Stereotactic body radiation therapy is the preferred treatment modality for patients with inoperable early-stage non-small cell lung cancer. However, comparative outcomes between stereotactic body radiation therapy and surgery for high-risk patients remain controversial. The primary aim of the present meta-analysis was to assess overall survival in matched and unmatched patient cohorts undergoing stereotactic body radiation therapy or surgery. Secondary end points included cancer-specific survival, disease-free survival, disease recurrence, and perioperative outcomes.

Genetic nomenclature for Caenorhabditis species and other nematodes is supervised by WormBase in collaboration with the Caenorhabditis Genetics Center (CGC) and with essential input from the community of scientists working on C. elegans and other nematodes.

WormBase (http://www.wormbase.org) is a central data repository for nematode biology. Initially created as a service to the Caenorhabditis elegans research field, WormBase has evolved into a powerful research tool in its own right. In the past 2 years, we expanded WormBase to include the complete genomic sequence, gene predictions and orthology assignments from a range of related nematodes. This comparative data enrich the C. elegans data with improved gene predictions and a better understanding of gene function. In turn, they bring the wealth of experimental knowledge of C. elegans to other systems of medical and agricultural importance. Here, we describe new species and data types now available at WormBase. In addition, we detail enhancements to our curatorial pipeline and website infrastructure to accommodate new genomes and an extensive user base.

WormBase (www.wormbase.org) is the major publicly available database of information about Caenorhabditis elegans, an important system for basic biological and biomedical research. Derived from the initial ACeDB database of C. elegans genetic and sequence information, WormBase now includes the genomic, anatomical and functional information about C. elegans, other Caenorhabditis species and other nematodes. As such, it is a crucial resource not only for C. elegans biologists but the larger biomedical and bioinformatics communities. Coverage of core areas of C. elegans biology will allow the biomedical community to make full use of the results of intensive molecular genetic analysis and functional genomic studies of this organism. Improved search and display tools, wider cross-species comparisons and extended ontologies are some of the features that will help scientists extend their research and take advantage of other nematode species genome sequences.

Early life adversity impairs normal hippocampal function and connectivity in various mammalian species, including humans and rodents. According to the 'cumulative model' the number of early adversities can be summed up to determine the risk for developing psychopathology later in life. In contrast, the 'dimensional model' argues that 'Deprivation' and 'Threat' impact different developmental processes that should not be added in determining clinical outcomes. Here we examine these predictions in male and female mice exposed to a single adversity - limited bedding (LB) - versus mice exposed to multiple adversities - unpredictable postnatal stress (UPS) - focusing on microglia-mediated synaptic pruning in the developing hippocampus. Exposure to both LB and UPS reduced the ramification of microglia, impaired their ability to phagocytose synaptic material in vivo and ex vivo, and decreased expression of TREM2. Abnormal phagocytic activity was associated with increased spine density in CA1 pyramidal neurons that was seen in 17-day-old groups and persisted in peri-pubescent 29-day-old LB and UPS mice. Exposure to LB caused more severe impairment in microglial ramification and synaptic engulfment compared to UPS, outcomes that were accompanied by a UPS-specific increase in the expression of several genes implicated in synaptic pruning. We propose that despite being a single stressor, LB represents a more severe form of early deprivation, and that appropriate levels of hippocampal stimulation during the second and third weeks of life are necessary to support normal microglial ramification and synaptic pruning. Further, impaired synaptic pruning during this critical period of hippocampal development contributes to the abnormal hippocampal function and connectivity seen in UPS and LB later in life.

Short paragraphs that describe gene function, referred to as gene summaries, are valued by users of biological knowledgebases for the ease with which they convey key aspects of gene function. Manual curation of gene summaries, while desirable, is difficult for knowledgebases to sustain. We developed an algorithm that uses curated, structured gene data at the Alliance of Genome Resources (Alliance; www.alliancegenome.org) to automatically generate gene summaries that simulate natural language. The gene data used for this purpose include curated associations (annotations) to ontology terms from the Gene Ontology, Disease Ontology, model organism knowledgebase (MOK)-specific anatomy ontologies and Alliance orthology data. The method uses sentence templates for each data category included in the gene summary in order to build a natural language sentence from the list of terms associated with each gene. To improve readability of the summaries when numerous gene annotations are present, we developed a new algorithm that traverses ontology graphs in order to group terms by their common ancestors. The algorithm optimizes the coverage of the initial set of terms and limits the length of the final summary, using measures of information content of each ontology term as a criterion for inclusion in the summary. The automated gene summaries are generated with each Alliance release, ensuring that they reflect current data at the Alliance. Our method effectively leverages category-specific curation efforts of the Alliance member databases to create modular, structured and standardized gene summaries for seven member species of the Alliance. These automatically generated gene summaries make cross-species gene function comparisons tenable and increase discoverability of potential models of human disease. In addition to being displayed on Alliance gene pages, these summaries are also included on several MOK gene pages.

We show that a binary oncolytic/helper-dependent adenovirus (CAdVEC) that both lyses tumor cells and locally expresses the proinflammatory cytokine IL-12 and PD-L1 blocking antibody has potent antitumor activity in humanized mouse models. On the basis of these preclinical studies, we treated four patients with a single intratumoral injection of an ultralow dose of CAdVEC (NCT03740256), representing a dose of oncolytic adenovirus more than 100-fold lower than used in previous trials. While CAdVEC caused no significant toxicities, it repolarized the tumor microenvironment with increased infiltration of CD8 T cells. A single administration of CAdVEC was associated with both locoregional and abscopal effects on metastases and, in combination with systemic administration of immune checkpoint antibodies, induced sustained antitumor responses, including one complete and two partial responses. Hence, in both preclinical and clinical studies, CAdVEC is safe and even at extremely low doses is sufficiently potent to induce significant tumor control through oncolysis and immune repolarization.

WormBase (www.wormbase.org) has been serving the scientific community for over 11 years as the central repository for genomic and genetic information for the soil nematode Caenorhabditis elegans. The resource has evolved from its beginnings as a database housing the genomic sequence and genetic and physical maps of a single species, and now represents the breadth and diversity of nematode research, currently serving genome sequence and annotation for around 20 nematodes. In this article, we focus on WormBase's role of genome sequence annotation, describing how we annotate and integrate data from a growing collection of nematode species and strains. We also review our approaches to sequence curation, and discuss the impact on annotation quality of large functional genomics projects such as modENCODE.

WormBase (http://www.wormbase.org/) is a highly curated resource dedicated to supporting research using the model organism Caenorhabditis elegans. With an electronic history predating the World Wide Web, WormBase contains information ranging from the sequence and phenotype of individual alleles to genome-wide studies generated using next-generation sequencing technologies. In recent years, we have expanded the contents to include data on additional nematodes of agricultural and medical significance, bringing the knowledge of C. elegans to bear on these systems and providing support for underserved research communities. Manual curation of the primary literature remains a central focus of the WormBase project, providing users with reliable, up-to-date and highly cross-linked information. In this update, we describe efforts to organize the original atomized and highly contextualized curated data into integrated syntheses of discrete biological topics. Next, we discuss our experiences coping with the vast increase in available genome sequences made possible through next-generation sequencing platforms. Finally, we describe some of the features and tools of the new WormBase Web site that help users better find and explore data of interest.

With a large increase in the volume and type of data archived in GigaScience Database (GigaDB) since its launch in 2011, we have studied the metrics and user patterns to assess the important aspects needed to best suit current and future use. This has led to new front-end developments and enhanced interactivity and functionality that greatly improve user experience. In this article, we present an overview of the current practices including the Biocurational role of the GigaDB staff, the broad usage metrics of GigaDB datasets and an update on how the GigaDB platform has been overhauled and enhanced to improve the stability and functionality of the codebase. Finally, we report on future directions for the GigaDB resource.

WormBase (www.wormbase.org) is a central repository for research data on the biology, genetics and genomics of Caenorhabditis elegans and other nematodes. The project has evolved from its original remit to collect and integrate all data for a single species, and now extends to numerous nematodes, ranging from evolutionary comparators of C. elegans to parasitic species that threaten plant, animal and human health. Research activity using C. elegans as a model system is as vibrant as ever, and we have created new tools for community curation in response to the ever-increasing volume and complexity of data. To better allow users to navigate their way through these data, we have made a number of improvements to our main website, including new tools for browsing genomic features and ontology annotations. Finally, we have developed a new portal for parasitic worm genomes. WormBase ParaSite (parasite.wormbase.org) contains all publicly available nematode and platyhelminth annotated genome sequences, and is designed specifically to support helminth genomic research.

Failure to detect co-expression of estrogen receptor-alpha (ERalpha) and proliferation 'markers' such as Ki67 in human mammary epithelium led to the view that estrogen acts indirectly to stimulate mammary epithelial proliferation. The mitotic index was so low in prior studies, however, that transient co-expression of ERalpha and Ki67 during the cell cycle could have been below detection limits.

Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1-/- hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.

Frailty is a prevalent condition among Canadians; over one million are diagnosed as medically frail, and in the next ten years this number will double. Information and telecommunication technologies can provide a low-cost method for managing frailty more proactively. This study aims to examine the range and extent of information and telecommunication technologies for managing frailty in older adults, their technology readiness level, the evidence, and the associated outcomes. A systematic literature review was conducted. Four databases were searched for studies: Medline, EMBASE, CINAHL, and Web of Science. In total, we included 19 studies (out of 9,930) for the data abstraction. Overall, our findings indicate that (1) the proposed frailty phenotype is the most common ground truth to be used for assessing frailty; (2) the most common uses of information and telecommunication technologies for managing frailty are detection, and monitoring and detection, while interventional studies on frailty are very rare; (3) the five main types of information and telecommunication technologies for managing frailty in older adults are information and telecommunication technology-based platforms, smartphones, telemonitoring (home monitoring), wearable sensors and devices (commercial off-the-shelf), and multimedia formats for online access; (4) the technology readiness level of information and telecommunication technologies for managing frailty in older adults is the "Technology Demonstration" level, i.e., not yet ready to be operated in an actual operating environment; and (5) the level of evidence is still low for information and telecommunication technology studies that manage frailty in older adults. In conclusion, information and telecommunication technologies for managing frailty in the older adult population are not yet ready to be full-fledged technologies for this purpose.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a 5-year survival rate of 6% following a diagnosis, and novel therapeutic modalities are needed. Protease-activated receptor 1 (PAR1) is abundantly overexpressed by both tumor cells and multiple stroma cell subsets in the tumor microenvironment (TME), thereby offering a suitable immunotherapy target.

The mechanisms by which childhood maltreatment increases anxiety is unclear, but a propensity for increased defensive behavior in rodent models of early life stress (ELS) suggests that work in rodents may clarify important mechanistic details about this association. A key challenge in studying the effects of ELS on defensive behavior in rodents is the plethora of inconsistent results. This is particularly prominent with the maternal separation (MS) literature, one of the most commonly used ELS models in rodents. To address this issue we conducted a systematic review and meta-analysis, examining the effects of MS on exploratory-defensive behavior in mice and rats using the open field test (OFT) and the elevated plus maze (EPM). This search yielded a total of 49 studies, 24 assessing the effect of MS on behavior in the EPM, 11 tested behavior in the OFT, and 14 studies provided data on both tasks. MS was associated with increased defensive behavior in rats (EPM: Hedge's g = -0.48, p = 0.02; OFT: Hedge's g = -0.33, p = 0.05), effect sizes that are consistent with the anxiogenic effect of early adversity reported in humans. In contrast, MS did not alter exploratory behavior in mice (EPM: Hedge's g = -0.04, p = 0.75; OFT: Hedge's g = -0.03, p = 0.8). There was a considerable amount of heterogeneity between studies likely related to the lack of standardization of the MS protocol. Together, these findings suggest important differences in the ability of MS to alter circuits that regulate defensive behaviors in mice and rats.

Acute retinal necrosis is a rare yet devastating disease, with significant ocular morbidity. Over the past several decades, initial treatment regimens have shifted from intravenous antivirals requiring hospital admission to the routine use of oral antivirals with intravitreal antivirals for immediate local control. Given the rarity of this disease process and a lack of large-scale research trials, debate continues over recommended practice guidelines. In this paper, we review current diagnostic criteria and recommend a treatment algorithm based on available evidence.

WormBase (https://wormbase.org/) is a mature Model Organism Information Resource supporting researchers using the nematode Caenorhabditis elegans as a model system for studies across a broad range of basic biological processes. Toward this mission, WormBase efforts are arranged in three primary facets: curation, user interface and architecture. In this update, we describe progress in each of these three areas. In particular, we discuss the status of literature curation and recently added data, detail new features of the web interface and options for users wishing to conduct data mining workflows, and discuss our efforts to build a robust and scalable architecture by leveraging commercial cloud offerings. We conclude with a description of WormBase's role as a founding member of the nascent Alliance of Genome Resources.

Exposure to early life stress (ELS) causes abnormal hippocampal development and functional deficits in rodents and humans, but no meta-analysis has been used yet to quantify the effects of different rodent models of ELS on hippocampal-dependent memory. We searched PubMed and Web of Science for publications that assessed the effects of handling, maternal separation (MS), and limited bedding and nesting (LBN) on performance in the Morris water maze (MWM), novel object recognition (NOR), and contextual fear conditioning (CFC). Forty-five studies met inclusion criteria (n = 451-763 rodents per test) and were used to calculate standardized mean differences (Hedge's g) and to assess heterogeneity, publication bias, and the moderating effects of sex and species (rats vs. mice). We found significantly lower heterogeneity in LBN compared to handling and MS with no consistent effects of sex or species across the three paradigms. LBN and MS caused similar cognitive deficits in tasks that rely heavily on the dorsal hippocampus, such as MWM and NOR, and were significantly different compared to the improved performance seen in rodents exposed to handling. In the CFC task, which relies more on the ventral hippocampus, all three paradigms showed reduced freezing with moderate effect sizes that were not statistically different. These findings demonstrate the utility of using meta-analysis to quantify outcomes in a large number of inconsistent preclinical studies and highlight the need to further investigate the possibility that handling causes different alterations in the dorsal hippocampus but similar outcomes in the ventral hippocampus when compared to MS and LBN.

Ensembl Genomes (http://www.ensemblgenomes.org) is an integrating resource for genome-scale data from non-vertebrate species. The project exploits and extends technologies for genome annotation, analysis and dissemination, developed in the context of the vertebrate-focused Ensembl project, and provides a complementary set of resources for non-vertebrate species through a consistent set of programmatic and interactive interfaces. These provide access to data including reference sequence, gene models, transcriptional data, polymorphisms and comparative analysis. This article provides an update to the previous publications about the resource, with a focus on recent developments. These include the addition of important new genomes (and related data sets) including crop plants, vectors of human disease and eukaryotic pathogens. In addition, the resource has scaled up its representation of bacterial genomes, and now includes the genomes of over 9000 bacteria. Specific extensions to the web and programmatic interfaces have been developed to support users in navigating these large data sets. Looking forward, analytic tools to allow targeted selection of data for visualization and download are likely to become increasingly important in future as the number of available genomes increases within all domains of life, and some of the challenges faced in representing bacterial data are likely to become commonplace for eukaryotes in future.