1,406 research outputs found
Recommended from our members
Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors.
The tremendous clinical success of immune checkpoint inhibition (ICI), particularly targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1/2 (PD-L1/2) pathway, has resulted in application to multiple cancers, as a monotherapy and as a companion to both conventional and novel agents. Despite this, the precise mechanisms underlying the anti-tumor effects of PD-1/PD-L1 blockade remain unclear. Emphasis has centered on its reversal of tumor-specific CD8+ T-cell exhaustion, although many cell types and processes are likely impacted. Due to the complex and pervasive roles of PD-1/PD-L1 on T-cell biology, including on initial T-cell priming, PD-1 blockade likely affects all aspects of T- cell responses, and these other effects may be even more critical for durable anti-tumor responses. Delineating these complex interactions necessitates in vivo modeling. By far, the healthy, young and inbred laboratory mouse, transplanted with an extensively cultured tumor cell line, has been the predominant preclinical model used to assess potential therapeutic efficacies. However, these mouse models often do not adequately reflect the tumor progression and cellular and genetic heterogeneity found within human cancers. Furthermore, laboratory mice also present with a vastly restricted immune profile compared to humans. This commentary discusses some of the critical questions that need to be addressed to optimize the use of ICI as well as caveats and limitations for consideration when extrapolating preclinical mouse data to the human cancer scenario
Focusing on the essentials: learning for performance
As The World health report 2006 emphasized, there is increasing consensus that training programmes should focus on "know-how" instead of "know-all." Health workers need to know how to do the job they will be expected to do. IntraHealth International's Learning for performance: a guide and toolkit for health worker training and education programs offers a step-by-step, customizable approach designed to develop the right skills linked to job responsibilities. Using Learning for performance (LFP) yields more efficient training that focuses on what is essential for health workers to do their jobs and on effective learning methods, while addressing the factors that ensure application of new skills on the job
Adding value to milk by increasing its protein and CLA contents
End of project reportThe mid-summer milk protein study was undertaken on 34 commercial dairy farms in 2005 to evaluate the influence of dietary and management variables on milk protein content in mid-season. Data on grass composition, genetic merit of the herds and milk protein content were collected and analysed by multiple regression. Both calving date and genetic merit for milk protein content were significantly associated with milk protein content and were used as adjustment factors when evaluating the association between measures of grass quality and milk protein content. Milk protein content was associated with grass OMD (P = 0.04) and NDF content (P = 0.02) but not with CP content (P = 0.80). It is concluded that herds calving earlier, with a greater genetic merit for milk protein content and consuming better quality pasture would have greater milk protein contents in mid-season
The serotonin 1A (5-HT1A) receptor as a pharmacological target in depression
Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT1A) receptor in the pathophysiology of depression. Stimulation of the 5-HT1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT1A ‘biased agonism’, using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT1A biased agonists
CURA Operations and Communications. Tentative Recommendations.
Center for Urban and Regional Affairs, University of Minnesota
Short-term serotonergic but not noradrenergic antidepressant administration reduces attentional vigilance to threat in healthy volunteers
Anxiety is associated with threat-related biases in information processing such as heightened attentional vigilance to potential threat. Such biases are an important focus of psychological treatments for anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of a range of anxiety disorders. The aim of this study was to assess the effect of an SSRI on the processing of threat in healthy volunteers. A selective noradrenergic reuptake inhibitor (SNRI), which is not generally used in the treatment of anxiety, was used as a contrast to assess the specificity of SSRI effects on threat processing. Forty-two healthy volunteers were randomly assigned to 7 d double-blind intervention with the SSRI citalopram (20 mg/d), the SNRI reboxetine (8 mg/d), or placebo. On the final day, attentional and interpretative bias to threat was assessed using the attentional probe and the homograph primed lexical decision tasks. Citalopram reduced attentional vigilance towards fearful faces but did not affect the interpretation of ambiguous homographs as threatening. Reboxetine had no significant effect on either of these measures. Citalopram reduces attentional orienting to threatening stimuli, which is potentially relevant to its clinical use in the treatment of anxiety disorders. This finding supports a growing literature suggesting that an important mechanism through which pharmacological agents may exert their effects on mood is by reversing the cognitive biases that characterize the disorders that they treat. Future studies are needed to clarify the neural mechanisms through which these effects on threat processing are mediated
Water quality changes during the first meter of managed aquifer recharge
The capacity of an artificial recharge field to alter organic matter and the bacterial flora of surface water was assessed by following changes in bacterial communities and composition of natural organic matter (NOM) over the first meter of infiltration depth. The sampling strategy applied in this study ensured that water samples consisted only of infiltrated water, excluding natural groundwater. Water was sampled at 50 and 100 cm below the surface of an infiltration basin divided into two halves; one side was dried and frozen and one was infiltrating water during the winter period prior to the sampling period. Bacterial cell counts, proportions of intact cells and community fingerprints were determined by flow cytometry, and NOM was characterized using total organic carbon (TOC), UV254 nm-absorbance (UVA) and fluorescence spectroscopy. Around 40% of the NOM was removed after only 50 cm. Protein-like components were reduced to a larger extent (45-50%) than the humic-like components (25%), suggesting removal of mostly biodegradable fractions of NOM. After only 50 cm of infiltration, about 99% total cell count (TCC) was removed. The flow cytometric data revealed that the bacterial communities collected after infiltration from the basin area that had been dried and frozen were more similar to those in the raw water. This suggests that drying and freezing the basin negatively impacted its treatment capacity. The results from this study highlight the importance of a well-developed biofilm and unsaturated zone for artificial recharge
- …