Using nucleolytic toxins as restriction enzymes enables new RNA applications.

Over the past five decades, DNA restriction enzymes have revolutionized biotechnology. While these enzymes are widely used in DNA research and DNA engineering, the emerging field of RNA and mRNA therapeutics requires sequence-specific RNA endoribonucleases. Here, we describe EcoToxN1, a member of the type III toxin-antitoxin family of sequence-specific RNA endoribonucleases, and its use in RNA and mRNA analysis.

Quality by design approach to improve quality and decrease cost of in vitro transcription of mRNA using design of experiments.

In vitro transcription (IVT) reaction is an RNA polymerase-catalyzed production of messenger RNA (mRNA) from DNA template, and the unit operation with highest cost of goods in the mRNA drug substance production process. To decrease the cost of mRNA production, reagents should be optimally utilized. Due to the catalytic, multicomponent nature of the IVT reaction, optimization is a multi-factorial problem, ideally suited to design-of-experiment approach for optimization and identification of design space.

Rapid and scalable detection of synthetic mRNA byproducts using polynucleotide phosphorylase and polythymidine oligonucleotides.

Production and storage of synthetic mRNA can introduce a variety of byproducts which reduce the overall integrity and functionality of mRNA vaccines and therapeutics. mRNA integrity is therefore designated as a critical quality attribute which must be evaluated with state-of-the-art analytical methods before clinical use. The current study first demonstrates the effect of heat degradation on transcript translatability and then describes a novel enzymatic approach to assess the integrity of conventional mRNA and long self-amplifying mRNA.

Application of mathematical optimization to exploit regional nutrient recycling potential of biogas plant digestate.

Nutrients can be circulated back to agriculture from waste streams through anaerobic digestion and digestate processing. Digestate processing, however, is making slow progress as circulated nutrient products have not been cost competitive compared to fossil fertilizers and not designed from the farmer's perspective to truly match with the regional nutrient need. In this study, the aim is to assess apply mathematical optimization to the design of a cost-optimal processing route for a biogas plant's digestate to produce fertilizer products based on specified regional needs.

Acquired Resistance to EZH2 Inhibitor GSK343 Promotes the Differentiation of Human DLBCL Cell Lines toward an ABC-Like Phenotype.

Diffuse large B-cell lymphoma (DLBCL) accounts for 40% of non-Hodgkin lymphoma, and 30% to 40% of patients will succumb to relapsed/refractory disease (rrDLBCL). Patients with rrDLBCL generally have low long-term survival rates due to a lack of efficient salvage therapies. Small-molecule inhibitors targeting the histone methyltransferase EZH2 represent an emerging group of novel therapeutics that show promising clinical efficacy in patients with rrDLBCL.

Two-year survival with nivolumab in previously treated advanced non-small-cell lung cancer: A real-world pooled analysis of patients from France, Germany, and Canada.

Objectives: Immune checkpoint inhibitors have become the standard of care for metastatic non-small-cell lung cancer (NSCLC) progressing during or after platinum-based chemotherapy. Real-world clinical practice tends to represent more diverse patient characteristics than randomized clinical trials. We sought to evaluate overall survival (OS) outcomes in the total study population and in key subsets of patients who received nivolumab for previously treated advanced NSCLC in real-world settings in France, Germany, or Canada.

Fabrication of All-Solid Organic Electrochromic Devices on Absorptive Paper Substrates Utilizing a Simplified Lateral Architecture.

Poly(3,4-ethylenedioxythiophene) doped with the polymer anion poly(styrenesulfonate), PEDOT:PSS, is a common electrochromic material used in the preparation of electrochromic devices (ECDs). In this paper, the PEDOT:PSS doped with a solvent was used both as the electrode and the electrochromic functional layer for fabrication of ECDs on absorptive paper surfaces. The doped PEDOT:PSS dispersion was assessed for the film-forming evenness, sheet resistance and conductivity, and the performance of prepared ECDs for their color contrast and switching dynamics.

Managing a Large-Scale Multiomics Project: A Team Science Case Study in Proteogenomics.

Highly collaborative scientists are often called on to extend their expertise to different types of projects and to expand the scope and scale of projects well beyond their previous experience. For a large-scale project involving "big data" to be successful, several different aspects of the research plan need to be developed and tested, which include but are not limited to the experimental design, sample collection, sample preparation, metadata recording, technical capability, data acquisition, approaches for data analysis, methods for integration of different data types, recruitment of additional expertise as needed to guide the project, and strategies for clear communication throughout the project. To capture this process, we describe an example project in proteogenomics that built on our collective expertise and experience.

The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been reported in several cases. We performed comprehensive molecular profiling on samples from 14 patients diagnosed with UESL.

Application of Bayesian predictive probability for interim futility analysis in single-arm phase II trial.

Background: Bayesian predictive probability design, with a binary endpoint, is gaining attention for the phase II trial due to its innovative strategy. To make the Bayesian design more accessible, we elucidate this Bayesian approach with a R package to streamline a statistical plan, so biostatisticians and clinicians can easily integrate the design into clinical trial.

Methods: We utilize a Bayesian framework using Bayesian posterior probability and predictive probability to build a R package and develop a statistical plan for the trial design.

Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.

Background: Nivolumab was the first immuno-oncology agent available for the treatment of lung cancer in Canada. In the present study, we evaluated the real-world benefit of nivolumab in Canadian patients with lung cancer.

Methods: Patients included in the cohort were identified from a registry of patients treated through expanded access to nivolumab before and after Health Canada approval.

Mixed Integer Linear Programming Optimization of Gas Supply to a Local Market.

Remote or stranded areas that cannot be supplied by natural gas through transmission pipelines can access gas through terminals for liquefied natural gas (LNG), from where LNG is distributed by trucks or compressed and regasified into regional distribution networks. The gas supply may be further augmented by local biogas or synthetic natural gas. A model for optimization of such regional gas supply chains is presented in the paper, considering a combination of pipeline and truck delivery to a set of customers with given energy demands.

The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity.

The microenvironment provides a functional substratum supporting tumour growth. Hyaluronan (HA) is a major component of this structure. While the role of HA in malignancy is well-defined, the mechanisms driving its biosynthesis in cancer are poorly understood.

Single Nucleotide Polymorphisms Associated with Pain Sensitivity After Laparoscopic Cholecystectomy.

Objective: To systematically evaluate variations in single-nucleotide polymorphisms within 13 candidate pain genes in patients differing in phenotype characteristics based on a composite measure of pain sensitivity.

Methods: In a case-control study, 149 patients scheduled for laparoscopic cholecystectomy were individually categorized according to preoperative pain sensitivity and postoperative pain intensity. Cases (pain group) reported cannulation-induced pain intensity higher than 2.

Peroxisomes protect lymphoma cells from HDAC inhibitor-mediated apoptosis.

Peroxisomes are a critical rheostat of reactive oxygen species (ROS), yet their role in drug sensitivity and resistance remains unexplored. Gene expression analysis of clinical lymphoma samples suggests that peroxisomes are involved in mediating drug resistance to the histone deacetylase inhibitor (HDACi) Vorinostat (Vor), which promotes ROS-mediated apoptosis. Vor augments peroxisome numbers in cultured lymphoma cells, concomitant with increased levels of peroxisomal proteins PEX3, PEX11B, and PMP70.

Depressed mood, anxiety, and the use of labor analgesia.

Relatively little is known about mental health and labor pain. The aim of this study was to assess if self-rated antenatal depressed mood and anxiety are associated with pain-related behaviors and self-reported labor pain. We also wanted to replicate our previous finding of altered labor pain behavior in carriers of a specific guanosine triphosphate cyclohydrolase 1 gene (GCH1) haplotype.

Prediction of postoperative pain from assessment of pain induced by venous cannulation and propofol infusion.

Background: Postoperative pain may lead to delayed mobilization, persisting pain, and psychosocial distress. There are no simple and reliable techniques for prediction of postoperative pain. This study was designed to evaluate if pain induced by venous cannulation or propofol injection can be used to predict postoperative pain.

Environmentally friendly transistors and circuits on paper.

We created environmentally friendly low-voltage, ion-modulated transistors (IMTs) that can be fabricated successfully on a paper substrate. A range of ionic liquids (ILs) based on choline chloride (ChoCl) were used as the electrolytic layer in the IMTs. Different organic compounds were mixed with ChoCl to create solution-processable deep eutectic mixtures that are liquid or semiliquid at room temperature.

The role of eIF4E in response and acquired resistance to vemurafenib in melanoma.

In eukaryotic cells, the rate-limiting component for cap-dependent mRNA translation is the translation initiation factor eIF4E. eIF4E is overexpressed in a variety of human malignancies, but whether it has a role in melanoma remains obscure. We hypothesized that eIF4E promotes melanoma cell proliferation and facilitates the development of acquired resistance to the BRAF inhibitor vemurafenib.

Genetic and pharmacologic inhibition of eIF4E reduces breast cancer cell migration, invasion, and metastasis.

The translation initiation factor eIF4E is an oncogene that is commonly overexpressed in primary breast cancers and metastases. In this article, we report that a pharmacologic inhibitor of eIF4E function, ribavirin, safely and potently suppresses breast tumor formation. Ribavirin administration blocked the growth of primary breast tumors in several murine models and reduced the development of lung metastases in an invasive model.

Eukaryotic translation initiation factor 4E as a novel therapeutic target in hematological malignancies and beyond.

Introduction: The eukaryotic translation initiation factor 4E (eIF4E) is a key regulator of protein synthesis, and an oncogene. Its expression and activity are frequently elevated in cancer, and have been shown to correlate with poor prognosis. Efforts to target eIF4E have thus yielded much interest, with some clinical success.