Tumores neuroendocrinos: la era de las terapias dirigidas

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the second most prevalent group of advanced gastrointestinal tract tumors. Resources invested in research on this patient population have exponentially increased in recent years, and this has become one of the most attractive fields for oncological research. Several proangiogenic proteins have been found to be overexpressed in GEP-NETs, including vascular endothelial growth factor and its receptors and the more closely related intracellular signaling pathways such as the epidermal growth factor pathway, type I insulin-like growth factor receptor, and the PI3K-(PTEN)-AKT-mTOR pathway. The recent results of the three most important Phase III studies in GEP-NETs have allowed for approval of two targeted agents, sunitinib and everolimus, for the treatment of patients with pancreatic neuroendocrine tumors after decades of minimal advances in this population.     

Detection and Quantitation of Circulating Tumor Cell Dynamics by Bioluminescence Imaging in an Orthotopic Mammary Carcinoma Model

Circulating tumor cells (CTCs) have been detected in the bloodstream of both early-stage and advanced cancer patients. However, very little is know about the dynamics of CTCs during cancer progression and the clinical relevance of longitudinal CTC enumeration. To address this, we developed a simple bioluminescence imaging assay to detect CTCs in mouse models of metastasis. In a 4T1 orthotopic metastatic mammary carcinoma mouse model, we demonstrated that this quantitative method offers sensitivity down to 2 CTCs in 0.1–1mL blood samples and high specificity for CTCs originating from the primary tumor, independently of their epithelial status. In this model, we simultaneously monitored blood CTC dynamics, primary tumor growth, and lung metastasis progression over the course of 24 days. Early in tumor development, we observed low numbers of CTCs in blood samples (10–15 cells/100 µL) and demonstrated that CTC dynamics correlate with viable primary tumor growth. To our knowledge, these data represent the first reported use of bioluminescence imaging to detect CTCs and quantify their dynamics in any cancer mouse model. This new assay is opening the door to the study of CTC dynamics in a variety of animal models. These studies may inform clinical decision on the appropriate timing of blood sampling and value of longitudinal CTC enumeration in cancer patients.     

Changing fish distributions challenge the effective management of European fisheries

Changes in fish distribution are being observed across the globe. In Europe's Common Fisheries Policy, the share of the catch of each fish stock is split among management areas using a fixed allocation key known as ‘Relative Stability’: in each management area, member states get the same proportion of the total catch each year. That proportion is largely based on catches made by those member states in the 1970s. Changes in distribution can, therefore, result in a mismatch between quota shares and regional abundances within management areas, with potential repercussions for the status of fish stocks and the fisheries that depend on them. Assessing distribution changes is crucial to ensure adequate management and sustainable exploitation of our fish resources. We analysed scientific survey data using a three-tiered analytical approach to provide, for the first time, an overview of changes in distribution for 19 northeast Atlantic fish species encompassing 73 commercial stocks over 30 yr. All species have experienced changes in distribution, five of which did so across management areas. A cross-species analysis suggested that shifts in areas of suitable thermal habitat, and density-dependent use of these areas, are at least partly responsible for the observed changes. These findings challenge the current use of relative stability to allocate quotas.     

Global diversity and biogeography of deep-sea pelagic prokaryotes

The deep-sea is the largest biome of the biosphere, and contains more than half of the whole ocean''s microbes. Uncovering their general patterns of diversity and community structure at a global scale remains a great challenge, as only fragmentary information of deep-sea microbial diversity exists based on regional-scale studies. Here we report the first globally comprehensive survey of the prokaryotic communities inhabiting the bathypelagic ocean using high-throughput sequencing of the 16S rRNA gene. This work identifies the dominant prokaryotes in the pelagic deep ocean and reveals that 50% of the operational taxonomic units (OTUs) belong to previously unknown prokaryotic taxa, most of which are rare and appear in just a few samples. We show that whereas the local richness of communities is comparable to that observed in previous regional studies, the global pool of prokaryotic taxa detected is modest (~3600 OTUs), as a high proportion of OTUs are shared among samples. The water masses appear to act as clear drivers of the geographical distribution of both particle-attached and free-living prokaryotes. In addition, we show that the deep-oceanic basins in which the bathypelagic realm is divided contain different particle-attached (but not free-living) microbial communities. The combination of the aging of the water masses and a lack of complete dispersal are identified as the main drivers for this biogeographical pattern. All together, we identify the potential of the deep ocean as a reservoir of still unknown biological diversity with a higher degree of spatial complexity than hitherto considered.     

Human Papillomavirus Infection in HIV-1 Infected Women in Catalonia (Spain): Implications for Prevention of Cervical Cancer

Background

High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women.

Methods

We enrolled 479 HIV-1–infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis.

Results

Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age <30 years (odds ratio[OR],2.5; 95%confidence interval[CI],1.1–5.6). The factors associated with the presence of HSIL or low-grade squamous intraepithelial lesions (LSIL) were CD4T-lymphocyte count <200cells/mm³ versus >500cells/mm³ (OR,8.4; 95%CI,3.7–19.2), HIV-1 viral load >10,000copies/mL versus <400copies/mL (OR,2.1; 95%CI,1.0–4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0–3.9). Sixty percent of HIV-1–infected women had had one Pap smear within the last 2 years.

Conclusions

The high prevalence of HPV infection and cervical lesions in the HIV-1–infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1–infected women.     

Evaluación de un programa de intervención en residencias geriátricas para reducir la frecuentación hospitalaria

Objectives

This study describes the outcomes of an intervention program in Nursing Homes and their effects on emergency room attendance, hospital admissions, and pharmaceutical expenditure.

Material and methods

This involved non-randomised community intervention in Nursing Homes with a control group. The program was implemented gradually from 2007 to 2009 in 10 Nursing Homes (857 beds) which participated voluntarily. The control group consisted of 14 Nursing homes (1,200 beds), which refused to participate or were not assigned to our Primary Care centres. Intervention consisted of comprehensive geriatric assessment and follow-up visits by trained personnel, review and adjustment of drug treatment, case management and staff training.

Results

In the Nursing Homes where the program was carried out, emergency room attendance decreased from 1165‰ (95%CI 1100-1240]) in 2006 to 674‰ (95%CI 620-730) in 2009, while in the control group it increased from 1071 (95%CI 1020-1130) to 1246‰ (95%CI 1190-1310). The hospital admissions also decreased from 48.4% (95%CI 45-52) in 2006 to 32.1% (95%CI 29-35) in 2009, while in the control group increased from 43.5% (95%CI 41-46) to 55.8% (95%CI 53-59). There was also a 9% reduction in pharmacy cost compared with an increase of 11.9% in the control group.

Conclusions

The intervention has proved effective at reducing hospital admissions and emergency room attendance in institutionalised patients, thereby streamlining pharmacy costs.     

Understanding the Connection between Epigenetic DNA Methylation and Nucleosome Positioning from Computer Simulations

Cytosine methylation is one of the most important epigenetic marks that regulate the process of gene expression. Here, we have examined the effect of epigenetic DNA methylation on nucleosomal stability using molecular dynamics simulations and elastic deformation models. We found that methylation of CpG steps destabilizes nucleosomes, especially when these are placed in sites where the DNA minor groove faces the histone core. The larger stiffness of methylated CpG steps is a crucial factor behind the decrease in nucleosome stability. Methylation changes the positioning and phasing of the nucleosomal DNA, altering the accessibility of DNA to regulatory proteins, and accordingly gene functionality. Our theoretical calculations highlight a simple physical-based explanation on the foundations of epigenetic signaling.     

siRNA enrichment in Argonaute 2-depleted Blattella germanica

BackgroundRNA interference (RNAi) is a cellular mechanism used to fight various threats, including transposons, aberrant RNAs, and some types of viruses. This mechanism relies on the detection of dsRNA molecules, which through a pathway involving Dicer-2 (Dcr-2) and Argonaute 2 (AGO2), produces small interfering RNAs (siRNAs) that bind to the complementary RNAs triggering their degradation.MethodsUsing the cockroach Blattella germanica as a model, we examined AGO2 activity by depleting its mRNA using RNAi and analyzing the phenotypes produced.ResultsDepleting AGO2 expression had no remarkable effect on nymphal development or reproduction. dsRNA treatment triggered an immediate and transitory increase in AGO2 expression, independently of Dcr-2 action. In addition, we analyzed the siRNAs generated after injecting a heterologous dsRNA in control and AGO2-depleted animals. The results revealed that obtained siRNAs mapped non-uniformly along the dsRNA sequence. In AGO2-depleted animals, the proportion of 22 nucleotide reads was higher and accumulations of reads appeared in areas less well-represented in the controls. We also detected a preference for cytosine as the first nucleotide in controls that was significantly attenuated in AGO2-depleted individuals.Conclusions/general significanceThe siRNAs produced from a dsRNA mapped heterogeneously along the length of the dsRNA and this arrangement depends on the dsRNA sequence. AGO2 exerts its role as nuclease on the siRNA duplexes independently of its action on the corresponding mRNA. This study sheds light on an extremely useful process for reverse genetics in laboratories, in addition to the design of more effective, specific, and eco-friendly pest-control strategies.