In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses. Using a novel clinical-stage anti-ICOS immunoglobulin G4 mAb (feladilimab), which induces but does not deplete ICOS+ T cells and their rodent analogs, we provide an end-to-end evaluation of the antitumor potential of antibody-mediated ICOS costimulation alone and in combination with programmed cell death protein 1 (PD-1) blockade. We demonstrate, consistently, that ICOS is expressed in a range of cancers, and its induction can stimulate growth of antitumor reactive T cells. Furthermore, feladilimab, alone and with a PD-1 inhibitor, induced antitumor activity in mouse and humanized tumor models. In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Preliminary data showing clinical benefit in patients with cancer treated with feladilimab alone or in combination with pembrolizumab was reported previously; with example cases described here. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies.Significance:Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.

Quinones are attractive pharmacological scaffolds for developing new agents for the treatment of different transmissible and non-transmissible human diseases due to their capacity to alter the cell redox homeostasis.The bioactivity and potential mode of action of 19 p-quinone derivatives fused to different aromatic rings (carbo or heterocycles) and harboring distinct substituents were investigated in infective Trypanosoma brucei brucei. All the compounds, except for a furanequinone (EC50=38 mu M), proved to be similarly or even more potent (EC50 = 0.5-5.5 mu M) than the clinical drug nifurtimox (EC50 = 5.3 mu M). Three furanequinones and one thia-zolequinone displayed a higher selectivity than nifurtimox. Two of these selective hits resulted potent inhibitors of T. cruzi proliferation (EC50=0.8-1.1 mu M) but proved inactive against Leishmania infantum amastigotes.Most of the p-quinones induced a rapid and marked intracellular oxidation in T. b. brucei. DFT calculations on the oxidized quinone (Q), semiquinone (Q center dot-) and hydroquinone (QH2) suggest that all quinones have negative Delta G for the formation of Q center dot-. Qualitative and quantitative structure-activity relationship analyses in two or three dimensions of different electronic and biophysical descriptors of quinones and their corresponding bioactivities (killing potency and oxidative capacity) were performed.Charge distribution over the quinone ring carbons of Q and Q.-and the frontier orbitals energies of SUMO (Q.-) and LUMO (Q) correlate with their oxidative and trypanocidal activity. QSAR analysis also highlighted that both bromine substitution in the p-quinone ring and a bulky phenyl group attached to the furane and thiazole rings (which generates a negative charge due to the 7C electron system polarized by the nearby heteroatoms) are favorable for activity.By combining experimental and in silico procedures, this study disclosed important information about p-qui-nones that may help to rationally tune their electronic properties and biological activities.

In the past decade, the south of Chile has experienced a considerable increase in recreational fishing, which has brought greater pressure to bear on the ecosystems. One of the more important gaps in recreational fishing management is the availability of a methodological framework that would make it possible to identify and assess areas that are suitable for developing this activity. The purpose of this research is to propose a methodology to evaluate areas with the best potential for the development of recreational fishing. The methodology is based on Spatial Multi-Criteria Analysis (SMCA) and was applied in the hydrographic basins of the Valdivia River and lake Ranco in the Los Ríos Region in the south of Chile. The application of the SMCA methodology made it possible to select six areas with a high potential for recreational fishing, which share suitable characteristics in terms of their assessed attributes: (a) landscape, (b) water quality, (c) biological yield and (d) navigability, among others. The SMCA methodology made it possible to conduct a comprehensive valuation of the natural resources, assessing not only the optimal conditions for recreational fishing but also environmental aspects such as landscape quality and accessibility, which are highly valued and essential to sustain recreational fishing activities. Thus, it is possible to provide support both to the objectives of economic development regarding recreational fishing and the goals of protecting and managing the natural environment.

Antibodies used for in vitro and in vivo assays, and experimental model

Expression dynamics and cellular localization of ICOS.

Clinical patient case studies of feladilimab monotherapy and in combination with pembrolizumab. A, Clinical history and treatment details for a patient with melanoma who received feladilimab monotherapy and a patient with oropharyngeal squamous cell carcinoma who received feladilimab in combination with pembrolizumab. Tumor sample immunohistochemistry and expression of markers for TIL activation, cytotoxic function and proliferation for the monotherapy case study (B) and the combination therapy case study (C). See Supplementary Fig. S11B for CT imaging of tumor lesions for the patient with oropharyngeal squamous cell carcinoma. CPS, combined positive score; CT, computed tomography; HLA-DR, human leukocyte antigen-DR; HPV, human papillomavirus; PD-L1, programmed death ligand-1; TIL, tumor-infiltrating lymphocyte.

Exemplar flow cytometry gating strategy.

Affinity and kinetics

Gene expression in human T-cell

Flow cytometry gating strategy for ICOS on individual T cell populations.

The Cautin river is closely related to the economic development of Temuco city, Chile, and this river has along its course different kinds of human intervention. The present study aims to characterise the benthonic macroinvertebrate communities using species co-occurrence and niche sharing null models to understand the pres-ence of a random or structured pattern in species assemblages for ten stations throughout the main course of the Cautin river from its origin to its low zones. The results of co-occurrence null model revealed that species associations are structured in one of three models, whereas two models revealed that species associations are random, whereas the results of the niche sharing null model revealed the absence of niche sharing, which would indicate the lack of interspecific competition. The obtained results provide information about the ecological structure and function in the benthos of the Cautin river, which would be similar to other descriptions for other Argentinean and Chilean Patagonian rivers.

Supplementary Figures 1-3 PDF file - 245K, Supplementary Figure 1: Dose-dependent pharmacodynamic effect of GSK2656157 on PERK in mouse pancreas. Supplementary Figure 2: Specificity of phospho-PERK antibody in mouse cells. Supplementary Figure 3: Effect of PERK inhibitor on RNA expression in tumor xenografts.

Antibodies used for in vitro and in vivo assays, and experimental model

Healthy human donor CD4+ T cells were pre-activated with antiCD3/CD28 for 48 hours and then re-stimulated with plate-bound anti-CD3 in the presence of increasing concentrations of soluble or plate-bound feladilimab or isotype control for 72 hours. IFNg levels were then assessed from cell-free supernatants using Meso Scale Discovery (MSD)-based detection.

Feladilimab induces phospho-AKT in ICOS-expressing Ba/F3 cells and cytokine production in PBMC from healthy donors and cancer patients.

Supplementary Material PDF file - 147K, Supplementary Methods: Immunohistochemistry and magnetic resonance imaging. Supplementary Table 1: Kinase selectivity profiling of GSK2656157. Supplementary Table 2: Gene list for Human UPR array

1) A large obstacle in food web ecology is the time and effort required to adequately describe the structure of a food web using individual predator guts. Food web models such as the allometric diet breadth model (ADBM) can be used to circumvent this problem by predicting the interactions based on easily measured characteristics, such as the size of organisms. However, diet data such as that which comes from analysis of predator guts is still required to parameterise these food web models, and collecting and analysing these data from the field is an expensive and time-consuming task. Therefore, it is important to know how many predator guts are required to parameterise food web models to obtain food web structures with high accuracy and precision. 2) Here, we explore seven exceptionally well-characterised food webs and determine the minimum number of predator guts needed to accurately predict their structure using the ADBM. We use Bayesian computation to parameterise the ADBM, and true skill statistics to measure the goodness of fit, and do so while varying the number of predator guts used in the parameterisation to test the effect of sampling effort. 3) We found that relatively few, and many fewer than were actually collected, predator guts can be used to parameterise the ADBM. The lowest number of predator guts was 27% of the number of available predator guts. The number of predator guts required to accurately characterise food webs increases by ---7 +/- 2.2 guts for 10 units increase in the number of trophic links and ---9 +/- 4.7 guts for a unit increase in the number of species. 4) These results suggest that one need not collect and analyse such a large quantity of predator guts in order to adequately predict the structure of a food web, thereby reducing sampling effort consid-erably, while having little effect on precision or accuracy of predictions.

Supplementary Table S1, Figures S1-2. Supplementary Table S1. Comparison of treatment outcomes between the overall study population of the COMPARZ trial and the PD-L1 study population. Supplementary Figure S1. CD8+ T cells scoring system. Supplementary Figure S2. Association of overall survival (OS) with PD-L1 expression status on tumor cell membrane.

A pseudo-three-component synthesis of N-aroylmethylimidazoles 3 with three new C–N bonds formed regioselectively under microwave conditions was developed. Products were obtained by reacting two equivalents of aroylmethyl bromide (ArCOCH2Br, 1) with the appropriate amidine salt (RCN2H3.HX, 2) and with K2CO3 as a base in acetonitrile. The bicomponent reaction also occurred, giving the expected 4(5)-aryl-1H-imidazoles 4. Notably, the ratio of products 3 and 4 is governed by steric factors of the amidine 2 (i.e., R = H, CH3, Ph). Therefore, a computational study was carried out to understand the reaction course regarding product ratio (3/4), regioselectivity, and the steric effects of the amidine substituent group.

The Cautín River is closely related with the economic development of Temuco city, (38°S; Chile). Existing knowledge of the Cautín River is limited to information about its biological characteristics as a reference for the evaluation and assessment of water quality. The object of this study was to develop taxonomic characterisation of the benthic macroinvertebrates along the main course of the Cautín River, and to study the community structure using correlation analysis between community parameters. To carry out this research, the macroinvertebrate community was studied in 10 sampling sites distributed along the main course of the river. The samples were taken in summer (1997 and 2000), when optimal hydrological conditions existed. Analysis of the samples showed that the benthic fauna was composed of 56 taxa, the dominant group being insects with 48 taxa. Three main sectors were recognised in the course of the Cautín River: high, middle and low. Each sector has restricted-distribution species, while other species are widely distributed along the river. These distribution patterns seem to be influenced by dissolved oxygen concentration, temperature, altitudinal distribution and anthropo-cultural activity, present at every sampling site. Finally, this research provides a first approach to the biology of the Cautín River. Further studies could be planned on the basis of this knowledge to investigate water quality indicators based on macroinvertebrate communities.