Workshop on Learning and Evaluating Recommendations with Impressions (LERI)

Recommender systems typically rely on past user interactions as the primary source of information for making predictions. However, although highly informative, past user interactions are strongly biased. Impressions, on the other hand, are a new source of information that indicate the items displayed on screen when the user interacted (or not) with them, and have the potential to impact the field of recommender systems in several ways. Early research on impressions was constrained by the limited availability of public datasets, but this is rapidly changing and, as a consequence, interest in impressions has increased. Impressions present new research questions and opportunities, but also bring new challenges. Several works propose to use impressions as part of recommender models in various ways and discuss their information content. Others explore their potential in off-policy-estimation and reinforcement learning. Overall, the interest of the community is growing, but efforts in this direction remain disconnected. Therefore, we believe that a workshop would be useful in bringing the community together

Stability of the antimalarial drug dihydroartemisinin in under physiologically-relevant conditions : implications for clinical treatment, pharmacokinetic and in vitro assays

Artemisinins are peroxidic antimalarial drugs known to be very potent but chemically highly unstable; they degrade in the presence of ferrous iron, Fe(II)-heme or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is both an antimalarial drug on its own and the main metabolite of other artemisinins. The behavior of DHA in PBS, plasma or erythrocytes lysate at different temperatures and pH ranges was examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on P. falciparum, and the extent of decomposition of DHA was established through use of HPLC-ECD analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide. A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocytes lysate: activity was reduced by half after 3 hours and almost completely abolished after 24 hours. Serum-enriched media also affected DHA activity. Effects were temperature and pH-dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as they are to experimental and drug storage conditions. Disorders such as fever, hemolysis or acidosis associated with malaria severity may contribute to artemisinins instability and reduce their clinical efficacy

Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody-“decoy” strategy

MET, a master gene sustaining "invasive growth," is a relevant target for cancer precision therapy. In the vast majority of tumors, wild-type MET behaves as a "stress-response" gene and relies on the ligand (HGF) to sustain cell "scattering," invasive growth and apoptosis protection (oncogene "expedience"). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti-MET antibody (MvDN30) inducing "shedding" (i.e., removal of MET from the cell surface), with a "decoy" (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction-and subsequent neutralization-we identified a single aminoacid in the extracellular domain of MET-lysine 842-that is critical for MvDN30 binding and engineered the corresponding recombinant decoyMET (K842E). DecoyMET(K842E) retains the ability to bind HGF with high affinity and inhibits HGF-induced MET phosphorylation. In HGF-dependent cellular models, MvDN30 antibody and decoyMET(K842E) used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell "scattering." The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In a preclinical model, built by orthotopic transplantation of a human pancreatic carcinoma in SCID mice engineered to express human HGF, concomitant treatment with antibody and decoy significantly reduces metastatic spread. The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand-dependent MET activation, providing proof of concept in favor of combined target therapy of MET "expedience.

From pre-and probiotics to post-biotics: A narrative review

Background and aims: Gut microbiota (GM) is a complex ecosystem containing bacteria, viruses, fungi, and yeasts. It has several functions in the human body ranging from immunomodulation to metabolic. GM derangement is called dysbiosis and is involved in several host diseases. Pre-, probiotics, and symbiotics (PRE-PRO-SYMB) have been extensively developed and studied for GM re-modulation. Herein, we review the literature data regarding the new concept of postbiotics, starting from PRE-PRO-SYMB. Methods: We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials, and case series using the following keywords and acronyms and their associations: Gut microbiota, prebiotics, probiotics, symbiotic, and postbiotics. Results: Postbiotics account for PRO components and metabolic products able to beneficially affect host health and GM. The deeper the knowledge about them, the greater their possible uses: The prevention and treatment of atopic, respiratory tract, and inflammatory bowel diseases. Conclusions: Better knowledge about postbiotics can be useful for the prevention and treatment of several human body diseases, alone or as an add-on to PRE-PRO-SYMB

Phagocytosis of hemozoin (native and synthetic malaria pigment), and Plasmodium falciparum intraerythrocyte-stage parasites by human and mouse phagocytes

Hemozoin, the detoxification product of hemoglobin heme, piles up as electron-dense material in the food vacuole (FV) of intraerythrocytic malaria parasites (malaria pigment). In infected individuals, pigment is internalized by both circulating and resident phagocytes, thus modulating their functions. Synthetic beta-hematin, prepared in vitro from hematin (ferriprotoporphyrin IX hydroxide) in acidic condition, is spectroscopically identical to hemozoin. In this electron microscopy study, native and synthetic hemozoin also prove to be morphologically indistinguishable (large polygonal crystals with apparent transverse banding) and to undergo the same process when internalized by phagocytes (primarily a direct uptake of crystals, similar to what is described for asbestos fibers). On the contrary, whole parasites appear to follow a classical endocytic pathway. This suggests that there may be differences between the ingestion of free particles and whole parasites in terms of modulation of phagocytes' functions

Gene and protein expression in response to different growth temperatures and oxygen availability in Burkholderia thailandensis.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Public Library of Science via the DOI in this record.Burkholderia thailandensis, although normally avirulent for mammals, can infect macrophages in vitro and has occasionally been reported to cause pneumonia in humans. It is therefore used as a model organism for the human pathogen B. pseudomallei, to which it is closely related phylogenetically. We characterized the B. thailandensis clinical isolate CDC2721121 (BtCDC272) at the genome level and studied its response to environmental cues associated with human host colonization, namely, temperature and oxygen limitation. Effects of the different growth conditions on BtCDC272 were studied through whole genome transcription studies and analysis of proteins associated with the bacterial cell surface. We found that growth at 37°C, compared to 28°C, negatively affected cell motility and flagella production through a mechanism involving regulation of the flagellin-encoding fliC gene at the mRNA stability level. Growth in oxygen-limiting conditions, in contrast, stimulated various processes linked to virulence, such as lipopolysaccharide production and expression of genes encoding protein secretion systems. Consistent with these observations, BtCDC272 grown in oxygen limitation was more resistant to phagocytosis and strongly induced the production of inflammatory cytokines from murine macrophages. Our results suggest that, while temperature sensing is important for regulation of B. thailandensis cell motility, oxygen limitation has a deeper impact on its physiology and constitutes a crucial environmental signal for the production of virulence factors.This work was supported by Fondazione CARIPLO (Progetto Vaccini, contract number 2009–3577) and by Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (project FIRB RBLA039LSF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

TOpic: rare and special cases, the real "Strange cases"

Introduction: The bladder hernia represents approximately 1-3% of all inguinal hernias, where patients aged more than 50 years have a higher incidence (10%). Many factors contribute to the development of a bladder hernia, including the presence of a urinary outlet obstruction causing chronic bladder distention, the loss of bladder tone, pericystitis, the perivesical bladder fat protrusion and the obesity

Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1

Serpinb1 is an inhibitor of neutrophil granule serine proteases cathepsin G, proteinase-3 and elastase. One of its core physiological functions is to protect neutrophils from granule protease-mediated cell death. Mice lacking Serpinb1a (Sb1a-/-), its mouse ortholog, have reduced bone marrow neutrophil numbers due to cell death mediated by cathepsin G and the mice show increased susceptibility to lung infections. Here, we show that conditional deletion of Serpinb1a using the Lyz2-cre and Cebpa-cre knock-in mice effectively leads to recombination-mediated deletion in neutrophils but protein-null neutrophils were only obtained using the latter recombinase-expressing strain. Absence of Serpinb1a protein in neutrophils caused neutropenia and increased granule permeabilization-induced cell death. We then generated transgenic mice expressing human Serpinb1 in neutrophils under the human MRP8 (S100A8) promoter. Serpinb1a expression levels in founder lines correlated positively with increased neutrophil survival when crossed with Sb1a-/- mice, which had their defective neutrophil phenotype rescued in the higher expressing transgenic line. Using new conditional and transgenic mouse models, our study demonstrates the presence of a relatively low Serpinb1a protein threshold in neutrophils that is required for sustained survival. These models will also be helpful in delineating recently described functions of Serpinb1 in metabolism and cancer