Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell-engaging bispecific antibody targeting human claudin 6.

We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)-formulated RNA (RNA-LNP) encoding a T cell-engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1.

The morphology, functionality, and longevity of a novel all human hepatic cell-based tri-culture system.

There remains a significant need for a convenient, phenotypically stable long-term culture platform for primary human hepatocytes (PHHs) for use in pharmacological and toxicological applications. Conventional in vitro models are often inconvenient, burdensome to use, and unable to support a multitude of donor lots or maintain PHH structural and functional properties over extended time. To address these limitations, an all-human cell-based hepatic tri-culture system (HTCS) has been developed comprised of frozen vials of PHHs and feeder cells.

Towards a digital twin for supporting multi-agency incident management in a smart city.

Cost-effective on-demand computing resources can help to process the increasing number of large, diverse datasets generated from smart internet-enabled technology, such as sensors, CCTV cameras, and mobile devices, with high temporal resolution. Category 1 emergency services (Ambulance, Fire and Rescue, and Police) can benefit from access to (near) real-time traffic- and weather data to coordinate multiple services, such as reassessing a route on the transport network affected by flooding or road incidents. However, there is a tendency not to utilise available smart city data sources, due to the heterogeneous data landscape, lack of real-time information, and communication inefficiencies.

Characterization of primary mouse hepatocyte spheroids as a model system to support investigations of drug-induced liver injury.

Primary mouse hepatocytes isolated from genetically defined and/or diverse lines and disease models are a valuable resource for studying the impact of genetic and environmental factors on drug response and disease. However, standard monolayer cultures result in a rapid decline in mouse hepatocyte viability and functionality. Therefore, we evaluated 3D spheroid methodology for long-term culture of primary mouse hepatocytes, initially to support investigations of drug-induced liver injury (DILI).

Apical root resorption after orthodontic treatment in patients with unilateral cleft lip and palate.

Objectives: The aims of this retrospective longitudinal study were to present the incidence of external apical root resorption (EARR) in the maxillary anterior teeth of patients with complete unilateral cleft lip and palate (CUCLP) and to evaluate the influence of orthodontic treatment variables on the development of EARR.

Material And Methods: Forty-one patients with CUCLP participated in the study. Orthopantomograms (OPGs), taken before (T2) treatment with multiband orthodontic appliances (MBA), and periapical radiographs (PAs) of the maxillary anterior teeth taken at the end (T3) of orthodontic treatment (OT) were assessed for EARR.

Hepatocyte-Derived Exosomes Promote Liver Immune Tolerance: Possible Implications for Idiosyncratic Drug-Induced Liver Injury.

Most idiosyncratic drug-induced liver injury appears to result from an adaptive immune attack on the liver. Recent evidence suggests that the T-cell response may be facilitated by the loss of immune tolerance. In this study, we explored the hypothesis that constitutively released hepatocyte-derived exosomes (HDE) are important for maintaining normal liver immune tolerance.

The century experiment: the first twenty years of UC Davis' Mediterranean agroecological experiment.

The Century Experiment at the Russell Ranch Sustainable Agriculture Facility at the University of California, Davis provides long-term agroecological data from row crop systems in California's Central Valley starting in 1993. The Century Experiment was initially designed to study the effects of a gradient of water and nitrogen availability on soil properties and crop performance in ten different cropping systems to measure tradeoffs and synergies between agricultural productivity and sustainability. Currently systems include 11 different cropping systems-consisting of four different crops and a cover crop mixture-and one native grass system.

miR-122 Release in Exosomes Precedes Overt Tolvaptan-Induced Necrosis in a Primary Human Hepatocyte Micropatterned Coculture Model.

Idiosyncratic drug-induced liver injury (IDILI) is thought to often result from an adaptive immune attack on the liver. However, it has been proposed that the cascade of events culminating in an adaptive immune response begins with drug-induced hepatocyte stress, release of exosomal danger signals, and innate immune activation, all of which may occur in the absence of significant hepatocelluar death. A micropatterned coculture model (HepatoPac) was used to explore the possibility that changes in exosome content precede overt necrosis in response to the IDILI drug tolvaptan.

Outside the envelope: rare events disrupt the relationshipbetween climate factors and species interactions.

The order in which species arrive during community assembly can be an important driver of community composition and function. However, the strength of these priority effects can be variable, in part because of strong site and year effects. To understand how priority effects vary in importance with abiotic conditions, we initiated identical community assembly experiments in which we varied the timing of arrival of native and exotic grass species in each of 4 yr across three grassland sites in northern California.

Persistent asymmetrical priority effects in a California grassland restoration experiment.

The order of species arrival can dramatically alter the trajectory of community development. While there is experimental evidence that priority effects can be important drivers of community structure early on, the persistence and duration of these effects is unclear. Here we report on a community assembly experiment in which a mix of four native grasses and a mix of four native forbs were planted on their own, together, or with one-year priority over the other guild.

Subtoxic Alterations in Hepatocyte-Derived Exosomes: An Early Step in Drug-Induced Liver Injury?

Drug-induced liver injury (DILI) is a significant clinical and economic problem in the United States, yet the mechanisms that underlie DILI remain poorly understood. Recent evidence suggests that signaling molecules released by stressed hepatocytes can trigger immune responses that may be common across DILI mechanisms. Extracellular vesicles released by hepatocytes, principally hepatocyte-derived exosomes (HDEs), may constitute one such signal.

Plant communities in harsh sites are less invaded: a summary of observations and proposed explanations.

Plant communities in abiotically stressful, or 'harsh', habitats have been reported to be less invaded by non-native species than those in more moderate habitats. Here, we synthesize descriptive and experimental evidence for low levels of invasion in habitats characterized by a variety of environmental stressors: low nitrogen; low phosphorus; saline, sodic or alkaline soils; serpentine soils; low soil moisture; shallow/rocky soils; temporary inundation; high shade; high elevation; and high latitude. We then discuss major categories of hypotheses to explain this pattern: the propagule limitation mechanism suggests invasion of harsh sites is limited by relatively low arrival rates of propagules compared with more moderate habitats, while invasion resistance mechanisms suggest that harsh habitats are inherently less invasible due to stressful abiotic conditions and/or increased effects of biotic resistance from resident organisms.

Chemotherapy of second stage human African trypanosomiasis: comparison between the parenteral diamidine DB829 and its oral prodrug DB868 in vervet monkeys.

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT.

Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates.

Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction.

Safety, pharmacokinetic, and efficacy studies of oral DB868 in a first stage vervet monkey model of human African trypanosomiasis.

There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD).

A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models.

DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing.

Discovery and hit-to-lead optimization of novel allosteric glucokinase activators.

We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high substrate level.

A vHTS approach for the identification of beta-adrenoceptor ligands.

Using a vHTS based on a pharmacophore alignment on known beta3-adrenoceptor ligands, a set of intriguing beta-adrenoceptor ligands was identified, optimization of which resulted in a selective and potent human beta2-AR antagonist.

Use of cassette dosing in sandwich-cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport.

Hepatocellular accumulation of bile acids due to inhibition of the canalicular bile salt export pump (BSEP/ABCB11) is one proposed mechanism of drug-induced liver injury (DILI). Some hepatotoxic compounds also are potent inhibitors of bile acid uptake by Na(+)-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1). This study used a cassette dosing approach in rat and human sandwich-cultured hepatocytes (SCH) to determine whether known or suspected hepatotoxic drugs inhibit bile acid transport individually or in combination.

Effect of albumin on the biliary clearance of compounds in sandwich-cultured rat hepatocytes.

The purpose of the present study was to evaluate the effects of bovine serum albumin (BSA) and essentially fatty acid-free BSA (BSA-FAF) on the biliary clearance of compounds in sandwich-cultured rat hepatocytes. Unbound fraction, biliary excretion index (BEI), and unbound intrinsic biliary clearance (intrinsic Clbiliary') were determined for digoxin, pravastatin, and taurocholate in the absence or presence of BSA or BSA-FAF. BSA had little effect on the BEI or intrinsic Clbiliary' of these compounds.

Bioelectric impedance predicts total body water, blood pressure, and heart rate during hemodialysis in children and adolescents.

Objective: The purposes of our study were to: (1) assess if changes in the volemic status of children and adolescents over the course of standard dialysis could be observed using bioelectric impedance (BIA); and (2) evaluate whether the variability of blood pressure (systolic blood pressure, SBP; diastolic blood pressure, DBP) and heart rate (HR) could be explained by independent variables from BIA data.

Design: We used a randomized, single-blinded treatment and repeated-measures design.

Setting: This study took place at the DaVita Children's Dialysis Center (Chicago, IL).

A novel class of potent NF-kappaB signaling inhibitors.

A novel class of NF-kappaB pathway signaling inhibitors was discovered by virtual screening, medicinal chemistry, and QSAR analysis. An initial set of compounds inhibited NF-kappaB signaling in a whole cell reporter gene assay in the micro-molar range. Activity was improved step by step by medicinal chemistry to yield nano-molar signaling inhibitors.

Role of CYP3A and CYP2E1 in alcohol-mediated increases in acetaminophen hepatotoxicity: comparison of wild-type and Cyp2e1(-/-) mice.

CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(-/-) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(-/-) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity.

4SCan/vADME: intelligent library screening as a shortcut from hits to lead compounds.

Managing to solve the first step in drug discovery - the hit finding - can be a quite elaborate task, but it is only the initial step to the final goal; hit-to-lead optimisation still lies ahead and consumes even more time and resources. The solution is rather simple, that is, to take only the most promising compounds into account; but who is going to decide which ones are the most promising among a list of tens of millions of compounds in a virtual combinatorial library? 4SCan/vADME helps by bridging the gap between virtual (combinatorial) libraries designed by chemists and the in silico methods, docking and alignment, for screening databases. After choosing a random starting set, the implemented learning and prediction algorithm iteratively considers only combinations of fragments that have shown to result in more suitable interactions by the chosen method.

Role of the nuclear receptor pregnane X receptor in acetaminophen hepatotoxicity.

The pregnane X receptor (PXR) is a transcriptional regulator of xenobiotic metabolizing enzymes, including cytochrome P450 3A (CYP3A), and transporters. Pretreatment of mice and rats with inducers of CYP3A increases acetaminophen (APAP) hepatotoxicity. In untreated mice, the amount of hepatic CYP3A11 mRNA is 4-fold greater in PXR(-/-) mice compared to wild-type mice (Guo et al.