Enhanced responses of the anterior cingulate cortex neurones to colonic distension in viscerally hypersensitive rats

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65998/1/jphysiol.2005.096073.pd

Semi-intact ex vivo approach to investigate spinal somatosensory circuits

The somatosensory input that gives rise to the perceptions of pain, itch, cold and heat are initially integrated in the superficial dorsal horn of the spinal cord. Here, we describe a new approach to investigate these neural circuits in mouse. This semi-intact somatosensory preparation enables recording from spinal output neurons, while precisely controlling somatosensory input, and simultaneously manipulating specific populations of spinal interneurons. Our findings suggest that spinal interneurons show distinct temporal and spatial tuning properties. We also show that modality selectivity — mechanical, heat and cold — can be assessed in both retrogradely labeled spinoparabrachial projection neurons and genetically labeled spinal interneurons. Finally, we demonstrate that interneuron connectivity can be determined via optogenetic activation of specific interneuron subtypes. This new approach may facilitate key conceptual advances in our understanding of the spinal somatosensory circuits in health and disease

Diversity, distribution and conservation of the terrestrial reptiles of Oman (Sauropsida, Squamata)

All authors: Salvador Carranza , Meritxell Xipell, Pedro Tarroso, Andrew Gardner, Edwin Nicholas Arnold, Michael D. Robinson, Marc Simó-Riudalbas, Raquel Vasconcelos, Philip de Pous, Fèlix Amat, Jiří Šmíd, Roberto Sindaco, Margarita Metallinou †, Johannes Els, Juan Manuel Pleguezuelos, Luis Machado, David Donaire, Gabriel Martínez, Joan Garcia-Porta, Tomáš Mazuch, Thomas Wilms, Jürgen Gebhart, Javier Aznar, Javier Gallego, Bernd-Michael Zwanzig, Daniel Fernández-Guiberteau, Theodore Papenfuss, Saleh Al Saadi, Ali Alghafri, Sultan Khalifa, Hamed Al Farqani, Salim Bait Bilal, Iman Sulaiman Alazri, Aziza Saud Al Adhoobi, Zeyana Salim Al Omairi, Mohammed Al Shariani, Ali Al Kiyumi, Thuraya Al Sariri, Ahmed Said Al Shukaili, Suleiman Nasser Al Akhzami.In the present work, we use an exceptional database including 5,359 records of 101 species of Oman’s terrestrial reptiles together with spatial tools to infer the spatial patterns of species richness and endemicity, to infer the habitat preference of each species and to better define conservation priorities, with especial focus on the effectiveness of the protected areas in preserving this unique arid fauna. Our results indicate that the sampling effort is not only remarkable from a taxonomic point of view, with multiple observations for most species, but also for the spatial coverage achieved. The observations are distributed almost continuously across the two-dimensional climatic space of Oman defined by the mean annual temperature and the total annual precipitation and across the Principal Component Analysis (PCA) of the multivariate climatic space and are well represented within 17 out of the 20 climatic clusters grouping 10% of the explained climatic variance defined by PC1 and PC2. Species richness is highest in the Hajar and Dhofar Mountains, two of the most biodiverse areas of the Arabian Peninsula, and endemic species richness is greatest in the Jebel Akhdar, the highest part of the Hajar Mountains. Oman’s 22 protected areas cover only 3.91% of the country, including within their limits 63.37% of terrestrial reptiles and 50% of all endemics. Our analyses show that large areas of the climatic space of Oman lie outside protected areas and that seven of the 20 climatic clusters are not protected at all. The results of the gap analysis indicate that most of the species are below the conservation target of 17% or even the less restrictive 12% of their total area within a protected area in order to be considered adequately protected. Therefore, an evaluation of the coverage of the current network of protected areas and the identification of priority protected areas for reptiles using reserve design algorithms are urgently needed. Our study also shows that more than half of the species are still pending of a definitive evaluation by the International Union for Conservation of Nature (IUCN).This work was funded by grants CGL2012-36970, CGL2015-70390-P from the Ministerio de Economía y Competitividad, Spain (cofunded by FEDER) to SC, the project Field study for the conservation of reptiles in Oman, Ministry of Environment and Climate Affairs, Oman (Ref: 22412027) to SC and grant 2014-SGR-1532 from the Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya to SC. MSR is funded by a FPI grant from the Ministerio de Economía y Competitividad, Spain (BES-2013-064248); RV, PT and LM were funded by Fundação para a Ciência e Tecnologia (FCT) through post-doc grants (SFRH/BPD/79913/2011) to RV, (SFRH/BPD/93473/2013) to PT and PhD grant (SFRH/BD/89820/2012) to LM, financed by Programa Operacional Potencial Humano (POPH) – Quadro de Referência Estrategico Nacional (QREN) from the European Social Fund and Portuguese Ministerio da Educação e Ciência

Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction Networks

The high rates of failure in oncology drug clinical trials highlight the problems of using pre-clinical data to predict the clinical effects of drugs. Patient population heterogeneity and unpredictable physiology complicate pre-clinical cancer modeling efforts. We hypothesize that gene networks associated with cancer outcome in heterogeneous patient populations could serve as a reference for identifying drug effects. Here we propose a novel in vivo genetic interaction which we call ‘synergistic outcome determination’ (SOD), a concept similar to ‘Synthetic Lethality’. SOD is defined as the synergy of a gene pair with respect to cancer patients' outcome, whose correlation with outcome is due to cooperative, rather than independent, contributions of genes. The method combines microarray gene expression data with cancer prognostic information to identify synergistic gene-gene interactions that are then used to construct interaction networks based on gene modules (a group of genes which share similar function). In this way, we identified a cluster of important epigenetically regulated gene modules. By projecting drug sensitivity-associated genes on to the cancer-specific inter-module network, we defined a perturbation index for each drug based upon its characteristic perturbation pattern on the inter-module network. Finally, by calculating this index for compounds in the NCI Standard Agent Database, we significantly discriminated successful drugs from a broad set of test compounds, and further revealed the mechanisms of drug combinations. Thus, prognosis-guided synergistic gene-gene interaction networks could serve as an efficient in silico tool for pre-clinical drug prioritization and rational design of combinatorial therapies

11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.

Background Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial.Methods HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032).Findings Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89-1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group.Interpretation 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit.Funding F Hoffmann-La Roche (Roche)

Statistical learning leads to persistent memory: evidence for one-year consolidation

Statistical learning is a robust mechanism of the brain that enables the extraction of environmental patterns, which is crucial in perceptual and cognitive domains. However, the dynamical change of processes underlying long-term statistical memory formation has not been tested in an appropriately controlled design. Here we show that a memory trace acquired by statistical learning is resistant to inference as well as to forgetting after one year. Participants performed a statistical learning task and were retested one year later without further practice. The acquired statistical knowledge was resistant to interference, since after one year, participants showed similar memory performance on the previously practiced statistical structure after being tested with a new statistical structure. These results could be key to understand the stability of long-term statistical knowledge