What Makes a Top-Performing Precision Medicine Search Engine? Tracing Main System Features in a Systematic Way

From 2017 to 2019 the Text REtrieval Conference (TREC) held a challenge task on precision medicine using documents from medical publications (PubMed) and clinical trials. Despite lots of performance measurements carried out in these evaluation campaigns, the scientific community is still pretty unsure about the impact individual system features and their weights have on the overall system performance. In order to overcome this explanatory gap, we first determined optimal feature configurations using the Sequential Model-based Algorithm Configuration (SMAC) program and applied its output to a BM25-based search engine. We then ran an ablation study to systematically assess the individual contributions of relevant system features: BM25 parameters, query type and weighting schema, query expansion, stop word filtering, and keyword boosting. For evaluation, we employed the gold standard data from the three TREC-PM installments to evaluate the effectiveness of different features using the commonly shared infNDCG metric.Comment: Accepted for SIGIR2020, 10 page

The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner

All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly. When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation

IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression

Immune checkpoint blockade therapy induces the AHR-activating enzyme IL4I1, which promotes tumor progression, through its effects on tumor cell motility and adaptive immunity

ADOnIS - An ontology-based information system providing seamless integration of structured and unstructured data

The CRC AquaDiva is a large collaborative project spanning a variety of domains, such as biology, geology, chemistry, and computer science with the common goal to better understand the Earth's critical zone in particular how environmental conditions and surface properties shape the structure, properties, and functions of the subsurface. This necessitates the collection and integration of large volumes of heterogeneous data. Besides this structured data, knowledge is also encoded in an unstructured form in publications. Ideally, scientists should be able to seamlessly access both types of information. To this end, we are developing the AquaDiva Ontology-based Information System, ADOnIS. This system gives scientists various ways to upload their datasets into a common repository based on the BExIS framework. To enhance the integration process and to resolve conflicts among heterogeneous datasets, we build a conceptual, ontology-based layer on top of the common repository. Finally, the system grants different mechanisms to search and look for a specific piece of information and/or knowledge, including keyword search, semantic search, and interactive search. In all cases, search results will contain structured data as well as publications obtained from PubMed by using SeMedico. The normal search provides the possibility for a scientist to enter a keyword (or a set of keywords) looking for the existence of this keyword either in the set of available metadata or primary data applying an exact match technique. This kind of search completely ignores the semantics of keywords as well as their relationships. Therefore, ADOnIS also provides semantic search exploiting features introduced by the conceptual layer. Finally, interactive search offers a view covering all the geo-related datasets displayed on a map

ADOnIS: An ontology-based information system providing seamless integration of structured and unstructured data

Scientific information is contained in structured data like spreadsheets as well as in unstructured data like text. For example, scientific results can manifest themselves in one or more data sets containing main characteristics of the scientific process and one or more publications related to the dataset(s). From a scientist's perspective, it is desirable to obtain seamless access to this information regardless of whether it is based on structured or unstructured data. To this end, we developed and continuously extend the AquaDiva Ontology-based Information System, ADOnIS, which endeavors to provide such functionality

Phosphoproteomics Profiling Defines a Target Landscape of the Basophilic Protein Kinases AKT, S6K, and RSK in Skeletal Myotubes

Phosphorylation-dependent signal transduction plays an important role in regulating the functions and fate of skeletal muscle cells. Central players in the phospho-signaling network are the protein kinases AKT, S6K, and RSK as part of the PI3K-AKT-mTOR-S6K and RAF-MEK-ERK-RSK pathways. However, despite their functional importance, knowledge about their specific targets is incomplete because these kinases share the same basophilic substrate motif RxRxxp[ST]. To address this, we performed a multifaceted quantitative phosphoproteomics study of skeletal myotubes following kinase inhibition. Our data corroborate a cross talk between AKT and RAF, a negative feedback loop of RSK on ERK, and a putative connection between RSK and PI3K signaling. Altogether, we report a kinase target landscape containing 49 so far unknown target sites. AKT, S6K, and RSK phosphorylate numerous proteins involved in muscle development, integrity, and functions, and signaling converges on factors that are central for the skeletal muscle cytoskeleton. Whereas AKT controls insulin signaling and impinges on GTPase signaling, nuclear signaling is characteristic for RSK. Our data further support a role of RSK in glucose metabolism. Shared targets have functions in RNA maturation, stability, and translation, which suggests that these basophilic kinases establish an intricate signaling network to orchestrate and regulate processes involved in translation

Hypothermia versus normothermia after out-of-hospital cardiac arrest

BACKGROUND Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.)