Computationally Driven Discovery of a BCR-ABL1 Kinase Inhibitor with Activity in Multidrug-Resistant Chronic Myeloid Leukemia.

The permeability glycoprotein, encoded by the gene, is widely implicated in multidrug resistance (MDR), as it has been shown to reduce the intracellular concentration of most small molecule therapeutics, including the majority of the breakpoint cluster region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used in the treatment of Philadelphia chromosome positive (Ph+) leukemias. With this in mind, we describe an integrated theoretical and experimental approach to shed light on substituent effects in the pendant anilino moiety of 4-anilinoquinazolines and 4-anilinoquinoline-3-carbonitrile-based kinase inhibitors and their influence on P-gp-mediated efflux. This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor that exhibits a marked reduction in P-gp-mediated efflux ratio and potent activity in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived cell line (K562/Dox) overexpressing P-gp.

Atypical -Alkyl to -Noralkoxy Switch in a Dual cSRC/BCR-ABL1 Kinase Inhibitor Improves Drug Efflux and hERG Affinity.

We describe an atypical amine bioisostere, the trisubstituted hydroxylamine, that upon incorporation into an approved dual cSRC/BCR-ABL1 kinase inhibitor yields , a compound that retains potent biological activity and couples it with improved drug efflux and hERG affinity at the expense of only a 2 atomic mass unit increase in molecular weight. Contrary to the common expectation for hydroxylamines in medicinal chemistry, is well tolerated and lacks the mutagenicity and genotoxicity so often ascribed to lesser substituted hydroxylamines. A matched molecular pair (MMP) analysis suggests that the beneficial properties conferred by the -alkyl to -noralkoxy switch arises from a reduction in basicity of the piperazine unit.

Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer.

Metastases to the brain remain a significant problem in lung cancer, as treatment by most small-molecule targeted therapies is severely limited by efflux transporters at the blood-brain barrier (BBB). Here, we report the discovery of a selective, orally bioavailable, epidermal growth factor receptor (EGFR) inhibitor, , that exhibits high brain penetration and potent activity in osimertinib-resistant cell lines bearing L858R/C797S and exon19del/C797S EGFR resistance mutations. , induced tumor regression in an intracranial patient-derived xenograft (PDX) murine model suggesting it as a potential lead for the treatment of localized and metastatic non-small-cell lung cancer (NSCLC) driven by activating mutant bearing EGFR.

Structural characterisation of nanoalloys for (photo)catalytic applications with the Sapphire library.

A non-trivial interplay rules the relationship between the structure and the chemophysical properties of a nanoparticle. In this context, characterization experiments, molecular dynamics simulations and electronic structure calculations may allow the variables that determine a given property to be pinpointed. Conversely, a rigorous computational characterization of the geometry and chemical ordering of metallic nanoparticles and nanoalloys enables discrimination of which descriptors could be linked with their stability and performance.

Exploring AuRh Nanoalloys: A Computational Perspective on the Formation and Physical Properties.

We studied the formation of AuRh nanoalloys (between 20-150 atoms) in the gas phase by means of Molecular Dynamics (MD) calculations, exploring three possible formation processes: one-by-one growth, coalescence, and nanodroplets annealing. As a general trend, we recover a predominance of Rh@Au core-shell ordering over other chemical configurations. We identify new structural motifs with enhanced thermal stabilities.

Reading the ground: Understanding the response of bioelectric microbes to anthropogenic compounds in soil based terrestrial microbial fuel cells.

Electrogenic bacteria produce power in soil based terrestrial microbial fuel cells (tMFCs) by growing on electrodes and transferring electrons released from the breakdown of substrates. The direction and magnitude of voltage production is hypothesized to be dependent on the available substrates. A sensor technology was developed for compounds indicative of anthropological activity by exposing tMFCs to gasoline, petroleum, 2,4-dinitrotoluene, fertilizer, and urea.

The use of organ donor blood in liver transplantation.

Background: Blood removed from organs during deceased donor organ procurement is routinely discarded but is a potential resource for donor-specific transfusion (DST) in subsequent liver transplantation (LT). This study retrospectively analyses the impact of DST on intraoperative bank blood product usage, long-term graft, and patient survival, as well as frequency of rejection post-LT.

Methods: A total of 992 adult LT performed from 1993 to 2018 in a single quaternary center were included.

Alveolar rhabdomyosarcomas involving serous cavity fluid specimens exhibit diverse cytomorphologies: A case report and review of the literature.

Involvement of serous cavity specimens by alveolar rhabdomyosarcoma (ARMS) is a rare event and only a few case reports have been reported in the literature, with conflicting cytomorphologic patterns. Herein, we report on a 41-year-old man with no significant past medical history who presented with pancytopenia and shortness of breath and was found to have widely metastatic sinonasal alveolar rhabdomyosarcoma, including involvement of the pleura. The pleural fluid specimen was cellular and contained ARMS cells in small-to-medium sized three-dimensional fragments that resembled an adenocarcinoma or mesothelioma, and numerous single cells were seen in the background.

Review of SMARCA4 (BRG1)-deficient carcinomas following a malignant pleural effusion specimen confounded by reduced claudin-4 expression.

SMARCA4-deficient neoplasms are recently characterized high-grade malignancies associated with a poor prognosis. The SMARCA4 gene encodes BRG1, which is part of the SWI/SNF complex. SMARCA4-deficient neoplasms have an undifferentiated, often rhabdoid morphology, and demonstrate loss of BRG1 nuclear expression on immunohistochemistry.

The role of changing temperature in microbial metabolic processes during permafrost thaw.

Approximately one fourth of the Earth's Northern Hemisphere is underlain by permafrost, earth materials (soil, organic matter, or bedrock), that has been continuously frozen for at least two consecutive years. Numerous studies point to evidence of accelerated climate warming in the Arctic and sub-Arctic where permafrost is located. Changes to permafrost biochemical processes may critically impact ecosystem processes at the landscape scale.

A systematic review of small for size syndrome after major hepatectomy and liver transplantation.

Background: Major hepatectomy (MH) and particular types of liver transplantation (LT) (reduced size graft, living-donor and split-liver transplantation) lead to a reduction in liver mass. As the portal venous return remains the same it results in a reciprocal and proportionate rise in portal venous pressure potentially resulting in small for size syndrome (SFSS). The aim of this study was to review the incidence, diagnosis and management of SFSS amongst recipients of LT and MH.

Epidemiology and outcomes of acute liver failure in Australia.

Background: Acute liver failure (ALF) is a life-threatening syndrome with varying aetiologies requiring complex care and multidisciplinary management. Its changing incidence, aetiology and outcomes over the last 16 years in the Australian context remain uncertain.

Aim: To describe the changing incidence, aetiology and outcomes of ALF in South Eastern Australia.

The Measurement of Donor-Specific Cell-Free DNA Identifies Recipients With Biopsy-Proven Acute Rejection Requiring Treatment After Liver Transplantation.

Background: Assessment of donor-specific cell-free DNA (dscfDNA) in the recipient is emerging as a noninvasive biomarker of organ rejection after transplantation. We previously developed a digital polymerase chain reaction (PCR)-based approach that readily measures dscfDNA within clinically relevant turnaround times. Using this approach, we characterized the dynamics and evaluated the clinical utility of dscfDNA after liver transplantation (LT).

Keanu: a novel visualization tool to explore biodiversity in metagenomes.

Background: One of the main challenges when analyzing complex metagenomics data is the fact that large amounts of information need to be presented in a comprehensive and easy-to-navigate way. In the process of analyzing FASTQ sequencing data, visualizing which organisms are present in the data can be useful, especially with metagenomics data or data suspected to be contaminated. Here, we describe the development and application of a command-line tool, Keanu, for visualizing and exploring sample content in metagenomics data.

Emergency presentations of acute biliary pain: changing patterns of management in a tertiary institute.

Background: Acute biliary pain is the most common presentation of gallstone disease. Untreated patients risk recurrent pain, cholecystitis, obstructive jaundice, pancreatitis and multiple hospital presentations. We examine the outcome of implementing a policy to offer laparoscopic cholecystectomy on index presentation to patients with biliary colic in a tertiary hospital in Australia.

Bidirectional GPR119 Agonism Requires Peptide YY and Glucose for Activity in Mouse and Human Colon Mucosa.

The lipid sensor G protein-coupled receptor 119 (GPR119) is highly expressed by enteroendocrine L-cells and pancreatic β-cells that release the hormones, peptide YY (PYY) and glucagonlike peptide 1, and insulin, respectively. Endogenous oleoylethanolamide (OEA) and the dietary metabolite, 2-monoacylglycerol (2-OG), can each activate GPR119. Here, we compared mucosal responses with selective, synthetic GPR119 agonists (AR440006 and AR231453) and the lipids, OEA, 2-OG, and N-oleoyldopamine (OLDA), monitoring epithelial ion transport as a readout for L-cell activity in native mouse and human gastrointestinal (GI) mucosae.

Discovery of APD371: Identification of a Highly Potent and Selective CB Agonist for the Treatment of Chronic Pain.

The discovery of a novel, selective and fully efficacious CB agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB receptor to avoid tachyphylaxis.

Age 80 years and over is not associated with increased morbidity and mortality following pancreaticoduodenectomy.

Background: Pancreaticoduodenectomy (PD) is associated with high morbidity, which is perceived to be increased in the elderly. To our knowledge there have been no Australian series that have compared outcomes of patients over the age of 80 undergoing PD to those who are younger.

Methods: Patients who underwent PD between January 2008 and November 2015 were identified from a prospectively maintained database.

A case of massive hemoptysis following transesophageal echocardiogram.

Introduction: Tracheal intubation leading to injury of the airway is a rare complication of transesophageal echocardiography (TEE). Tracheal trauma is not a described complication of TEE, and safety literature for this procedure remains silent on the matter. We describe the case of a patient on systemic anticoagulation and antiplatelet therapy who underwent TEE and suffered massive hemoptysis requiring bronchial artery embolization (BAE).

A novel immune function biomarker identifies patients at risk of clinical events early following liver transplantation.

Balancing immunosuppression after liver transplant is difficult, with clinical events common. We investigate whether a novel immune biomarker based on a laboratory platform with widespread availability that measures interferon γ (IFNγ) after stimulation with a lyophilized ball containing an adaptive and innate immune stimulant can predict events following transplantation. A total of 75 adult transplant recipients were prospectively monitored in a blinded, observational study; 55/75 (73.