Development of Celiac Disease Therapeutics: The Sixth Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics Workshop

The Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics VI Workshop, held on July 22, 2021, provided a forum for patients and representatives from academia, industry, patient advocacy groups, and Food and Drug Administration to discuss drug development for celiac disease (CeD). The workshop focused on the approach of histologic assessments in clinical trials, considerations for pediatric drug development, and the use of a gluten challenge (GC) in clinical trials. Given that no histologic scoring system is widely accepted for use in clinical trials at this time, early-phase clinical trials should ideally explore a variety of histologic scales and assess the histologic findings of CeD as individual measures to inform future trials. When planning pediatric drug development in CeD, appropriate use of extrapolation of efficacy data from adequate, well-controlled studies in adults could facilitate timely access to safe and effective therapies for pediatric patients. Identification of a fit-for-purpose pediatric clinical outcome assessment could further advance pediatric drug development. Histologic responses to the GC depend on exposure, dose, and duration; short exposures do not appear to cause long-term consequences. However, the GC should be incorporated into clinical trials in a thoughtful manner to generate interpretable results and ensure patient safety. Ongoing collaboration between all stakeholders will facilitate the development of safe and effective therapeutics for CeD

Serum small extracellular vesicle‐derived LINC00853 as a novel diagnostic marker for early hepatocellular carcinoma

This study aimed to identify novel long noncoding RNA (lncRNA) biomarkers for hepatocellular carcinoma (HCC) using publicly available tissue genomic datasets and validate their diagnostic utility for early‐stage HCC. Differentially expressed lncRNAs between 371 HCC and 50 nontumor tissues were obtained from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA_LIHC) project. Subsequently, the expression of the serum‐ and extracellular vesicle (EV)‐derived lncRNA was assessed in 10 patients with HCC and 10 healthy controls using RT–qPCR. The candidate lncRNAs were validated in 90 HCC and 92 non‐HCC (29 healthy control, 28 chronic hepatitis, 35 liver cirrhosis) patients. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated for the candidate lncRNAs and the current HCC biomarker, alpha‐fetoprotein (AFP). SFTA1P, HOTTIP, HAGLROS, LINC01419, HAGLR, CRNDE, and LINC00853 were markedly upregulated in HCC in TCGA_LIHC dataset. Among them, LINC00853 has not been reported in relation to HCC before. In patients with HCC, only expression of small EV‐derived LINC00853 (EV‐LINC00853) was increased. EV‐LINC00853 showed excellent discriminatory ability in the diagnosis of all‐stage HCC (AUC = 0.934, 95% confidence interval = 0.887–0.966). Moreover, using a 14‐fold increase and 20 ng·mL−1 as cutoffs for EV‐LINC00853 expression and AFP level, respectively, EV‐LINC00853 was found to have a sensitivity of 93.75% and specificity of 89.77%, while AFP showed only 9.38% sensitivity and 72.73% specificity for the diagnosis of early‐stage HCC (mUICC stage I). EV‐LINC00853 had a positivity of 97% and 67% in AFP‐negative and AFP‐positive early HCC, respectively. Serum EV‐derived LINC00853 may be a novel potential diagnostic biomarker for early HCC, especially for AFP‐negative HCC

The benefits, limitations and opportunities of preclinical models for neonatal drug development

Increased research to improve preclinical models to inform the development of therapeutics for neonatal diseases is an area of great need. This article reviews five common neonatal diseases – bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, perinatal hypoxic–ischemic encephalopathy and neonatal sepsis – and the available in vivo, in vitro and in silico preclinical models for studying these diseases. Better understanding of the strengths and weaknesses of specialized neonatal disease models will help to improve their utility, may add to the understanding of the mode of action and efficacy of a therapeutic, and/or may improve the understanding of the disease pathology to aid in identification of new therapeutic targets. Although the diseases covered in this article are diverse and require specific approaches, several high-level, overarching key lessons can be learned by evaluating the strengths, weaknesses and gaps in the available models. This Review is intended to help guide current and future researchers toward successful development of therapeutics in these areas of high unmet medical need

Unconventional Three-Armed Luminogens Exhibiting Both Aggregation-Induced Emission and Thermally Activated Delayed Fluorescence Resulting in High-Performing Solution-Processed Organic Light-Emitting Diodes

In this work, three-armed luminogens <b>IAcTr-out</b> and <b>IAcTr-in</b> were synthesized and used as emitters bearing triazine and indenoacridine moieties in thermally activated delayed fluorescence organic light-emitting diodes (OLEDs). These molecules could form a uniform thin film via the solution process and also allowed the subsequent deposition of an electron transporting layer either by vacuum deposition or by an all-solution coating method. Intriguingly, the new luminogens displayed aggregation-induced emission (AIE), which is a unique photophysical phenomenon. As a nondoped emitting layer (EML), <b>IAcTr-in</b> showed external quantum efficiencies (EQEs) of 11.8% for the hybrid-solution processed OLED and 10.9% for the all-solution processed OLED with a low efficiency roll-off. This was evident by the higher photoluminescence quantum yield and higher rate constant of reverse intersystem crossing of <b>IAcTr-in</b>, as compared to <b>IAcTr-out</b>. These AIE luminogens were used as dopants and mixed with the well-known host material 1,3-bis­(<i>N</i>-carbazolyl)­benzene (mCP) to produce a high-efficiency OLED with a two-component EML. The maximum EQE of 17.5% was obtained when using EML with <b>IAcTr-out</b> doping (25 wt %) into mCP, and the OLED with EML bearing <b>IAcTr-in</b> and mCP showed a higher maximum EQE of 18.4% as in the case of the nondoped EML-based device