brazil and several countries in Asia. The fact that populations in such diverse locations all have short stature in common suggests the presence of strong selective pressures on this phenotype, but this has never been proved. David Comas and colleagues from the Institute of Evolutionary Biology (IBE: CSIC-UPF) have recently published in the journal Human Genetics the first genetic hint of adaptive evolution in the African Pygmy phenotype.

Mbuti pygmy men in Congo

They have developed a novel approach to survey the genetic architecture of phenotypes, one in which the genetic analysis also incorporated environmental variables to understand local adaptation. They have applied it to study the genomic covariation between allele frequencies and height measurements among Pygmy and non-Pygmy populations. The results show that the genomic regions that most likely participate in the genetic architecture of the phenotype, are those associated to bone homeostasis and skeletal remodeling, which could therefore be a key biological process underlying the Pygmy phenotype. They have also proved that these regions have most likely evolved under positive selection. These results are consistent with the independent emergence of the Pygmy height in other continents with similar environments, and support the putative adaptive role of the short stature of Pigmies.

David Comas’ group on Human Genome Diversity has also recently studied another very particular ethnic group, that from the Basque country in Spain. The Basque people have received considerable attention from anthropologists, geneticists and linguists during the last century due to the singularity of their language and to other cultural and biological characteristics. But any attempt to address the questions of their origin, uniqueness and heterogeneity has suffered from a weak study-design where populations were not analyzed in an adequate geographic and population context. In their last paper, published in Molecular Biology and Evolution, the group has tried to solve that by analyzing the Y chromosome and mitochondrial DNA of ∼900 individuals from 18 populations, including some where Basque is currently spoken and others where Basque might have been spoken in historical times.

The results indicate that Basque-speaking populations are similar to geographically surrounding non-Basque populations, and that their genetic uniqueness is based on a lower amount of external influences compared to other Iberians and French populations. The rough overlap of the pre-Roman tribe location and the current dialect limits supports the notion that the environmental diversity in the region has played a recurrent role in cultural differentiation at different time periods.

References:
Mendizabal I, Marigorta UM, Lao O, Comas D. Adaptive evolution of loci covarying with the human African Pygmy phenotype. Hum Genet. 2012 Mar 11

Martínez-Cruz B, Harmant C, Platt DE, Haak W, Manry J, Ramos-Luis E, Soria-Hernanz DF, Bauduer F, Salaberria J, Oyharçabal B, Quintana-Murci L, Comas D, the Genographic Consortium. Evidence of pre-Roman tribal genetic structure in Basques from uniparentally inherited markers. Mol Biol Evol. 2012 Mar 12;

Focus on addiction: a CSHL course at the PRBB

Next July 18-25 a Cold Spring Harbour Laboratory (CSHL) summer course on “Cellular biology of addiction” will take place at the PRBB. The deadline for registration has just been extended until March 30, so hurry up!!

The course is organized by Rafael Maldonado, from the UPF and it is addressed both to experienced researchers and those new to the field. Its aim is to explain and discuss the latest advances and the major gaps in cell and molecular biology of drug addiction, although other subjects such as learning, memory and drug development will also be included.

The course is co-organized by Brigitte L. Kieffer from CERBM, University of Strasbourg, Chris Evans from the University of California, Los Angeles, USA and Antonello Bonci from the National Institute on Drug Abuse-NIDA, Baltimore, USA.

To see the speakers, costs and to register, you can go to the CSHL summer course website. Make sure you don’t miss this opportunity!

The role of Pap1 in oxidative stress and drug resistance

The transcription factor Pap1 in fission yeast is the homologue of mammalian c-Jun, which is part of the AP-1 complex that regulates genes controlling cellular differentiation, proliferation and apoptosis. Pap1 was identified, because it confers resistance to several drugs and it was also seen that this phenomenon is associated with the activation of oxidative stress signaling pathways in several microbes. Surprisingly, recent research by the Oxidative Stress and Cell Cycle group of Elena Hidalgo from the CEXS-UPF demonstrates now that the gain of drug resistance does not correlate with enhanced tolerance to oxidative stress.

The article published in Nucleic Acid Research presents evidence that only oxidized nuclear Pap1, but not the reduced one, interacts with the transcription regulator Prr1 and activates antioxidant genes. The activities responsible for multidrug resistance, on the other hand, are triggered by nuclear Pap1 irrespective of its oxidation state. So it looks like there are two non-overlapping Pap1-dependent gene expression programs.

Furthermore it could be shown that the drug tolerance gene Caf5, an efflux pump, gets over-expressed, when non-oxidized Pap1 accumulates in the nucleus in the absence of Prr1. At present, Caf5 seems to be sufficient to explain the drug resistance phenotype.

Association of oxidized Pap1 and Prr1 is required for the activation of the antioxidant, but not the drug resistance, genes. (A) In wild-type cells, oxidation of Pap1 upon H2O2 stress induces its nuclear accumulation and its association with Prr1. The heterodimer is then able to activate both sets of promoters, the antioxidant (trr1, srx1, ctt1) and the drug resistance (obr1, caf5, c663.08c) genes. (B) In cells defective in Pap1 export (such as cells lacking Hba1 or expressing Pap1.C523D), the transcription factor cannot be oxidized by H2O2, cannot associate with Prr1 and can only trigger transcription of the drug resistance genes. (C) Similarly, in cells lacking Prr1, H2O2-oxidized Pap1 will only be able to activate drug resistance genes.

Reference:

Calvo IA, García P, Ayté J, Hidalgo E
The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2.
Nucleic Acids Res. 2012 Feb 16;
[PDF]

Advances in prostate and urothelial cancer

Dr. Joaquim Bellmunt

Prostate cancer is the most common cancer in Western men and, when the disease is advanced, no curative agents are available. Joaquim Bellmunt, from the Medical Oncology department of the Hospital del Mar, researcher at the IMIM and professor at the UPF, has recently written a report on recent advances in the management of high-risk localized and metastatic prostate cancer. Together with some colleagues, Bellmunt participated in the 3rd annual Interactive Genitourinary Cancer Conference, held in Budapest last spring, and has summarized what was discussed there for the British Journal of Urology International. The report includes debates over radical prostatectomy versus radiation therapy, about how androgen deprivation therapy or adjuvant chemotherapy can help, or about the development of new agents, which has been aided by a greater understanding of the molecular mechanisms of resistance to current therapies.

Published in the Journal of Clinical Oncology, Bellmunt has recently been involved with different colleagues in a randomized phase III study comparing the efficiency of several drug combinations in the treatment of patients with locally advanced or metastatic urothelial cancer. From 2001 to 2004, 626 patients were randomly assigned to two combinations of drugs: a 2-drug combination with gemcitabine and cisplatin (GC) and a 3-drug combination in which paclitaxel was also included (PCG). After nearly 5 years of follow-up, the authors conclude that addition of paclitaxel to GC provides a higher response rate and a 3.1-month survival benefit. However, this increase was not statistically significant, say the authors, meaning that novel approaches will be required to obtain major improvements in survival of incurable urothelial cancer.

Recently, Bellmunt also participated in the identification of a mutation that confers resistance to cetuximab, one of the drugs used to treat colorectal cancer. You can read that story in this earlier post.

References:
Bellmunt J, Attard G, Bahl A, Huland H, Klotz L, Kuban D, Oudard S, Watson W. Advances in the management of high-risk localised and metastatic prostate cancer. BJU Int. 2012 Mar;109 Suppl 2:8-13

Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized Phase III Study Comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Cancer Without Prior Systemic Therapy: EORTC Intergroup Study 30987. J Clin Oncol. 2012 Feb 27;

Her Majesty the Queen visits our research park

The March 2012 edition of the PRBB newspaper, El.lipse, a monthly bilingual newspaper, is now available.

To download a PDF version please click here. You can see a multimedia version here.

Her Majesty the Queen of Spain has visited the FPM at the PRBB this February. Also, find out about the core facilities coalition that supports research at the park. Matthieu Louis, from the Centre for Genomic regulation (CRG), tells us about his research into Drosophila neuroscience, and Anna Bigas (IMIM-Hospital del Mar Research Institute) explains her life as a scientist. Other news include the repositioning of drugs for rare diseases; improving the value of preleukaemia prognosis, the health cost of swine flu; the recent origin of North Africans; or understanding resistance to colorectal cancer treatment; or new pathways involved in bladder cancer. Finally, should ‘dangerous’ data be published? Find out our researchers’ views on this!

Repairing muscle after injury

Repairing a tissue after an injury requires the infiltration of inflammatory cells and the activation of the resident stem cells, which will restore the damaged tissue. But for full tissue recovery to happen, the inflammation that is first necessary must be resolved. The Myogenesis research group at the CEXS-UPF, led by Pura Muñoz-Cánoves, has recently provided evidence of how this happens.

For the inflammation to disappear, macrophages (a type of immune cells that are involved in the healing of muscle and other tissues) must switch from a pro-inflammatory to an anti-inflammatory phenotype. While it is known that disturbing the interactions between inflammatory cells and tissue resident cells prevents successful healing, the molecular mechanisms underlying the interactions between these cell types are practically unknown.

In an Extra Views article recently published in Cell Cycle, the authors review their work about how macrophages control stem cell-dependent tissue repair. In particular, Muñoz-Cánoves and colleagues demonstrated, in a paper in Journal of Cell Biologya new function for MAPK phosphatase MKP-1 (MKP-1) in the regulation of p38 MAPK (p38) signaling, which leads to the deactivation of macrophages during inflammation resolution after injury.

At advanced stages of regeneration, MKP-1 loss caused an unscheduled “exhaustion-like” state in muscle macrophages, in which neither pro- nor anti-inflammatory cytokines are expressed despite persistent tissue damage. This leads to reparation by the tissue stem cells.

Because this progressive attenuation of pro-inflammatory gene expression is also involved in the process of tolerance to bacterial infection, the authors discuss the potential similarities between the two mechanisms: inflammation resolution during tissue repair (studied in this work) and endotoxin tolerance.

Reference:

Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardí M, Caelles C, Serrano AL, Muñoz-Cánoves P
p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair.
J Cell Biol. 2011 Oct 17;195(2):307-22

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