A human kidney and liver organoid-based multi-organ-on-a-chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell-derived extracellular vesicles.

Mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs) show therapeutic potential in multiple disease models, including kidney injury. Clinical translation of sEVs requires further preclinical and regulatory developments, including elucidation of the biodistribution and mode of action (MoA). Biodistribution can be determined using labelled sEVs in animal models which come with ethical concerns, are time-consuming and expensive, and may not well represent human physiology. We hypothesised that, based on developments in microfluidics and human organoid technology, in vitro multi-organ-on-a-chip (MOC) models allow us to study effects of sEVs in modelled human organs like kidney and liver in a semi-systemic manner. Human kidney- and liver organoids combined by microfluidic channels maintained physiological functions, and a kidney injury model was established using hydrogenperoxide. MSC-sEVs were isolated, and their size, density and potential contamination were analysed. These sEVs stimulated recovery of the renal epithelium after injury. Microscopic analysis shows increased accumulation of PKH67-labelled sEVs not only in injured kidney cells, but also in the unharmed liver organoids, compared to healthy control conditions. In conclusion, this new MOC model recapitulates therapeutic efficacy and biodistribution of MSC-sEVs as observed in animal models. Its human background allows for in-depth analysis of the MoA and identification of potential side effects.

Logic-gated antibody pairs that selectively act on cells co-expressing two antigens.

The use of therapeutic monoclonal antibodies is constrained because single antigen targets often do not provide sufficient selectivity to distinguish diseased from healthy tissues. We present HexElect®, an approach to enhance the functional selectivity of therapeutic antibodies by making their activity dependent on clustering after binding to two different antigens expressed on the same target cell. lmmunoglobulin G (lgG)-mediated clustering of membrane receptors naturally occurs on cell surfaces to trigger complement- or cell-mediated effector functions or to initiate intracellular signaling. We engineer the Fc domains of two different lgG antibodies to suppress their individual homo-oligomerization while promoting their pairwise hetero-oligomerization after binding co-expressed antigens. We show that recruitment of complement component C1q to these hetero-oligomers leads to clustering-dependent activation of effector functions such as complement mediated killing of target cells or activation of cell surface receptors. HexElect allows selective antibody activity on target cells expressing unique, potentially unexplored combinations of surface antigens.

An efficient method to prepare supported bismuth nanoparticles as highly selective electrocatalyst for the conversion of CO2 into formate.

We report a cost-effective, straightforward synthesis of a novel electrocatalyst for the reduction of CO2 to formate, which achieves nearly complete Faradaic efficiency (FE) at an overpotential (η) of 0.88 V under ambient conditions. The electrocatalyst was prepared using bismuth subsalicylate as precursor and consists of bismuth nanoparticles (Bi NPs) with an average diameter of 5.5 nm supported on activated carbon.

Recent Advances in Extracellular Vesicles as Drug Delivery Systems and Their Potential in Precision Medicine.

Extracellular vesicles (EVs) are membrane-bilayered nanoparticles released by most cell types. Recently, an enormous number of studies have been published on the potential of EVs as carriers of therapeutic agents. In contrast to systems such as liposomes, EVs exhibit less immunogenicity and higher engineering potential. Here, we review the most relevant publications addressing the potential and use of EVs as a drug delivery system (DDS). The information is divided based on the key steps for designing an EV-mediated delivery strategy. We discuss possible sources and isolation methods of EVs. We address the administration routes that have been tested in vivo and the tissue distribution observed. We describe the current knowledge on EV clearance, a significant challenge towards enhancing bioavailability. Also, EV-engineering approaches are described as alternatives to improve tissue and cell-specificity. Finally, a summary of the ongoing clinical trials is performed. Although the application of EVs in the clinical practice is still at an early stage, a high number of studies in animals support their potential as DDS. Thus, better treatment options could be designed to precisely increase target specificity and therapeutic efficacy while reducing off-target effects and toxicity according to the individual requirements of each patient.

Dual Epitope Targeting and Enhanced Hexamerization by DR5 Antibodies as a Novel Approach to Induce Potent Antitumor Activity Through DR5 Agonism.

Higher-order death receptor 5 (DR5) clustering can induce tumor cell death; however, therapeutic compounds targeting DR5 have achieved limited clinical efficacy. We describe HexaBody-DR5/DR5, an equimolar mixture of two DR5-specific IgG1 antibodies with an Fc-domain mutation that augments antibody hexamerization after cell surface target binding. The two antibodies do not compete for binding to DR5 as demonstrated using binding competition studies, and binding to distinct epitopes in the DR5 extracellular domain was confirmed by crystallography. The unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent DR5 agonist activity by inducing efficient DR5 outside-in signaling and caspase-mediated cell death. Preclinical studies in vitro and in vivo demonstrated that maximal DR5 agonist activity could be achieved independent of Fc gamma receptor-mediated antibody crosslinking. Most optimal agonism was observed in the presence of complement complex C1, although without inducing complement-dependent cytotoxicity. It is hypothesized that C1 may stabilize IgG hexamers that are formed after binding of HexaBody-DR5/DR5 to DR5 on the plasma membrane, thereby strengthening DR5 clustering and subsequent outside-in signaling. We observed potent antitumor activity in vitro and in vivo in large panels of patient-derived xenograft models representing various solid cancers. The results of our preclinical studies provided the basis for an ongoing clinical trial exploring the activity of HexaBody-DR5/DR5 (GEN1029) in patients with malignant solid tumors.

Detection of Barrett's oesophagus through exhaled breath using an electronic nose device.

Timely detection of oesophageal adenocarcinoma (OAC) and even more so its precursor Barrett's oesophagus (BO) could contribute to decrease OAC incidence and mortality. An accurate, minimally-invasive screening method for BO for widespread use is currently not available. In a proof-of-principle study in 402 patients, we developed and cross-validated a BO prediction model using volatile organic compounds (VOCs) analysis with an electronic nose device. This electronic nose was able to distinguish between patients with and without BO with good diagnostic accuracy (sensitivity 91% specificity 74%) and seemed to be independent of proton pump inhibitor use, the presence of hiatal hernia, and reflux. This technique may enable an efficient, well-tolerated, and sensitive and specific screening method to select high-risk individuals to undergo upper endoscopy.

DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing.

BACKGROUND: DuoBody®-CD3xCD20 (GEN3013) is a full-length human IgG1 bispecific antibody (bsAb) recognizing CD3 and CD20, generated by controlled Fab-arm exchange. Its Fc domain was silenced by introduction of mutations L234F L235E D265A. METHODS: T-cell activation and T-cell-mediated cytotoxicity were measured by flow cytometry following co-culture with tumour cells. Anti-tumour activity of DuoBody-CD3xCD20 was assessed in humanized mouse models in vivo. Non-clinical safety studies were performed in cynomolgus monkeys. FINDINGS: DuoBody-CD3xCD20 induced highly potent T-cell activation and T-cell-mediated cytotoxicity towards malignant B cells in vitro. Comparison of DuoBody-CD3xCD20 to CD3 bsAb targeting alternative B-cell antigens, or to CD3xCD20 bsAb generated using alternative CD20 Ab, emphasized its exceptional potency. In vitro comparison with other CD3xCD20 bsAb in clinical development showed that DuoBody-CD3xCD20 was significantly more potent than three other bsAb with single CD3 and CD20 binding regions and equally potent as a bsAb with a single CD3 and two CD20 binding regions. DuoBody-CD3xCD20 showed promising anti-tumour activity in vivo, also in the presence of excess levels of a CD20 Ab that competes for binding. In cynomolgus monkeys, DuoBody-CD3xCD20 demonstrated profound and long-lasting B-cell depletion from peripheral blood and lymphoid organs, which was comparable after subcutaneous and intravenous administration. Peak plasma levels of DuoBody-CD3xCD20 were lower and delayed after subcutaneous administration, which was associated with a reduction in plasma cytokine levels compared to intravenous administration, while bioavailability was comparable. INTERPRETATION: Based on these preclinical studies, a clinical trial was initiated to assess the clinical safety of subcutaneous DuoBody-CD3xCD20 in patients with B-cell malignancies. FUNDING: Genmab.

Satellite cells maintain regenerative capacity but fail to repair disease-associated muscle damage in mice with Pompe disease.

Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa-/- satellite cells to regenerate muscle damage. Gaa-/- mice showed progressive muscle pathology from 15 weeks of age as reflected by increased lysosomal size, decreased fiber diameter and reduced muscle wet weight. Only during the first 15 weeks of life but not thereafter, we detected a gradual increase in centrally nucleated fibers and proliferating satellite cells in Gaa-/- muscle, indicating a mild regenerative response. The levels of Pax7-positive satellite cells were increased in Gaa-/- mice at all ages, most likely as result of enhanced satellite cell activation in young Gaa-/- animals. Surprisingly, both young and old Gaa-/- mice regenerated experimentally-induced muscle injury efficiently as judged by rapid satellite cell activation and complete restoration of muscle histology. In response to serial injury, Gaa-/- mice also regenerated muscle efficiently and maintained the satellite cell pool. These findings suggest that, similar to human patients, Gaa-/- mice have insufficient satellite cell activation and muscle regeneration during disease progression. The initial endogenous satellite cell response in Gaa-/- mice may contribute to the delayed onset of muscle wasting compared to human patients. The rapid and efficient regeneration after experimental muscle injury suggest that Gaa-/- satellite cells are functional stem cells, opening avenues for developing muscle regenerative therapies for Pompe disease.

Why and when hierarchy impacts team effectiveness: A meta-analytic integration.

Hierarchy has the potential to both benefit and harm team effectiveness. In this article, we meta-analytically investigate different explanations for why and when hierarchy helps or hurts team effectiveness, drawing on results from 54 prior studies (N = 13,914 teams). Our findings show that, on net, hierarchy negatively impacts team effectiveness (performance: ρ = -.08; viability: ρ = -.11), and that this effect is mediated by increased conflict-enabling states. Additionally, we show that the negative relationship between hierarchy and team performance is exacerbated by aspects of the team structure (i.e., membership instability, skill differentiation) and the hierarchy itself (i.e., mutability), which make hierarchical teams prone to conflict. The predictions regarding the positive effect of hierarchy on team performance as mediated by coordination-enabling processes, and the moderating roles of several aspects of team tasks (i.e., interdependence, complexity) and the hierarchy (i.e., form) were not supported, with the exception that task ambiguity enhanced the positive effects of hierarchy. Given that our findings largely support dysfunctional views on hierarchy, future research is needed to understand when and why hierarchy may be more likely to live up to its purported functional benefits. (PsycINFO Database Record

Trust and team performance: A meta-analysis of main effects, moderators, and covariates.

Cumulating evidence from 112 independent studies (N = 7,763 teams), we meta-analytically examine the fundamental questions of whether intrateam trust is positively related to team performance, and the conditions under which it is particularly important. We address these questions by analyzing the overall trust-performance relationship, assessing the robustness of this relationship by controlling for other relevant predictors and covariates, and examining how the strength of this relationship varies as a function of several moderating factors. Our findings confirm that intrateam trust is positively related to team performance, and has an above-average impact (ρ = .30). The covariate analyses show that this relationship holds after controlling for team trust in leader and past team performance, and across dimensions of trust (i.e., cognitive and affective). The moderator analyses indicate that the trust-performance relationship is contingent upon the level of task interdependence, authority differentiation, and skill differentiation in teams. Finally, we conducted preliminary analyses on several emerging issues in the literature regarding the conceptualization and measurement of trust and team performance (i.e., referent of intrateam trust, dimension of performance, performance objectivity). Together, our findings contribute to the literature by helping to (a) integrate the field of intrateam trust research, (b) resolve mixed findings regarding the trust-performance relationship, (c) overcome scholarly skepticism regarding the main effect of trust on team performance, and (d) identify the conditions under which trust is most important for team performance. (PsycINFO Database Record

Papillary fill response in single-tooth implants using abutments of different geometry.

OBJECTIVE: To evaluate the influence of abutment geometry on papillary fill in the esthetic zone in a delayed crown protocol. MATERIALS AND METHODS: Twenty-six subjects received two non-adjacent endosseous implants in the esthetic zone. Functional temporary crowns were installed 17-19 weeks later, using conventional (control) and curved (experimental) abutments. The abutments were randomized in each patient independently. Final crowns were cemented after 2 months (T0). Standard intraoral photographs and radiographs were made to evaluate papillary fill after 12 months (T12). The interproximal papilla fill was measured by means of the papilla index score (PIS) and related to the maximum bone level between the implant and the adjacent root as well as the peri-implant marginal bone level at T12, both measured radiographically. RESULTS: No statistically significant difference between the experimental and the control group could be demonstrated (P = 0.25). Ordinal regression analysis showed a positive correlation between the maximum bone level and papilla fill (P < 0.01) and a negative correlation between the peri-implant marginal bone level and papilla fill (P < 0.05). CONCLUSION: A concave abutment does not exhibit a better fill of the papilla compared with a straight abutment in single-tooth implant placement using a delayed protocol in the esthetic zone after 12 months of function.

Beyond shared perceptions of trust and monitoring in teams: implications of asymmetry and dissensus.

Past research has implicitly assumed that only mean levels of trust and monitoring in teams are critical for explaining their interrelations and their relationships with team performance. In this article, the authors argue that it is equally important to consider the dispersion in trust and monitoring that exists within teams. The authors introduce "trust asymmetry" and "monitoring dissensus" as critical dispersion properties of trust and monitoring and hypothesize that these moderate the relationships between mean monitoring, mean trust, and team performance. Data from a cross-lagged panel study and a partially lagged study support the hypotheses. The first study also offered support for an integrative model that includes mean and dispersion levels of both trust and monitoring. Overall, the studies provide a comprehensive and clear picture of how trust and monitoring emerge and function at the team level via mean and dispersion.