Aquatic-terrestrial transitions of feeding systems in vertebrates : a mechanical perspective

Transitions to terrestrial environments confront ancestrally aquatic animals with several mechanical and physiological problems owing to the different physical properties of water and air. As aquatic feeders generally make use of flows of water relative to the head to capture, transport and swallow food, it follows that morphological and behavioral changes were inevitably needed for the aquatic animals to successfully perform these functions on land. Here, we summarize the mechanical requirements of successful aquatic-to-terrestrial transitions in food capture, transport and swallowing by vertebrates and review how different taxa managed to fulfill these requirements. Amphibious ray-finned fishes show a variety of strategies to stably lift the anterior trunk, as well as to grab ground-based food with their jaws. However, they still need to return to the water for the intra-oral transport and swallowing process. Using the same mechanical perspective, the potential capabilities of some of the earliest tetrapods to perform terrestrial feeding are evaluated. Within tetrapods, the appearance of a mobile neck and a muscular and movable tongue can safely be regarded as key factors in the colonization of land away from amphibious habitats. Comparative studies on taxa including salamanders, which change from aquatic feeders as larvae to terrestrial feeders as adults, illustrate remodeling patterns in the hyobranchial system that can be linked to its drastic change in function during feeding. Yet, the precise evolutionary history in form and function of the hyolingual system leading to the origin(s) of a muscular and adhesive tongue remains unknown

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Improvements to cardiovascular Gene Ontology

Gene Ontology (GO) provides a controlled vocabulary to describe the attributes of genes and gene products in any organism. Although one might initially wonder what relevance a ‘controlled vocabulary’ might have for cardiovascular science, such a resource is proving highly useful for researchers investigating complex cardiovascular disease phenotypes as well as those interpreting results from high-throughput methodologies. GO enables the current functional knowledge of individual genes to be used to annotate genomic or proteomic datasets. In this way, the GO data provides a very effective way of linking biological knowledge with the analysis of the large datasets of post-genomics research. Consequently, users of high-throughput methodologies such as expression arrays or proteomics will be the main beneficiaries of such annotation sets. However, as GO annotations increase in quality and quantity, groups using small-scale approaches will gradually begin to benefit too. For example, genome wide association scans for coronary heart disease are identifying novel genes, with previously unknown connections to cardiovascular processes, and the comprehensive annotation of these novel genes might provide clues to their cardiovascular link. At least 4000 genes, to date, have been implicated in cardiovascular processes and an initiative is underway to focus on annotating these genes for the benefit of the cardiovascular community. In this article we review the current uses of Gene Ontology annotation to highlight why Gene Ontology should be of interest to all those involved in cardiovascular research

Choices of Stent and Cerebral Protection in the Ongoing ACST-2 Trial: A Descriptive Study (vol 53, pg 617, 2017)

Erratum for : "Choices of Stent and Cerebral Protection in the Ongoing ACST-2 Trial: A Descriptive Study." - http://hdl.handle.net/2078.1/20193