Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper.

Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.

Unlabelled: Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes.

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

Purpose: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.

Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models.

Cost-effectiveness analysis for avelumab first-line maintenance treatment of advanced urothelial carcinoma in Scotland.

The cost-effectiveness of avelumab first-line maintenance treatment for locally advanced or metastatic urothelial carcinoma in Scotland was assessed. A partitioned survival model was developed comparing avelumab plus best supportive care (BSC) versus BSC alone, incorporating JAVELIN Bladder 100 trial data, costs from national databases and published literature and clinical expert validation of assumptions. Incremental cost-effectiveness ratio (ICER) was estimated using lifetime costs and quality-adjusted life-years (QALY).

An obturator prosthesis for a 4-year-old child following treatment of a juvenile trabecular ossifying fibroma with a maxillary resection.

Juvenile trabecular ossifying fibroma (JTOF) is a benign fibro-osseous lesion that usually occurs in the maxilla or mandible. Individuals with JTOF of the maxilla will most commonly require a resection that can result in a significant palatal defect. Appearance and articulatory, masticatory, and deglutitory functions can be restored with a clasp-retained obturator.

The restorative dentistry management of adult cleft patients: 'the adult returner'.

This paper will discuss the management of adult patients with cleft lip and palate who return to care, often many decades after their initial course of treatment. This can be a very complex group of patients to treat as they often present with anxiety about dental care and often have other long-standing psychosocial issues. Working very closely with the multi-disciplinary team and the general dental practitioner is crucial to the successful outcome of care.

Restorative dentistry in the young cleft patient.

This clinical paper outlines the role of the restorative consultant in the treatment of young cleft lip and palate patients up to the end of their cleft package of care on their 22 birthday. The multidisciplinary nature of the care is highlighted, including the role of the general dental practitioner in caring for cleft patients in primary care. The various clinical treatment modalities used in this patient group are described with an emphasis on minimally invasive and adhesive approaches.

When (and when not) to use the Dahl Concept.

The Dahl Concept describes the re-establishment of occlusal contacts after the provision of a planned localised appliance or restoration in supraocclusion. Initially developed to create space for prosthetic rehabilitation of anterior teeth suffering from localised wear, the principle has later been successfully applied to a variety of situations, including the Hall technique and resin-bonded bridges cemented in supraocclusion. Despite high levels of success seen in the relevant literature and widespread adoption in specialist care, the wider profession appears to be far more cautious in its use.

Chemical Biology Approaches Confirm MCT4 as the Therapeutic Target of a Cellular Optimized Hit.

Lactic acid transport is a key process maintaining glycolytic flux in tumors. Inhibition of this process will result in glycolytic shutdown, impacting on cell growth and survival and thus has been pursued as a therapeutic approach for cancers. Using a cell-based screen in a MCT4-dependent cell line, we identified and optimized compounds for their ability to inhibit the efflux of intracellular lactic acid with good physical and pharmacokinetic properties.

Discovery of Clinical Candidate AZD0095, a Selective Inhibitor of Monocarboxylate Transporter 4 (MCT4) for Oncology.

Due to increased reliance on glycolysis, which produces lactate, monocarboxylate transporters (MCTs) are often upregulated in cancer. MCT4 is associated with the export of lactic acid from cancer cells under hypoxia, so inhibition of MCT4 may lead to cytotoxic levels of intracellular lactate. In addition, tumor-derived lactate is known to be immunosuppressive, so MCT4 inhibition may be of interest for immuno-oncology.

A functional analysis of 180 cancer cell lines reveals conserved intrinsic metabolic programs.

Cancer cells reprogram their metabolism to support growth and invasion. While previous work has highlighted how single altered reactions and pathways can drive tumorigenesis, it remains unclear how individual changes propagate at the network level and eventually determine global metabolic activity. To characterize the metabolic lifestyle of cancer cells across pathways and genotypes, we profiled the intracellular metabolome of 180 pan-cancer cell lines grown in identical conditions.

Heterogeneity of the cancer cell line metabolic landscape.

The unravelling of the complexity of cellular metabolism is in its infancy. Cancer-associated genetic alterations may result in changes to cellular metabolism that aid in understanding phenotypic changes, reveal detectable metabolic signatures, or elucidate vulnerabilities to particular drugs. To understand cancer-associated metabolic transformation, we performed untargeted metabolite analysis of 173 different cancer cell lines from 11 different tissues under constant conditions for 1,099 different species using mass spectrometry (MS).

Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper.

Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window.

Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs.

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity.

Tumour-on-chip microfluidic platform for assessment of drug pharmacokinetics and treatment response.

Microphysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. However, existing microfluidic devices are not yet able to deliver compounds to cell models in a way that reproduces the real physiological drug exposure. Here, we introduce a novel tumour-on-chip microfluidic system that mimics the pharmacokinetic profile of compounds on 3D tumour spheroids to evaluate their response to the treatments.

Cost Effectiveness of Ceftolozane/Tazobactam Compared with Meropenem for the Treatment of Patients with Ventilated Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

Introduction: The clinical efficacy and safety of ceftolozane/tazobactam for the treatment of ventilated hospital-acquired bacterial pneumonia (vHABP) and ventilator-associated bacterial pneumonia (VABP) has been demonstrated in the phase III randomised controlled trial ASPECT-NP. However, there are no published data on the cost-effectiveness of ceftolozane/tazobactam for vHABP/VABP. These nosocomial infections are associated with high rates of morbidity and mortality, and are increasingly complicated by growing rates of resistance and the inappropriate use of antimicrobials.

Macrophage Activation Status Rather than Repolarization Is Associated with Enhanced Checkpoint Activity in Combination with PI3Kγ Inhibition.

Suppressive myeloid cells mediate resistance to immune checkpoint blockade. PI3Kγ inhibition can target suppressive macrophages, and enhance efficacy of immune checkpoint inhibitors. However, how PI3Kγ inhibitors function in different tumor microenvironments (TME) to activate specific immune cells is underexplored.

Unilateral intrusion in a medically complex patient using an orthodontic mini-implant: A case report.

Orthognathic surgery offers a predictable treatment option for patients with skeletal discrepancies and corresponding dental malocclusions. In cases where surgery is not advised due to significant medical co-morbidity, the orthodontist must approach the treatment using different mechanical modalities. Orthodontic mini-implants can be a valuable adjunct in these cases.

Hypophosphataemic Rickets Secondary to Raine Syndrome: A Review of the Literature and Case Reports of Three Paediatric Patients' Dental Management.

Raine Syndrome (RS) also referred to as lethal osteosclerotic bone dysplasia describes an exceptionally rare autosomal recessive disorder with an estimated prevalence of <1 in 1,000,000. Endocrinological manifestations such as hypophosphataemic rickets depict a recent finding within the phenotypic spectrum of nonlethal RS. The dental sequelae of hypophosphataemic rickets are significant.

Costing the COVID-19 Pandemic: An Exploratory Economic Evaluation of Hypothetical Suppression Policy in the United Kingdom.

Objective: This study aims to cost and calculate the relative cost-effectiveness of the hypothetical suppression policies found in the Imperial College COVID-19 Response Team model.

Methods: Key population-level disease projections in deaths, intensive care unit bed days, and non-intensive care unit bed days were taken from the Imperial College COVID-19 Response Team report of March 2020, which influenced the decision to introduce suppression policies in the United Kingdom. National income loss estimates were from a study that estimated the impact of a hypothetical pandemic on the UK economy, with sensitivity analyses based on projections that are more recent.

Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.