Publications by authors named "Jonathan White"

461 Publications

Revealing the influence of steric bulk on the triplet-triplet annihilation upconversion performance of conjugated polymers.

Sci Rep 2021 Oct 1;11(1):19585. Epub 2021 Oct 1.

School of Chemistry, ARC Centre of Excellence in Exciton Science, University of Melbourne, Parkville, VIC, 3010, Australia.

A series of poly(phenylene-vinylene)-based copolymers are synthesized using the Gilch method incorporating monomers with sterically bulky sidechains. The photochemical upconversion performance of these polymers as emitters are investigated using a palladium tetraphenyltetrabenzoporphyrin triplet sensitizer and MEH-PPV as reference. Increased incorporation of sterically bulky monomers leads to a reduction in the upconversion efficiency despite improved photoluminescence quantum yield. A phosphorescence quenching study indicates issues with the energy transfer process between the triplet sensitizer and the copolymers. The best performance with 0.18% upconversion quantum yield is obtained for the copolymer containing 10% monomer with bulky sidechains.
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http://dx.doi.org/10.1038/s41598-021-99179-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486830PMC
October 2021

Single-cell nuclear architecture across cell types in the mouse brain.

Science 2021 Sep 30:eabj1966. Epub 2021 Sep 30.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

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http://dx.doi.org/10.1126/science.abj1966DOI Listing
September 2021

Development of a novel, pan-variant aerosol intervention for COVID-19.

bioRxiv 2021 Sep 14. Epub 2021 Sep 14.

Apeiron Biologics AG, Campus-Vienna-Biocenter 5, 1030 Vienna, Austria.

To develop a universal strategy to block SARS-CoV-2 cellular entry and infection represents a central aim for effective COVID-19 therapy. The growing impact of emerging variants of concern increases the urgency for development of effective interventions. Since ACE2 is the critical SARS-CoV-2 receptor and all tested variants bind to ACE2, some even at much increased affinity (see accompanying paper), we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here we show that intranasal administration of APN01 in a mouse model of SARS-CoV-2 infection dramatically reduced weight loss and prevented animal death. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers can now be initiated, with subsequent Phase II testing in individuals with SARS-CoV-2 infection. This strategy could be used to develop a viable and rapidly actionable therapy to prevent and treat COVID-19, against all current and future SARS-CoV-2 variants.
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http://dx.doi.org/10.1101/2021.09.14.459961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452093PMC
September 2021

An approach to assessing the contribution of the high LET effect in strategies for Auger endoradiotherapy.

Int J Radiat Biol 2021 Oct 6:1-8. Epub 2021 Oct 6.

School of Chemistry and Bio21 Institute, The University of Melbourne, Parkville, Australia.

The interest in exploiting Auger emitters in cancer therapy stems from their high linear energy transfer (LET)-type radiation damage to DNA. However, the design of Auger-emitter labeled vehicles that target the Auger cascade specifically to the DNA of tumour cells is challenging. Here we suggest a possible approach to evaluate tumour-targeting Auger-labeled conjugates by assessing the impact of a radioprotector known to be effective in protecting from low LET radiation, but not high LET radiation. Given some similarity between the energy spectrum of Auger electrons and that of secondary electrons from soft X-rays, we report the results of radioprotection experiments with 25 kVp X-rays. Clonogenic survival curves for cultured human keratinocytes were established for three different irradiation conditions: Cs γ-rays, 25 kVp X-rays and 320 kVp X-rays, and the effect of including a new radioprotector, denoted "2PH", was investigated. The extent of radioprotection by 2PH was comparable for all radiation conditions, although RBE was higher (about 1.7) for soft X-rays. Radioprotectors like 2PH will help to evaluate Auger endoradiotherapy strategies, by determining the relative contributions of the high-LET effects (not protected), compared to other components, such as Auger electrons not effectively targeted to DNA.
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http://dx.doi.org/10.1080/09553002.2021.1976862DOI Listing
October 2021

Selective Synthesis of -Symmetric BINOL-phosphates and P-chiral Phosphoramides Using Directed -Lithiation.

Org Lett 2021 09 27;23(18):7055-7058. Epub 2021 Aug 27.

Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.

Directed -lithiation (DoL) has been developed as an effective method for the -substitution of BINOL-phosphoric acid and BINOL--triflylphosphoramide (BINOL-P-acids). It can be employed in the rapid assembly of either mono- or disubstituted BINOL-P-acids, including unsymmetrical disubstitution through iterative DoL. Most significantly, DoL has proven to be highly effective in the diastereoselective desymmetrization of pseudo-symmetric BINOL--triflylphosphoramide, affording a chiral P-group.
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http://dx.doi.org/10.1021/acs.orglett.1c02430DOI Listing
September 2021

Oxorhenium(V) and Oxotechnetium(V) Complexes of NS Tetradentate Ligands with a Styrylpyridyl Functional Group: Toward Imaging Agents to Assist in the Diagnosis of Alzheimer's Disease.

Inorg Chem 2021 Sep 23;60(17):13669-13680. Epub 2021 Aug 23.

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.

Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-β (Aβ). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aβ plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [Tc═O] and [Re═O] motifs, and two rhenium complexes were characterized by X-ray crystallography. The rhenium(V) complexes interact with synthetic Aβ and amyloid plaques on human brain tissue. Two of the new ligands were radiolabeled with Tc using a kit-based approach, and their biodistribution in wild-type mice was evaluated. The presence of amide donors in the tetradentate ligand increased the stability of the respective [Tc═O] complexes but reduced brain uptake. While the complexes were able to cross the BBB, the degree of uptake in the brain was not sufficient to justify further investigation of these complexes.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01992DOI Listing
September 2021

GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer.

J Med Chem 2021 Aug 12;64(16):11841-11856. Epub 2021 Jul 12.

Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.

Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, (GDC-9545 or giredestrant). is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (, , , and ) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of in preclinical species and humans. exhibits low drug-drug interaction liability and demonstrates excellent and safety profiles. At low doses, induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1 mutant PDX or a wild-type ERα tumor model. Currently, is being evaluated in Phase III clinical trials.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00847DOI Listing
August 2021

Surgery and COVID-19: a rapid scoping review of the impact of the first wave of COVID-19 on surgical services.

BMJ Open 2021 06 15;11(6):e043966. Epub 2021 Jun 15.

Community Health Sciences, Surgery & Oncology, University of Calgary, Calgary, Alberta, Canada

Objectives: To understand how surgical services have been reorganised during and following public health emergencies, particularly the first wave of the COVID-19 pandemic, and the consequences for patients, healthcare providers and healthcare systems.

Design: A rapid scoping review.

Setting: We searched the MEDLINE, Embase and grey literature sources for documents and press releases from governments and surgical organisations or associations.

Participants: Studies examining surgical service delivery during public health emergencies including COVID-19, and the impact on patients, providers and healthcare systems were included.

Primary And Secondary Outcome Measures: Primary outcomes were strategies implemented for the reorganisation of surgical services. Secondary were the impacts of reorganisation and resuming surgical services, such as: adverse events (including morbidity and mortality), primary care and emergency department visits, length of hospital and ICU stay, and changes to surgical waitlists.

Results: One hundred and thirty-two studies were included in this review; 111 described reorganisation of surgical services, 55 described the consequences of reorganising surgical services; and 6 reported actions taken to rebuild surgical capacity in public health emergencies. Reorganisations of surgical services were grouped under six domains: case selection/triage, personal protective equipment (PPE) regulations and practice, workforce composition and deployment, outpatient and inpatient patient care, resident and fellow education, and the hospital or clinical environment. Service reorganisations led to large reductions in non-urgent surgical volumes, increases in surgical wait times and impacted medical training (ie, reduced case involvement) and patient outcomes (eg, increases in pain). Strategies for rebuilding surgical capacity were scarce but focused on the availability of staff, PPE and patient readiness for surgery as key factors to consider before resuming services.

Conclusions: Reorganisation of surgical services in response to public health emergencies appears to be context dependent and has far-reaching consequences that must be better understood in order to optimise future health system responses to public health emergencies.
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http://dx.doi.org/10.1136/bmjopen-2020-043966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210688PMC
June 2021

Test-retest assessment of non-contrast MRI sequences to characterise and quantify the small bowel wall in healthy participants.

MAGMA 2021 Jun 5. Epub 2021 Jun 5.

Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, UK.

Objective: Quantitative Magnetic Resonance Imaging sequences have been investigated as objective imaging biomarkers of fibrosis and inflammation in Crohn's disease.

Aim: To determine the repeatability and inter- and intra-observer agreement of these measures in the prepared small bowel wall.

Methods: Ten healthy participants were scanned at 3 T on 2 separate occasions using T1 and T2 relaxometry, IVIM-DWI and MT sequences. Test-retest repeatability was assessed using the coefficient of variation (CoV) and intra-class correlation coefficients (ICCs) were used to evaluate the intra- and inter-observer agreement RESULTS: Test-retest repeatability in the bowel wall was excellent for apparent diffusion coefficient (ADC), magnetisation transfer ratio (MTR), T1, and diffusion coefficient D (CoV 5%, 7%, 8%, and 10%, respectively), good for perfusion fraction (PF) (CoV 20%) and acceptable for T2 (CoV 21%). Inter-observer agreement was good for the T2, D and ADC (ICC = 0.89, 0.86, 0.76, respectively) and moderate for T1 (ICC = 0.55). Intra-observer agreement was similar to inter-observer agreement.

Discussion: This study showed variable results between the different parameters measured. Test-retest repeatability was at least acceptable for all parameters except pseudo-diffusion coefficient D*. Good inter- and intra-observer agreement was obtained for T2, ADC and D, with these parameters performing best in this technical validation study.
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http://dx.doi.org/10.1007/s10334-021-00931-2DOI Listing
June 2021

The road to personalised medicine in psoriatic arthritis.

Expert Rev Clin Immunol 2021 Aug 31;17(8):799-802. Epub 2021 May 31.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1080/1744666X.2021.1931125DOI Listing
August 2021

Real-life clinical experience of using diphencyclopropenone.

Authors:
Jonathan M White

Contact Dermatitis 2021 Oct 27;85(4):487. Epub 2021 May 27.

Department of Dermatology, Erasmus Hospital, Brussels, Belgium.

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http://dx.doi.org/10.1111/cod.13899DOI Listing
October 2021

JAK1 selective inhibitors for the treatment of spondyloarthropathies.

Rheumatology (Oxford) 2021 05;60(Suppl 2):ii39-ii44

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.

As our understanding of the pathogenesis of SpA improves, focus has turned to the role janus kinase (JAK)-mediated signal transduction and inhibiting its actions as a therapeutic mechanism. Small molecule inhibitors of JAK exist, with variable selectivity for the different JAK isoforms. Less selective JAK inhibitors have variable efficacy and safety profiles, prompting the investigation of selective JAK1 inhibition. In this review, we summarize the current phase 2 and 3 clinical trial data, evaluating the use of JAK1 selective inhibitors in the treatment of SpA, particularly AS and PsA. Selective JAK1 inhibition offers a promising therapeutic approach, however further longer-term trials are needed to fully establish their efficacy and safety at higher doses, and their use in the greater continuum of SpA.
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http://dx.doi.org/10.1093/rheumatology/keaa815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098108PMC
May 2021

Synthesis of New Triazolopyrazine Antimalarial Compounds.

Molecules 2021 Apr 21;26(9). Epub 2021 Apr 21.

Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, QLD 4111, Australia.

A radical approach to late-stage functionalization using photoredox and Diversinate chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM.
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http://dx.doi.org/10.3390/molecules26092421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122397PMC
April 2021

Total Synthesis of Viridiofungins A and B.

Org Lett 2021 05 22;23(9):3557-3560. Epub 2021 Apr 22.

School of Chemistry, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.

The total synthesis of viridiofungins A () and B () via β-lactone in 13 steps is reported. Key steps included an HF-mediated rearrangement of cyclobutene diester to form a bicyclic lactone , an olefin cross metathesis between disubstituted alkene and alkene in which isomerization was suppressed, and a novel β-lactone ring opening to form the amide. Deprotection then gave either viridiofungin A () or B () in high yield.
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http://dx.doi.org/10.1021/acs.orglett.1c00971DOI Listing
May 2021

The role of conformational heterogeneity in the excited state dynamics of linked diketopyrrolopyrrole dimers.

Phys Chem Chem Phys 2021 Apr;23(15):9357-9364

School of Chemistry, University of Melbourne, Melbourne, Australia.

Diketopyrrolopyrrole (DPP) derivatives have been proposed for both singlet fission and energy upconversion as they meet the energetic requirements and exhibit superior photostability compared to many other chromophores. In this study, both time-resolved electronic and IR spectroscopy have been applied to investigate excited state relaxation processes competing with fission in dimers of DPP derivatives with varying linker structures. A charge-separated (CS) state is shown to be an important intermediate with dynamics that are both solvent and linker dependent. The CS state is found for a subset of the total population of excited molecules and it is proposed that CS state formation requires suitably aligned dimers within a broader distribution of conformations available in solution. No long-lived triplet signatures indicative of singlet fission were detected, with the CS state likely acting as an alternative relaxation pathway for the excitation energy. This study provides insight into the role of molecular conformation in determining excited state relaxation pathways in DPP dimer systems.
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http://dx.doi.org/10.1039/d1cp00541cDOI Listing
April 2021

CHAL336 Benchmark Set: How Well Do Quantum-Chemical Methods Describe Chalcogen-Bonding Interactions?

J Chem Theory Comput 2021 May 21;17(5):2783-2806. Epub 2021 Apr 21.

School of Chemistry, The University of Melbourne, Victoria 3010, Australia.

We present the CHAL336 benchmark set-the most comprehensive database for the assessment of chalcogen-bonding (CB) interactions. After careful selection of suitable systems and identification of three high-level reference methods, the set comprises 336 dimers each consisting of up to 49 atoms and covers both σ- and π-hole interactions across four categories: chalcogen-chalcogen, chalcogen-π, chalcogen-halogen, and chalcogen-nitrogen interactions. In a subsequent study of DFT methods, we re-emphasize the need for using proper London dispersion corrections when treating noncovalent interactions. We also point out that the deterioration of results and systematic overestimation of interaction energies for some dispersion-corrected DFT methods does not hint at problems with the chosen dispersion correction but is a consequence of large density-driven errors. We conclude this work by performing the most detailed DFT benchmark study for CB interactions to date. We assess 109 variations of dispersion-corrected and dispersion-uncorrected DFT methods and carry out a detailed analysis of 80 of them. Double-hybrid functionals are the most reliable approaches for CB interactions, and they should be used whenever computationally feasible. The best three double hybrids are SOS0-PBE0-2-D3(BJ), revDSD-PBEP86-D3(BJ), and B2NCPLYP-D3(BJ). The best hybrids in this study are ωB97M-V, PW6B95-D3(0), and PW6B95-D3(BJ). We do not recommend using the popular B3LYP functional nor the MP2 approach, which have both been frequently used to describe CB interactions in the past. We hope to inspire a change in computational protocols surrounding CB interactions that leads away from the commonly used, popular methods to the more robust and accurate ones recommended herein. We would also like to encourage method developers to use our set for the investigation and reduction of density-driven errors in new density functional approximations.
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http://dx.doi.org/10.1021/acs.jctc.1c00006DOI Listing
May 2021

The effect of smoking on achieving meaningful clinical outcomes one year after lumbar tubular microdecompression: a matched-pair cohort analysis.

Spine J 2021 08 25;21(8):1303-1308. Epub 2021 Mar 25.

Department of Orthopedic Surgery, Wake Forest Baptist Health, Medical Center Boulevard, 4th Floor Comprehensive Cancer Center, Winston-Salem, NC 27157, USA; Department of Neurosurgery , Wake Forest Baptist Health, Medical Center Boulevard, 4th Floor Comprehensive Cancer Center, Winston-Salem, NC 27157, USA.

Background Context: There has been a shift in the spine literature in reporting meaningful outcomes, including meaningful clinically important difference (MCID), after surgery. The evidence on the effect of tobacco smoking at the time of lumbar tubular microdecompression (LTMD) on meaningful outcomes is limited.

Purpose: To compare differences in 1-year functional outcomes and rates of achieving MCID between current smokers and non-smokers who underwent LTMD for lumbar spinal stenosis (LSS).

Study Design: A nested case control study to compare the difference in patient reported outcomes (PROs) between smokers and non-smokers 1-year after undergoing LTMD.

Patient Sample: This study included patients that underwent single level LTMD by a single surgeon between January 2014 through August 2019.

Outcome Measures: Preoperative and postoperative PROs were recorded using the questionnaires EQ-5D, Oswestry Disability Index (ODI), and the visual analog scale (VAS) for back pain and leg pain. The MCID was also used.

Methods: Current tobacco smokers at the time of surgery were matched 1:2 to non-smokers by age (+/- 1year). Preoperative and postoperative functional scores were compared between the two groups using independent t-tests. Additionally, thresholds for achieving MCID were calculated for each individual functional score, and were compared using Fisher's exact test.

Results: Of the 183 patients with 1-year follow-up who met inclusion criteria, 35 patients were identified as smokers and were matched to 70 non-smokers. No statistical differences were identified between age, BMI, or gender. Comparison of preoperative PROs showed no statistically significant differences between smokers and non-smokers (p>0.05 for all), while smokers had statistically lower EQ-5D (p<0.001) and higher ODI (p=0.05), VAS back (p=0.033), and VAS leg (p=0.03) score averages at a minimum of one year follow-up. Evaluation of meaningful outcomes demonstrated non-smokers had higher rates of achieving MCID on at least 1 threshold score as compared to smokers (98.5% vs. 91.1%; p=0.043).

Conclusions: Current smokers at the time of surgery have inferior postoperative EQ-5D scores, increased pain and disability, and lower odds of achieving the MCID at 1-year after undergoing LTMD when compared to patients without any smoking history.
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http://dx.doi.org/10.1016/j.spinee.2021.03.020DOI Listing
August 2021

Endoscopic management of Barrett's dysplasia and early neoplasia: efficacy, safety and long-term outcomes in a UK tertiary centre.

Eur J Gastroenterol Hepatol 2021 Mar 12. Epub 2021 Mar 12.

NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham Nottingham Digestive Diseases Centre, The University of Nottingham, Nottingham University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester University Hospitals of Derby and Burton NHS Foundation Trust, Royal Derby Hospital, Derby Department of Pathology, Nottingham University Hospitals NHS Trust, Queen's Medical Centre Campus, Nottingham, UK.

Background And Objectives: Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are effective treatments for dysplastic Barrett's esophagus (BE). This study evaluates efficacy, durability and safety in a single high-volume UK tertiary centre with 15-years' experience.

Methods: Prospective data were collected from Nottingham University Hospitals 2004-2019 for endotherapy of dysplastic BE or intramucosal adenocarcinoma. Procedural outcome measures include complete resection, complications and surgery rates. Efficacy outcomes include complete remission of dysplasia (CR-D) and intestinal metaplasia (CR-IM), recurrence, treatment failure rates, durability of RFA, median follow up and tumor-associated mortality.

Results: A total of 319 lesions were resected; 671 RFAs were performed on 239 patients. Median age was 67 (±9.5) years, male:female ratio was 5:1 and median BE length was C3 [interquartile range (IQR): 6] M6 (IQR: 5). The most common lesion was Paris IIa (64%) with a median size of 10 mm (3-70). Final histology was adenocarcinoma in 50%. Complete resection rates were 96%. The multiband mucosectomy technique (91%) was most commonly used. The median number of RFA sessions was 3 (IQR: 2). The rates of CR-D and CR-IM were 90.4%% and 89.8% achieved after a median of 20.1 (IQR: 14) months. The most common complications: EMR was bleeding 2.2% and RFA was stricture (5.4%) requiring a median of 2 (range 1-7) dilatations. Median follow up post CR-IM/CR-D was 38 months (14-60). Metachronous lesions developed in 4.7% after CR-D and tumor-related mortality was 0.8%. Dysplasia and intestinal metaplasia-free survival at 5 years was 95 and 90%, respectively.

Conclusion: BE endotherapy is minimally invasive, effective, safe and deliverable in a day-case setting.
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http://dx.doi.org/10.1097/MEG.0000000000002121DOI Listing
March 2021

Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A Receptor in Living Cells.

J Med Chem 2021 05 16;64(10):6670-6695. Epub 2021 Mar 16.

Medicinal Chemistry, Monash University, Parkville, Victoria 3052, Australia.

The adenosine A receptor (AAR) is a G-protein-coupled receptor (GPCR) that provides important therapeutic opportunities for a number of conditions including congestive heart failure, tachycardia, and neuropathic pain. The development of AAR-selective fluorescent ligands will enhance our understanding of the subcellular mechanisms underlying AAR pharmacology facilitating the development of more efficacious and selective therapies. Herein, we report the design, synthesis, and application of a novel series of AAR-selective fluorescent probes based on 8-functionalized bicyclo[2.2.2]octylxanthine and 3-functionalized 8-(adamant-1-yl) xanthine scaffolds. These fluorescent conjugates allowed quantification of kinetic and equilibrium ligand binding parameters using NanoBRET and visualization of specific receptor distribution patterns in living cells by confocal imaging and total internal reflection fluorescence (TIRF) microscopy. As such, the novel AAR-selective fluorescent antagonists described herein can be applied in conjunction with a series of fluorescence-based techniques to foster understanding of AAR molecular pharmacology and signaling in living cells.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02067DOI Listing
May 2021

Respiratory Distress Syndrome Associated with Erythrodermic Psoriasis.

Case Rep Dermatol 2021 Jan-Apr;13(1):83-88. Epub 2021 Feb 4.

Department of Pneumology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.

Erythrodermic psoriasis is an uncommon and severe variant of psoriasis which may be associated with rare and severe complications such as acute respiratory distress syndrome. Early recognition of this life-threatening condition can allow prompt appropriate treatment. We report the case of a 69-year-old man with a long history of psoriasis who developed acute respiratory distress during a disease flare-up. There was no relevant past history (except for mild emphysema), known allergy, or recent treatment. Chest X-ray revealed new bilateral infiltrates, confirmed at chest computed tomography scan. Repeated cultures on aspirate of the bronchoalveolar lavage remained negative for viruses, bacteria, and parasites. Cardiac ultrasound was normal and high-dose corticosteroid therapy was initiated. Within a few days his clinical and radiological status improved significantly.
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http://dx.doi.org/10.1159/000511368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923713PMC
February 2021

Phytochemical Profiling and Biological Activity of the Australian Carnivorous Plant, .

J Nat Prod 2021 04 25;84(4):964-971. Epub 2021 Feb 25.

School of Science (Applied Chemistry and Environmental Science), RMIT University, GPO Box 2476 Melbourne, Victoria 3001, Australia.

Phytochemical profiling was undertaken on the crude extracts of to determine the nature of the chemical constituents present. In total, three new flavonol diglycosides (-), one new flavan-3-ol glycoside (), and 12 previously reported compounds of the flavonol (, ), flavan-3-ol (), flavanone (), 1,4-napthoquinone (, , , ), 2,3-dehydroxynapthalene-1,4-dione (-), and phenolic acid () structure classes were isolated and identified. Compounds -, , , and were assessed for antimicrobial activity, with compounds , , , and showing significant activity. Compounds , , and were also evaluated for anthelmintic activity against larval forms of , with compound being active.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00869DOI Listing
April 2021

Computational Study of the Donor-Acceptor Interactions Underlying the Variable Oxygen Probe.

J Org Chem 2021 Mar 16;86(5):3960-3969. Epub 2021 Feb 16.

School of Chemistry and Bio21 Institute, University of Melbourne, Parkville, VIC 3010, Australia.

The variable oxygen probe (VOP) is a crystallographic technique that has been used to explore the relative donor abilities of various filled orbitals ranging from vicinal lone pairs to polarized heteroatom-carbon bonds, remote π functionalities, and strained carbon-carbon (CC) bonds. In this study, the donor-acceptor interactions which underlie the VOP have been explored in the gas phase using density functional theory on the model systems - with natural bond orbital analysis of the various donor-acceptor interactions involving both neutral and charged σ* antibonding orbitals as the acceptor probes. Updated values for the VOP slopes of - were shown to relate qualitatively with the sum of all significant donor-acceptor interactions present in these derivatives. Application of the VOP to calculated structures of - with various -OR substituents revealed a similar relationship between the C-OR bond distance to p (ROH). However, the VOP slopes in the gas phase were significantly smaller in magnitude than those obtained from crystal structural data, likely due to the valence form (C-OR) being disfavored in the former, highlighting the advantage of the VOP as an experimental technique to discriminate donor ability more effectively than calculated structures.
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http://dx.doi.org/10.1021/acs.joc.0c02811DOI Listing
March 2021

Toward competency based continuing professional development for practicing surgeons.

Am J Surg 2021 Feb 5. Epub 2021 Feb 5.

Division of General Surgery, University of Alberta, 8440 112 St, Edmonton, AB, T6G 2R7, Canada.

Background: There has been a recent call for formal competency assessments of practicing physicians and surgeons to form a framework of competency based continuing professional development (CBCPD).

Methods: An email questionnaire was conducted regarding CBCPD. Responses were further used to inform development of semi-structured interviews.

Results: There were 58 questionnaire respondents (42%). There was moderate support for assessment of surgeons' technical skills (50.9%) or decision making (56.6%). Support was highest for a mechanism to flag surgeons in need of a focused competence assessment (83.0%). Eight surgeons participated in interviews. Interviews identified a range of benefits of CBCPD but also several challenges to implementation, including the need for fair, data-driven assessments, taking into account patient outcomes.

Conclusions: Through listening to surgeon concerns and recommendations for implementation strategies, this study's findings may support development of an effective CBCPD strategy with the potential to be embraced by surgeons and foster an environment of improved safety and performance.
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http://dx.doi.org/10.1016/j.amjsurg.2021.01.045DOI Listing
February 2021

Integrated spatial genomics reveals global architecture of single nuclei.

Nature 2021 02 27;590(7845):344-350. Epub 2021 Jan 27.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Identifying the relationships between chromosome structures, nuclear bodies, chromatin states and gene expression is an overarching goal of nuclear-organization studies. Because individual cells appear to be highly variable at all these levels, it is essential to map different modalities in the same cells. Here we report the imaging of 3,660 chromosomal loci in single mouse embryonic stem (ES) cells using DNA seqFISH+, along with 17 chromatin marks and subnuclear structures by sequential immunofluorescence and the expression profile of 70 RNAs. Many loci were invariably associated with immunofluorescence marks in single mouse ES cells. These loci form 'fixed points' in the nuclear organizations of single cells and often appear on the surfaces of nuclear bodies and zones defined by combinatorial chromatin marks. Furthermore, highly expressed genes appear to be pre-positioned to active nuclear zones, independent of bursting dynamics in single cells. Our analysis also uncovered several distinct mouse ES cell subpopulations with characteristic combinatorial chromatin states. Using clonal analysis, we show that the global levels of some chromatin marks, such as H3 trimethylation at lysine 27 (H3K27me3) and macroH2A1 (mH2A1), are heritable over at least 3-4 generations, whereas other marks fluctuate on a faster time scale. This seqFISH+-based spatial multimodal approach can be used to explore nuclear organization and cell states in diverse biological systems.
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http://dx.doi.org/10.1038/s41586-020-03126-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878433PMC
February 2021

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

N Engl J Med 2021 04 20;384(14):1301-1311. Epub 2021 Jan 20.

From the Department of Anesthesia and Intensive Care, Aalborg University Hospital, Aalborg University, Aalborg (O.L.S., T.L.K., S.A.R., J.B., A.E.S.E., A.-S.H.L., R.L.P., E.C., T.C.G., M.T.B., B.S.R.), Zealand University Hospital, Køge (L.M.P., S.E., J.P.L., C.A., C.B.M.), Rigshospitalet (A.P., B.A.B., J. Wetterslev, I.-L.J., M.H.M., L.Q., M.-B.N.K.) and the Section of Biostatistics, Department of Public Health (T.L.), University of Copenhagen, Bispebjerg, and Frederiksberg Hospital (C.S.M., M. Hjort, L.K.B.) and the Copenhagen Trial Unit (J. White, J.E.), Copenhagen, Nordsjaellands Hospital, Hillerod (M.H.B., M.S.-L., M.K.K., M. Hindborg), Randers Hospital, Randers (T.G., H.B.), Aarhus University Hospital, Skejby North, Aarhus (L.H.M.Ø., M.A.T.), Zealand University Hospital, Roskilde (T.H., B.U.), Viborg Hospital, Viborg (C.G.S., N.M.-N.), Kolding Hospital, Kolding (A.C.B., M. Bäcklund), Hvidovre Hospital, Hvidovre (U.G.P.), Herlev Hospital, Herlev (A.S.A.), Horsens Hospital, Horsens (L.B.), Herning Hospital, Herning (R.R.W.), Holbæk Hospital, Holbæk (S.B.T.), and Slagelse Hospital, Slagelse (S.A.I.) - all in Denmark; the Department of Intensive Care and Department of Clinical Research, University of Basel, Basel (M.S., A.H., C.E.G., N.Z.), and the Department of Intensive Care, Inselspital, University of Bern, Bern (J.C.S.) - both in Switzerland; the Department of Perioperative, Intensive Care and Pain Medicine, Helsinki University Hospital, Helsinki (M.B., M.O.); the Department of Critical Care, University Medical Center Groningen, Groningen, the Netherlands (F.K., W.D.); the Departments of Anesthesia and Intensive Care and of Clinical Research, Rikshospitalet, Oslo University Hospital, Oslo (J.H.L., T.N.A.); the Department of Intensive Care, Cardiff University Hospital of Wales, Cardiff, United Kingdom (M.M.); and the Department of Anesthesia and Intensive Care, Landspitali University Hospital, Reykjavik, Iceland (K.M.T.).

Background: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao) would result in lower mortality than using a higher target.

Methods: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days.

Results: At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24).

Conclusions: Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).
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http://dx.doi.org/10.1056/NEJMoa2032510DOI Listing
April 2021

Spectroscopic and Dynamic Properties of Electronically Excited Pendant Porphyrin Polymers with Backbones of Differing Flexibility.

J Phys Chem A 2020 Dec 15;124(51):10748-10757. Epub 2020 Dec 15.

School of Chemistry and ARC Centre of Excellence in Exciton Science, University of Melbourne, Parkville, Victoria 3010, Australia.

A zinc porphyrin-pendant norbornene polymer with a rigid backbone characterized by a 2:1 / isomeric structure ratio has been synthesized, and its spectroscopic and photophysical properties are examined. Zinc tetraphenylporphyrin, the porphyrin-substituted norbornene monomer, and a previously reported zinc porphyrin-pendant polymer with a flexible polymethylene backbone have been used as comparators. Unlike its flexible counterpart, the rigid norbornene polymer exhibits clear exciton splitting of its Soret band, much more rapid relaxation rates of its excited singlet states, and a very small yield of an unusually short-lived triplet state. Unlike the flexible pendant polymer, which exhibits excimeric fluorescence as a result of chromophore rotation, anti-Kasha emission from the norbornene polymer originates primarily from the unperturbed porphyrin region. The low triplet yield in the polymer is attributed to greatly increased rates of competing internal conversion within the singlet manifold. Nevertheless, upconverted delayed fluorescence that is quenched by oxygen is observed upon intense steady-state Q-band excitation of degassed polymer solutions, signaling direct triplet involvement. Consistent with the polymer's rigid structure, this biexcitonic process is assigned to ultrafast singlet exciton migration and triplet-triplet annihilation following absorption of a second photon by the small steady-state concentration of polymer triplets.
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http://dx.doi.org/10.1021/acs.jpca.0c09501DOI Listing
December 2020

On the importance of π-hole spodium bonding in tricoordinated Hg complexes.

Dalton Trans 2020 Dec;49(48):17547-17551

Department of Chemistry, Faculty of Science, University of Maragheh, P.O. Box 55181-83111, Maragheh, Iran.

A new coordination polymer [Hg(LI)I]n (1) and a new discrete coordination complex [Hg(HLII)I2] (2) are synthesized and X-ray characterized. The existence of positive π-holes at the spodium atoms in both compounds is evidenced by DFT calculations. In 1, a Hg-S semicoordination bond and a HgI spodium bond are formed at opposite sides of the π-hole. In 2, two different HgI spodium bonds are formed at both sides of the π-hole. This is the first study describing structure-guiding π-hole spodium bonding.
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http://dx.doi.org/10.1039/d0dt03938aDOI Listing
December 2020

Synthesis and fluorine-18 radiolabeling of a phospholipid as a PET imaging agent for prostate cancer.

Nucl Med Biol 2021 02 28;93:37-45. Epub 2020 Nov 28.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Australia; Department of Medicine, Melbourne University, Melbourne, Australia. Electronic address:

Introduction: Altered lipid metabolism and subsequent changes in cellular lipid composition have been observed in prostate cancer cells, are associated with poor clinical outcome, and are promising targets for metabolic therapies. This study reports for the first time on the synthesis of a phospholipid radiotracer based on the phospholipid 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (PC44:12) to allow tracking of polyunsaturated lipid tumor uptake via PET imaging. This tracer may aid in the development of strategies to modulate response to therapies targeting lipid metabolism in prostate cancer.

Methods: Lipidomics analysis of prostate tumor explants and LNCaP tumor cells were used to identify PC44:12 as a potential phospholipid candidate for radiotracer development. Synthesis of phosphocholine precursor and non-radioactive standard were optimised using click chemistry. The biodistribution of a fluorine-18 labeled analogue, N-{[4-(2-[F]fluoroethyl)-2,3,4-triazol-1-yl]methyl}-1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine ([F]2) was determined in LNCaP prostate tumor-bearing NOD SCID gamma mice by ex vivo biodistribution and PET imaging studies and compared to biodistribution of [F]fluoromethylcholine.

Results: [F]2 was produced with a decay-corrected yield of 17.8 ± 3.7% and an average radiochemical purity of 97.00 ± 0.89% (n = 6). Molar activity was 85.1 ± 3.45 GBq/μmol (2300 ± 93 mCi/μmol) and the total synthesis time was 2 h. Ex vivo biodistribution data demonstrated high liver uptake (41.1 ± 9.2%ID/g) and high splenic uptake (10.9 ± 9.1%ID/g) 50 min post-injection. Ex vivo biodistribution showed low absolute tumor uptake of [F]2 (0.8 ± 0.3%ID/g). However, dynamic PET imaging demonstrated an increase over time of the relative tumor-to-muscle ratio with a peak of 2.8 ± 0.5 reached 1 h post-injection. In contrast, dynamic PET of [F]fluoromethylcholine demonstrated no increase in tumor-to-muscle ratios due to an increase in both tumor and muscle over time. Absolute uptake of [F]fluoromethylcholine was higher and peaked at 60 min post injection (2.25 ± 0.29%ID/g) compared to [F]2 (1.44 ± 0.06%ID/g) during the 1 h dynamic scan period.

Conclusions And Advances In Knowledge: This study demonstrates the ability to radiolabel phospholipids and indicates the potential to monitor the in vivo distribution of phospholipids using fluorine-18 based PET.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071757PMC
February 2021

Tungsten Ligand-Based Sulfur-Atom-Transfer Catalysts: Synthesis, Characterization, Sustained Anaerobic Catalysis, and Mode of Aerial Deactivation.

Inorg Chem 2020 Dec 17;59(23):16824-16828. Epub 2020 Nov 17.

Department of Chemistry and Physics, La Trobe Institute of Molecular Sciences, La Trobe University, Melbourne, Victoria 3086, Australia.

The synthesis, properties, X-ray structures, and catalytic sulfur-atom-transfer (SAT) reactions of W(μ-S)(μ-S)(dtc)(dped) [; dtc = SCNR, where R = Me, Et, Bu, and Bn; dped = SCPh] and W(μ-S)(dtc)(dped) () are reported. These complexes represent the oxidized () and reduced () forms of anaerobic SAT catalysts operating through the bidirectional, ligand-based half-reaction (μ-S)(μ-S) ↔ (μ-S) + S. The catalysts are deactivated in air through the formation of catalytically inactive oxo complexes, (dtc)WO(μ-S)(μ-dped)W(dtc)(dped) (), prompting us to recommend that group 6 SAT activity be assessed under strictly anaerobic conditions.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02915DOI Listing
December 2020
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