Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

CASTNet: Community-Attentive Spatio-Temporal Networks for Opioid Overdose Forecasting

Opioid overdose is a growing public health crisis in the United States. This crisis, recognized as "opioid epidemic," has widespread societal consequences including the degradation of health, and the increase in crime rates and family problems. To improve the overdose surveillance and to identify the areas in need of prevention effort, in this work, we focus on forecasting opioid overdose using real-time crime dynamics. Previous work identified various types of links between opioid use and criminal activities, such as financial motives and common causes. Motivated by these observations, we propose a novel spatio-temporal predictive model for opioid overdose forecasting by leveraging the spatio-temporal patterns of crime incidents. Our proposed model incorporates multi-head attentional networks to learn different representation subspaces of features. Such deep learning architecture, called "community-attentive" networks, allows the prediction of a given location to be optimized by a mixture of groups (i.e., communities) of regions. In addition, our proposed model allows for interpreting what features, from what communities, have more contributions to predicting local incidents as well as how these communities are captured through forecasting. Our results on two real-world overdose datasets indicate that our model achieves superior forecasting performance and provides meaningful interpretations in terms of spatio-temporal relationships between the dynamics of crime and that of opioid overdose.Comment: Accepted as conference paper at ECML-PKDD 201

Viking navigation

A comprehensive description of the navigation of the Viking spacecraft throughout their flight from Earth launch to Mars landing is given. The flight path design, actual inflight control, and postflight reconstruction are discussed in detail. The preflight analyses upon which the operational strategies and performance predictions were based are discussed. The inflight results are then discussed and compared with the preflight predictions and, finally, the results of any postflight analyses are presented

Targeting the DNA damage response and repair in cancer through nucleotide metabolism

The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1

Rethinking place and the social work office in the delivery of children's social work services

Limited attention has been given to the concept of place in social work research and practice. This paper draws on the national evaluation of social work practices (SWPs) in England undertaken between 2009 and 2012. SWPs were pilot organisations providing independent social work services for children in out-of-home care in five sites. One factor distinguishing some of these pilots was their attention to place. The evaluation employed a mixed methods approach and we use data from interviews with 121 children and young people in out-of-home care, 19 birth parents and 31 interviews with SWP staff which explored their views and experiences of the SWP offices. Children and young people were alert to the stigma which could attach to social work premises and appreciated offices which were planned and furnished to appear less institutional and more ‘normal’. Daily interactions with staff which conveyed a sense of recognition and value to service users also contributed to a view of some SWP offices as accessible and welcoming places. Both children and parents appreciated offices that provided fun activities that positioned them as active rather than passive. Staff valued opportunities for influencing planning decisions about offices and place was seen to confer a value on them as well as on service users. However, not all the SWPs were able to achieve these aspects of place, and engaging children and families in place was less likely when the service user population was widely dispersed. Recognising the importance of place and how place is constructed through relationships between people as well as through the physical environment appeared to be key to creating offices that combated the stigma attached to out-of-home care. Those leading and managing children’s services should explore ways of involving local communities in planning social work offices and turn attention to making these offices accessible, welcoming, places

Cross Sections for Ionization of Water Vapor by 7-4000-keV Protons

Cross sections for production of electrons and positive ions by proton impact on water vapor have been measured from 7-4000 keV by the transverse-field method

Induction of distinct plant cell death programs by secreted proteins from the wheat pathogen Zymoseptoria tritici

Cell death processes in eukaryotes shape normal development and responses to the environment. For plant–microbe interactions, initiation of host cell death plays an important role in determining disease outcomes. Cell death pathways are frequently initiated following detection of pathogen-derived molecules which can lead to resistance or susceptibility to disease depending on pathogen lifestyle. We previously identified several small secreted proteins (SSPs) from the wheat-infecting fungus Zymoseptoria tritici that induce rapid cell death in Nicotiana benthamiana following Agrobacterium-mediated delivery and expression (agroinfiltration). Here we investigated whether the execution of host cells was mechanistically similar in response to different Z. tritici SSPs. Using RNA sequencing, we found that transient expression of four Z. tritici SSPs led to massive transcriptional reprogramming within 48 h of agroinfiltration. We observed that distinct host gene expression profiles were induced dependent on whether cell death occurs in a cell surface immune receptor-dependent or -independent manner. These gene expression profiles involved differential transcriptional networks mediated by WRKY, NAC and MYB transcription factors. In addition, differential expression of genes belonging to different classes of receptor-like proteins and receptor-like kinases was observed. These data suggest that different Z. tritici SSPs trigger differential transcriptional reprogramming in plant cells