Patients, parents and professional perspectives on molecular radiotherapy for neuroblastoma and paediatric neuroendocrine cancers.

Treatment with radioactive drugs (molecular radiotherapy, MRT) is an option for selected children with neuroblastoma and neuroendocrine cancers. As few hospitals are appropriately equipped and staffed to provide paediatric MRT, many families have to travel long distances from home for prolonged periods. To improve professional understanding of the challenges faced by children receiving these treatments and their parents, and to help them appreciate the difficulties faced by professionals in delivering complex treatments, a meeting bringing together parents, patients and professionals was held.

lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy.

Cryptosporidiosis is a diarrheal disease caused by infection with spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population.

Log D and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity.

The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D ranging from 2.

A National Referral Service for Paediatric Brachytherapy: An Evolving Practice and Outcomes Over 13 Years.

Aims: Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed.

Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center.

Background Idiopathic recurrent pericarditis (IRP) is an orphan disease that carries significant morbidity, partly driven by corticosteroid dependence. Innate immune modulators, colchicine and anti-interleukin-1 agents, pioneered in monogenic autoinflammatory diseases, have demonstrated remarkable efficacy in trials, suggesting that autoinflammation may contribute to IRP. This study characterizes the phenotype of patients with IRP and monogenic autoinflammatory diseases, and establishes whether autoinflammatory disease genes are associated with IRP.

Renal protection during 177lutetium DOTATATE molecular radiotherapy in children: a proposal for safe amino acid infusional volume during peptide receptor radionuclide therapy.

Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues such as 177-lutetium DOTATATE is an effective treatment modality for neuroendocrine tumours, paragangliomas, and neuroblastomas. However, renal and haematopoietic toxicities are the major limitations of this therapeutic approach. The renal toxicity of PRRT is mediated by renal proximal tubular reabsorption and interstitial retention of the radiolabelled peptides resulting in excessive renal irradiation that can be dose-limiting.

COVID-19 and autoinflammatory diseases: prevalence and outcomes of infection and early experience of vaccination in patients on biologics.

Objectives: The systemic autoinflammatory diseases are rare conditions; to date, data on coronavirus disease 2019 (COVID-19) infection and vaccination safety are scarce. Agents targeting innate immune pathways have transformed the management of affected patients, and their outcomes are of wider interest given the role of inflammation in both viral clearance and severe COVID-19 disease. We surveyed patients with systemic autoinflammatory disease on biologic therapy to determine the prevalence and outcomes of COVID-19 infection and to gather early safety data on vaccination.

Development and validation of the Intervention Skills Profile-Skills: A brief measure of student social-emotional and academic enabling skills.

The purpose of this study was to support the development and initial validation of the Intervention Selection Profile (ISP)-Skills, a brief 14-item teacher rating scale intended to inform the selection and delivery of instructional interventions at Tier 2. Teacher participants (n = 196) rated five students from their classroom across four measures (total student n = 877). These measures included the ISP-Skills and three criterion tools: Social Skills Improvement System (SSIS), Devereux Student Strengths Assessment (DESSA), and Academic Competence Evaluation Scales (ACES).

Paediatric Molecular Radiotherapy: Challenges and Opportunities.

The common contemporary indications for paediatric molecular radiotherapy (pMRT) are differentiated thyroid cancer and neuroblastoma. It may also have value in neuroendocrine cancers, and it is being investigated in clinical trials for other diseases. pMRT is the prototypical biomarker-driven, precision therapy, with a unique mode of delivery and mechanism of action.

Personalisation of Molecular Radiotherapy through Optimisation of Theragnostics.

Molecular radiotherapy, or targeted radionuclide therapy, uses systemically administered drugs bearing a suitable radioactive isotope, typically a beta emitter. These are delivered via metabolic or other physiological pathways to cancer cells in greater concentrations than to normal tissues. The absorbed radiation dose in tumour deposits causes chromosomal damage and cell death.

A phase IIa trial of molecular radiotherapy with 177-lutetium DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma.

Purpose: The objective of this phase IIa, open-label, single-centre, single-arm, two-stage clinical trial was to evaluate the safety and activity of 177-lutetium DOTATATE (LuDO) molecular radiotherapy in neuroblastoma.

Methods: Children with relapsed or refractory metastatic high-risk neuroblastoma were treated with up to four courses of LuDO. The administered activity was 75 to 100 MBq kg per course, spaced at 8- to 12-week intervals.

Cardiac monocytes and macrophages after myocardial infarction.

Improvements in early interventions after acute myocardial infarction (AMI), notably, the increased use of timely reperfusion therapy, have increased survival dramatically in recent decades. Despite this, maladaptive ventricular remodelling and subsequent heart failure (HF) following AMI remain a significant clinical challenge, particularly because several pre-clinical strategies to attenuate remodelling have failed to translate into clinical practice. Monocytes and macrophages, pleiotropic cells of the innate immune system, are integral in both the initial inflammatory response to injury and subsequent wound healing in many tissues, including the heart.

Reliability, validity, and accuracy of the intervention selection profile-Function: A brief functional assessment tool.

The purpose of this study was to evaluate the reliability, validity, and accuracy of scores from the Intervention Selection Profile-Function (ISP-Function): a brief functional assessment tool founded upon Direct Behavior Rating (DBR) methodology. Participants included 34 teacher-student dyads. Using the ISP-Function, teachers rated the extent to which students exhibited disruptive behavior, as well as the frequency with which disruptions were met with four consequences.

Pharmacokinetics of β-Lactam Antibiotics: Clues from the Past To Help Discover Long-Acting Oral Drugs in the Future.

β-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new β-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis.

Human P450-like oxidation of diverse proton pump inhibitor drugs by 'gatekeeper' mutants of flavocytochrome P450 BM3.

Production of drug metabolites is one area where enzymatic conversion has significant advantages over synthetic chemistry. These high value products are complex to synthesize, but are increasingly important in drug safety testing. The vast majority of drugs are metabolized by cytochromes P450 (P450s), with oxidative transformations usually being highly regio- and stereo-selective.

Sym004, a novel anti-EGFR antibody mixture, augments radiation response in human lung and head and neck cancers.

Sym004 represents a novel EGF receptor (EGFR)-targeting approach comprising a mixture of two anti-EGFR antibodies directed against distinct epitopes of EGFR. In contrast with single anti-EGFR antibodies, Sym004 induces rapid and highly efficient degradation of EGFR. In the current study, we examine the capacity of Sym004 to augment radiation response in lung cancer and head and neck cancer model systems.

Key mutations alter the cytochrome P450 BM3 conformational landscape and remove inherent substrate bias.

Cytochrome P450 monooxygenases (P450s) have enormous potential in the production of oxychemicals, due to their unparalleled regio- and stereoselectivity. The Bacillus megaterium P450 BM3 enzyme is a key model system, with several mutants (many distant from the active site) reported to alter substrate selectivity. It has the highest reported monooxygenase activity of the P450 enzymes, and this catalytic efficiency has inspired protein engineering to enable its exploitation for biotechnologically relevant oxidations with structurally diverse substrates.

Enhanced radiation sensitivity in HPV-positive head and neck cancer.

Patients with human papillomavirus (HPV+)-associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV-) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV- HNC cell lines using in vitro and in vivo techniques.

Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation.

EGF receptor (EGFR) inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR inhibitors, could inhibit tumor growth and cell-cycle progression in parallel with EGFR/HER3 signaling pathway modulation.

Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab.

The epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab, and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib, and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical successes, however many tumors remain non-responsive or acquire resistance during therapy.

Discovery of sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (GSK269984A) an EP(1) receptor antagonist for the treatment of inflammatory pain.

We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.