Discovery and Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity.

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties.

Fragment-Based Discovery of Novel MUS81 Inhibitors.

MUS81 is a structure-selective endonuclease that cleaves various branched DNA structures arising from natural physiological processes such as homologous recombination and mitosis. Due to this, MUS81 is able to relieve replication stress, and its function has been reported to be critical to the survival of many cancers, particularly those with dysfunctional DNA-repair machinery. There is therefore interest in MUS81 as a cancer drug target, yet there are currently few small molecule inhibitors of this enzyme reported, and no liganded crystal structures are available to guide hit optimization.

Therapeutic expression of RAS Degrader RRSP in Pancreatic Cancer via Nanocarrier-mediated mRNA delivery.

About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor growth. Despite progress in development of small molecules for treatment of mutant KRAS cancers, there is a need for a pan-RAS inhibitor that is effective against all RAS isoforms and variants and that avoids drug resistance. We have previously shown that the naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is a potent RAS degrader that can be re-engineered as a biologic therapy to induce regression of colorectal, breast, and pancreatic tumors.

Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.

Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55.

Pilot study to evaluate the use of remote patient monitoring to guide the timing of valve intervention in patients with severe asymptomatic aortic stenosis (APRAISE-AS): study protocol for a randomised controlled trial delivered in two tertiary cardiac centres in the UK.

Introduction: Aortic stenosis (AS) is common affecting >13% of adults over the age of 75 years. In people who develop symptoms, without valve replacement, prognosis is dismal with mortality as high as 50% at 1 year. In asymptomatic patients, the timing of valve intervention is less well defined and a strategy of watchful waiting is recommended.

A renewably sourced, circular photopolymer resin for additive manufacturing.

The additive manufacturing of photopolymer resins by means of vat photopolymerization enables the rapid fabrication of bespoke 3D-printed parts. Advances in methodology have continually improved resolution and manufacturing speed, yet both the process design and resin technology have remained largely consistent since its inception in the 1980s. Liquid resin formulations, which are composed of reactive monomers and/or oligomers containing (meth)acrylates and epoxides, rapidly photopolymerize to create crosslinked polymer networks on exposure to a light stimulus in the presence of a photoinitiator.

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

Objectives: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain.

Design: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial.

Setting: 34 UK hospitals.

Attaching artificial Achilles and tibialis cranialis tendons to bone using suture anchors in a rabbit model: assessment of outcomes.

Objective: The purpose of this study was to investigate the factors associated with outcomes of attaching artificial tendons to bone using suture anchors for replacement of biological tendons in rabbits.

Study Design: Metal suture anchors with braided composite sutures of varying sizes (USP #1, #2, or #5) were used to secure artificial tendons replacing both the Achilles and tibialis cranialis tendons in 12 New Zealand White rabbits. Artificial tendons were implanted either at the time of (immediate replacement, n=8), or four weeks after (delayed replacement, n=4) resection of the biological tendon.

Biomechanical phenotyping pipeline for stalk lodging resistance in maize.

Stalk lodging (structural failure crops prior to harvest) significantly reduces annual yields of vital grain crops. The lack of standardized, high throughput phenotyping methods capable of quantifying biomechanical plant traits prevents comprehensive understanding of the genetic architecture of stalk lodging resistance. A phenotyping pipeline developed to enable higher throughput biomechanical measurements of plant traits related to stalk lodging is presented.

Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage.

Background: Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community.

Methods: The PRIMORANT study had three phases.

Effectiveness and cost-effectiveness of Assets-based feeding help Before and After birth (ABA-feed) for improving breastfeeding initiation and continuation: protocol for a multicentre randomised controlled trial (Version 3.0).

Introduction: Breastfeeding has health benefits for infants and mothers, yet the UK has low rates with marked social inequalities. The Assets-based feeding help Before and After birth (ABA) feasibility study demonstrated the acceptability of a proactive, assets-based, woman-centred peer support intervention, inclusive of all feeding types, to mothers, peer supporters and maternity services. The ABA-feed study aims to assess the clinical and cost-effectiveness of the ABA-feed intervention compared with usual care in first-time mothers in a full trial.

Targeted stimulation of the vagus nerve reduces renal injury in female mice with systemic lupus erythematosus.

Pharmacological stimulation of the vagus nerve has been shown to suppress inflammation and reduce blood pressure in a murine model of systemic lupus erythematosus (SLE) that is characterized by hypertension, inflammation, renal injury and dysautonomia. The present study aims to directly stimulate vagal nerves at the level of the dorsal motor nucleus of the vagus (DMV) using designer receptors exclusively activated by designer drugs (DREADDs) to determine if there is similar protection and confirm mechanism. Female NZBWF1/J (SLE) mice and NZW/LacJ mice (controls, labeled as NZW throughout) received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or control virus into the DMV at 31 weeks of age.

Renal angiomyolipoma: from imaging to intervention.

A high volume of cross-sectional imaging has created a window of opportunity for radiologists to identify renal angiomyolipomas (AMLs). The purpose of this review is to help the reader recognise the spectrum of renal AML appearances using different imaging methods and to gain an understanding of the classic and atypical features for appropriate lesion characterisation. Risk factors for AML growth and rupture will be highlighted.

Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function.

Plant homeodomain fingers (PHD-fingers) are a family of reader domains that can recruit epigenetic proteins to specific histone modification sites. Many PHD-fingers recognise methylated lysines on histone tails and play crucial roles in transcriptional regulation, with their dysregulation linked to various human diseases. Despite their biological importance, chemical inhibitors for targeting PHD-fingers are very limited.

Combining structural and coevolution information to unveil allosteric sites.

Understanding allosteric regulation in biomolecules is of great interest to pharmaceutical research and computational methods emerged during the last decades to characterize allosteric coupling. However, the prediction of allosteric sites in a protein structure remains a challenging task. Here, we integrate local binding site information, coevolutionary information, and information on dynamic allostery into a structure-based three-parameter model to identify potentially hidden allosteric sites in ensembles of protein structures with orthosteric ligands.

Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor.

Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings.

Measurement of changes in uterine and fibroid volume during treatment of heavy menstrual bleeding (HMB).

Study Question: Does application of an unbiased method for analysis of magnetic resonance (MR) images reveal any effect on uterine or fibroid volume from treatment of heavy menstrual bleeding (HMB) with three 12-week courses of the selective progesterone receptor modulator ulipristal acetate (SPRM-UPA)?

Summary Answer: Application of an unbiased method for analysis of MR images showed that treatment of HMB with SPRM-UPA was not associated with a significant reduction in the volume of the uterus or in the volume of uterine fibroids.

What Is Known Already: SPRM-UPA shows therapeutic efficacy for treating HMB. However, the mechanism of action (MoA) is not well understood and there have been mixed reports, using potentially biased methodology, regarding whether SPRM-UPA has an effect on the volume of the uterus and fibroids.

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids.

Ice nucleation in aqueous solutions of short- and long-chain poly(vinyl alcohol) studied with a droplet microfluidics setup.

Poly(vinyl alcohol) (PVA) has ice binding and ice nucleating properties. Here, we explore the dependence of the molecular size of PVA on its ice nucleation activity. For this purpose, we studied ice nucleation in aqueous solutions of PVA samples with molar masses ranging from 370 to 145 000 g mol-1, with a particular focus on oligomer samples with low molar mass.

WILL (When to induce labour to limit risk in pregnancy hypertension): Protocol for a multicentre randomised trial.

Objectives: To address optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well.

Study Design: Pragmatic, non-masked randomised trial.

Inclusion: maternal age ≥16 years, chronic or gestational hypertension, singleton pregnancy, live fetus, 36-37 weeks' gestation, and able to give documented informed consent.