Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers.

One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 (), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents (NCT04657068 and NCT05798611).

Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

Purpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.

Experimental Design: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models.

Quantitative, titratable and high-throughput reporter assays to measure DNA double strand break repair activity in cells.

Repair of DNA damage is essential for the maintenance of genome stability and cell viability. DNA double strand breaks (DSBs) constitute a toxic class of DNA lesion and multiple cellular pathways exist to mediate their repair. Robust and titratable assays of cellular DSB repair (DSBR) are important to functionally interrogate the integrity and efficiency of these mechanisms in disease models as well as in response to genetic or pharmacological perturbations.

Targeting ATR in Cancer Medicine.

As a key component of the DNA Damage Response, the Ataxia telangiectasia and Rad3-related (ATR) protein is a promising druggable target that is currently widely evaluated in phase I-II-III clinical trials as monotherapy and in combinations with other rational antitumor agents, including immunotherapy, DNA repair inhibitors, chemo- and radiotherapy. Ongoing clinical studies for this drug class must address the optimization of the therapeutic window to limit overlapping toxicities and refine the target population that will most likely benefit from ATR inhibition. With advances in the development of personalized treatment strategies for patients with advanced solid tumors, many ongoing ATR inhibitor trials have been recruiting patients based on their germline and somatic molecular alterations, rather than relying solely on specific tumor subtypes.

Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models.

Purpose: DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy.

Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta.

Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ.

Global Globin Network Consensus Paper: Classification and Stratified Roadmaps for Improved Thalassaemia Care and Prevention in 32 Countries.

The Global Globin Network (GGN) is a project-wide initiative of the Human Variome/Global Variome Project (HVP) focusing on haemoglobinopathies to build the capacity for genomic diagnosis, clinical services, and research in low- and middle-income countries. At present, there is no framework to evaluate the improvement of care, treatment, and prevention of thalassaemia and other haemoglobinopathies globally, despite thalassaemia being one of the most common monogenic diseases worldwide. Here, we propose a universally applicable system for evaluating and grouping countries based on qualitative indicators according to the quality of care, treatment, and prevention of haemoglobinopathies.

Predictive validity of a qualitative and quantitative Prechtl's General Movements Assessment at term age: Comparison between preterm infants and term infants with HIE.

Aim: To determine (1) if the General Movement Optimality Score (GMOS) at term age enhances prediction of motor impairment at 12 and 24 months of age in high-risk infants, when compared to a global General Movement Assessment (GMA), and (2) compare predictive validity for two high-risk populations: infants born preterm and infants born at term with hypoxic ischaemic encephalopathy who have received therapeutic hypothermia.

Methods: Fifty-nine extremely preterm or term age infants with hypoxic ischaemic encephalopathy underwent term age GMA. A GMA score of normal or abnormal, and a comparative numerical General Movement Optimality Score (GMOS, total values 5-42) were assigned.

The effect of cannabis policies on treatment outcomes for cannabis use among U.S. adults.

Background: Research has explored the impact of various medical cannabis policies on substance use treatment admission in recent years, but we know little about factors related to participants' treatment engagement and outcome. To fill this gap in the existing literature, this study used national data to examine the influence of cannabis policies (decriminalized, medical, and recreational) and referral sources (criminal justice vs. voluntary) on treatment completion and length of stay.

Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.

To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor.

The Real-Life Outcome of VACOped Boot in the Management of Diabetic Foot Ulcers.

The total contact cast (TCC) is considered the gold standard treatment to off-load diabetic foot ulcers (DFUs); however, the use of TCC can be limited due to various reasons such as underlying infections, ischemia, and patient's reluctance. Removable cast walkers are used in such cases, and the VACOped boot is one such device. The aim of this study was to analyze the results of the VACOped boot in the treatment of DFUs in real life.

"Can I Live": Black American Adolescent Boys' Reports of Police Abuse and the Role of Religiosity on Mental Health.

State sanctioned violence aimed at Black individuals and communities is an issue that has pervaded American history and society since before the establishment of the United States. For Black males, anticipating and preparing for involuntary police contact, unfortunately, is an inevitable part of life. The purpose of this study is to examine the impact of reports of police abuse on mental health and perceived racial out-group perceptions and the protective role of religiosity among a nationally representative sample of Black American adolescent boys (M = 14.

Fluoride occurrence in the lower East African Rift System, Southern Malawi.

Countries located on the East African Rift System (EARS) are vulnerable to fluoride in their groundwater; a vulnerability for the developing country of Malawi at the southern rift periphery that is not well characterised. Groundwater fluoride occurrence in Malawi is documented here to better understand and manage fluoride risks posed. Available literature and Gov't of Malawi archive fluoride data spanning some fifty years have been collated and augmented by our own 2016-18 surveys of groundwater quality in Southern Malawi, targeting deep-sourced springs.

SOMANZ position paper on the management of nausea and vomiting in pregnancy and hyperemesis gravidarum.

This is a brief summary of the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) evidence-based guideline for the management of nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum (HG). The full guideline and executive summary including auditable outcomes are freely available on the SOMANZ website [https://www.somanz.

Ketonuria Is Associated with Changes to the Abundance of in the Gut Microbiota of Overweight and Obese Women at 16 Weeks Gestation: A Cross-Sectional Observational Study.

The gut microbiome in pregnancy has been associated with various maternal metabolic and hormonal markers involved in glucose metabolism. Maternal ketones are of particular interest due to the rise in popularity of low-carbohydrate diets. We assessed for differences in the composition of the gut microbiota in pregnant women with and without ketonuria at 16 weeks gestation.

A oocyte model system to study action potentials.

Action potentials (APs) are the functional units of fast electrical signaling in excitable cells. The upstroke and downstroke of an AP is generated by the competing and asynchronous action of Na- and K-selective voltage-gated conductances. Although a mixture of voltage-gated channels has been long recognized to contribute to the generation and temporal characteristics of the AP, understanding how each of these proteins function and are regulated during electrical signaling remains the subject of intense research.

Prevalence of maternal urinary ketones in pregnancy in overweight and obese women.

Background: Ketonuria may be associated with adverse fetal outcomes. This study aimed to determine the prevalence of ketonuria at three time points in pregnancy and to assess whether ketonuria correlates with a clinical indication for performing a urine test.

Methods: Women had fasting urinary ketone levels measured at 16 and 28 weeks gestation and random ketone levels measured close to 36 weeks gestation.

Increasing the involvement of diverse populations in genomics-based health care-lessons from haemoglobinopathies.

Integrating genomic medicine into health care delivery poses significant challenges to health professionals. To draw clinical benefit from genomic information, there is a need to build an evidence-based relationship between genotype and the physical expression of that genomic information. The work presented here uses preliminary work in the field of haemoglobinopathies to address two important challenges: to ensure that health care professionals in low- and middle-income countries are actively involved in the processes that will support genomic medicine, and that equity and diversity concerns are met so that clinical services can have relevance across all population and sub-population groups.

SOMANZ guidelines for the investigation and management sepsis in pregnancy.

SOMANZ (Society of Obstetric Medicine Australia and New Zealand) has written a guideline to provide evidence-based guidance for the investigation and care of women with sepsis in pregnancy or the postpartum period. The guideline is evidence-based and incorporates recent changes in the definition of sepsis. The etiology, investigation and treatment of bacterial, viral and non-infective causes of sepsis are discussed.

Fabrication and Application of Isotopically Labelled Gold Arrays for Multiplexed Peptide Analysis.

A new array-based technology for the simultaneous capture, chemical labelling and mass spectrometry analysis of peptides is presented. Isotopically labelled self-assembled monolayer (SAM) gold arrays are constructed and used simultaneously to capture and label a range of peptides. The array-immobilised, labelled peptides were released by MALDI ablation, analysed by MALDI mass spectrometry and readily identified as labelled peptides from their characteristic isotope pattern.

Management of thyroid disease in pregnancy - Room for improvement in the first trimester.

Background: First-trimester care of maternal thyroid dysfunction has previously been shown to be poor. This study evaluates early management of thyroid dysfunction in pregnancy in Australia.

Methods: Patients reviewed by the Obstetric Medicine team for thyroid dysfunction from 1 January 2012 to 30 June 2013 were included.

Poor compliance with community-acquired pneumonia antibiotic guidelines in a large Australian private hospital emergency department.

Aims: This study evaluated guideline concordance and time to administration of antibiotics in community-acquired pneumonia (CAP) in a private Australian emergency department (ED). Two key components in the management of CAP are timely administration and appropriate choice of antibiotic therapy. The use of antibiotics outside of guidelines can potentially increase rates of antibiotic resistance.