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Author: Adam Nelson (182)


Mar
2018

Managing Dyslipidemia in Type 2 Diabetes.

Endocrinol Metab Clin North Am 2018 Mar 20;47(1):153-173. Epub 2017 Dec 20.
Adam J Nelson, Simon K Rochelau, Stephen J Nicholls
Cardiovascular disease is the most frequent cause of morbidity and mortality among individuals with diabetes and although there has been significant reduction in excess risk, these individuals remain at least twice as likely to sustain atherosclerotic events. Aggressive management of traditional factors, such as dyslipidemia, remains the cornerstone of risk mitigation. Diabetes and its associated insulin resistance generate qualitative and quantitative changes in lipid profile, which complicate effective treatment.

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Jan
2018

Human papillomavirus (HPV) infections cause a significant proportion of cancers worldwide, predominantly squamous cell carcinomas (SCC) of the mucosas and skin. High-risk HPV types are associated with SCCs of the anogenital and oropharyngeal tract. HPV oncogene activities and the biology of SCCs have been intensely studied in laboratory models and humans.

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Jan
2018

Parents/caregivers of hospitalized patients are at risk of sleep disruption. We performed a cross-sectional quantitative and qualitative evaluation of sleep in parents/caregivers of children undergoing hematopoietic stem cell transplant (HSCT; n = 17). Additionally, we explored the frequency of room entries for hospitalized patients undergoing HSCT (n = 189 nights).

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Dec
1969

Proteasome inhibitors, such as bortezomib and carfilzomib, are FDA approved for the treatment of hemopoietic cancers, but recent studies have shown their great potential for treatment of solid tumors. BaxΔ2, a unique proapoptotic Bax isoform, promotes non-mitochondrial cell death and sensitizes cancer cells to chemotherapy. However, endogenous BaxΔ2 proteins are unstable and susceptible to proteasomal degradation.

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Jan
2018

Timely antibiotic administration in immunocompromised patients is associated with improved outcomes. The aim of our study was to decrease the mean time to administration of antibiotics in hospitalized bone marrow transplant patients with fever from 75 to <60 minutes.
By using the Model of Improvement, we performed plan-do-study-act cycles to design, test, and implement high-reliability interventions to decrease time to antibiotics.

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Nov
2017

Sleep-disordered breathing (SDB) is associated with cardiovascular disease and systemic inflammation in adults but this remains to be explored in children, especially in children with the most common form of SDB, i.e. primary snoring/mild SDB.

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Feb
2018

We prospectively examined rates of outpatient oral medication adherence in children after hematopoietic stem cell transplant (post-HSCT). For 6 months after first discharge post-HSCT, 50 patients (aged 0 to 16 years) and their primary caregivers agreed to store 1 oral medication in an electronic pill bottle that date and time stamps each bottle opening. Demographics, disease, donor type, and prescribed post-HSCT medication regimen were collected via chart review.

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Nov
2017

Chest pain is a common presenting complaint in general practice. Serum troponin testing is an important clinical tool to help identify patients who present with suspected acute coronary syndrome (ACS).
This article will discuss the role of troponin testing in the diagnosis of ACS, and the role of high-sensitive troponin, which is now in widespread use.

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Nov
2017

A modular synthetic approach was developed that yielded thirty diverse lead-like scaffolds suitable for CNS drug discovery.

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Oct
2017

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A "top-down" synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp-rich scaffolds.

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Dec
1969

Preclinical studies have demonstrated improvements in renal blood flow after renal sympathetic denervation (RSDN); however, such effects are yet to be confirmed in patients with resistant hypertension. Herein, we assessed the effects of RSDN on renal artery blood flow and diameter at multiple time points post-RSDN.
Patients (n=11) with systolic blood pressures ≥160 mmHg despite taking three or more antihypertensive medications at maximum tolerated dose were recruited into this single-center, prospective, non-blinded study.

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Jun
2017

The modulation of protein-protein interactions (PPIs) represents a major challenge in modern chemical biology. Current approaches (high-throughput screening, computer aided ligand design) are recognised as having limitations in terms of identification of hit matter. Considerable success has been achieved in terms of developing new approaches to PPI modulator discovery using the p53/DM2 and Bcl-2 family of PPIs.

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Dec
1969

Bax∆2 is a functional pro-apoptotic Bax isoform having alterations in its N-terminus, but sharing the rest of its sequence with Baxα. Bax∆2 is unable to target mitochondria due to the loss of helix α1. Instead, it forms cytosolic aggregates and activates caspase 8.

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Nov
2017

- Transplant-associated thrombotic microangiopathy is a serious complication of hematopoietic stem cell transplant that may progress to multi-organ dysfunction. Transplant-associated thrombotic microangiopathy may involve the intestinal vasculature (intestinal transplant-associated thrombotic microangiopathy [iTMA]), causing patients to experience debilitating symptoms of ischemic colitis, including disproportionately severe abdominal pain and gastrointestinal bleeding, requiring heavy narcotic use and frequent transfusion support. Pathophysiology remains poorly investigated but may include endothelial damage mediated by inflammatory markers and the complement system.

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Aug
2017

Protocols incorporating high-sensitivity troponin to guide decision making in the disposition of patients with suspected acute coronary syndromes (ACS) in the emergency department have received a lot of attention. Traditionally, patients with chest pain have required long periods of observation in emergency department before being deemed safe for discharge. In an era of limited health service resources, a protocol that could discharge patients safely within an hour of presentation is extremely attractive.

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Aug
2017

Over the past quarter century, clinical trials have consistently demonstrated that lowering levels of low-density lipoprotein cholesterol (LDL-C) with statins reduces the rate of major adverse cardiovascular events. However, the findings that many patients continue to experience events or harbour inappropriately high LDL-C levels despite intensive statin therapy and the clinical reality of statin intolerance suggests that additional therapeutic strategies are required in order to achieve more effective reductions in cardiovascular risk. The emergence of inhibitory monoclonal antibodies targeted against proprotein convertase subtilisin kexin type 9 (PCSK9) provides a novel approach to reducing LDL-C levels.

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May
2017

A modular synthetic approach was developed in which variation of the triplets of building blocks used enabled systematic variation of the macrocyclic scaffolds prepared. The approach was demonstrated in the synthesis of 17 diverse natural product-like macrocyclic scaffolds of varied (12-20-membered) ring size. The biological relevance of the chemical space explored was demonstrated through the discovery of a series of macrocycles with significant antimycobacterial activity.

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Jul
2017

We describe our retrospective clinical experience with ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if <25 kg.

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May
2017

Embarking on a Chemical Space Odyssey.

J Med Chem 2017 May 24;60(9):3591-3593. Epub 2017 Mar 24.
Shiao Y Chow, Adam Nelson
The chemical space explored in drug discovery programs is restricted by a narrow reaction toolkit and the frequent failure of even these reactions with polar and functionalized substrates. Recently, high-throughput reaction optimization has been integrated into discovery workflows, thereby increasing the value of specific reaction classes in the toolkit. It is likely that high-throughput experimentation will enable expansion of the synthetic chemistry that is widely exploited in discovery, thereby increasing innovation in medicinal chemistry.

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Feb
2017

Sexual size dimorphism results when female and male body size is influenced differently by natural and sexual selection. Typically, in polygynous species larger male body size is thought to be favored in competition for mates and constraints on maximal body size are due to countervailing natural selection on either sex; however, it has been postulated that sexual selection itself may result in stabilizing selection at an optimal mass. Here we test this hypothesis by retrospectively assessing the influence of body mass, one metric of body size, on the fitness of 113 wild-derived house mice) residing within ten replicate semi-natural enclosures from previous studies conducted by our laboratory.

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Oct
2017

We observed pulmonary hypertension (PH), pericardial effusions, and left ventricular systolic dysfunction (LVSD) in multiple critically ill hematopoietic stem cell transplant (HSCT) recipients. We implemented routine structured echocardiography screening for HSCT recipients admitted to the pediatric intensive care unit (PICU) using a standardized multidisciplinary process.
HSCT recipients admitted to the PICU with respiratory distress, hypoxia, shock, and complications related to transplant-associated thrombotic microangiopathy were screened on admission and every 1-2 weeks thereafter.

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Mar
2017

Natural enzymes are constructed from the 20 proteogenic amino acids, which may then require posttranslational modification or the recruitment of coenzymes or metal ions to achieve catalytic function. Here, we demonstrate that expansion of the alphabet of amino acids can also enable the properties of enzymes to be extended. A chemical mutagenesis strategy allowed a wide range of noncanonical amino acids to be systematically incorporated throughout an active site to alter enzymic substrate specificity.

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Apr
2017

The introduction of fluorine has been widely exploited to tune the biological functions of small molecules. Indeed, around 20% of leading drugs contain at least one fluorine atom. Yet, despite profound effects of fluorination on conformation, there is only a limited toolkit of reactions that enable stereoselective synthesis of fluorinated compounds.

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Jul
2017

There is a need for high-quality screening collections that maximise hit rate and minimise the time taken in lead optimisation to derive a candidate drug. Identifying and accessing molecules that meet these criteria is a challenge. Within central nervous system (CNS)-focused drug discovery, this challenge is heightened by the requirement for lead compounds to cross the blood-brain barrier.

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Dec
2017

We evaluated the utility of computerized tomography (CT) with respect to sizing work-up for percutaneous left atrial appendage (LAA) closure, and implications for procedural safety and outcomes.
Contrast-enhanced multi-detector CT was routinely conducted to guide sizing for LAA closure in addition to transoesophageal echocardiography (TOE). Procedural safety and efficacy were prospectively assessed.

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Jan
2016

Transcatheter aortic valve implantation (TAVI) can now be considered a standard of care for inoperable and high-risk surgical patients with severe aortic stenosis, and its uptake worldwide is rapidly increasing. Indeed, many centers performing the procedure have now moved towards treating intermediate-risk patients with TAVI rather than referring them for surgical aortic valve replacement. Although the incidence of peri-procedural acute and subacute stroke following TAVI has fallen to 2-5%, its occurrence can be life-threatening and life-changing, and every effort must be made to improve patient outcome should stroke occur.

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Jan
2017

Estrogen Receptor-β (ERβ) has been implicated in many cancers. In prostate and breast cancer its function is controversial, but genetic studies implicate a role in cancer progression. Much of the confusion around ERβ stems from antibodies that are inadequately validated, yet have become standard tools for deciphering its role.

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Oct
2016

Evaluating New Chemistry to Drive Molecular Discovery: Fit for Purpose?

Angew Chem Int Ed Engl 2016 Oct 30;55(44):13650-13657. Epub 2016 Aug 30.
Daniel J Foley, Adam Nelson, Stephen P Marsden
As our understanding of the impact of specific molecular properties on applications in discovery-based disciplines improves, the extent to which published synthetic methods meet (or do not meet) desirable criteria is ever clearer. Herein, we show how the application of simple (and in many cases freely available) computational tools can be used to develop a semiquantitative understanding of the potential of new methods to support molecular discovery. This analysis can, among other things, inform the design of improved substrate scoping studies; direct the prioritization of specific exemplar structures for synthesis; and substantiate claims of potential future applications for new methods.

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Jan
2017

Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of non-malignant conditions. However, these children face an increased risk of late death and incident cancers after HSCT, which may occur many years after their initial HSCT.
We examined cancer occurrence and late mortality in a population-based cohort of 318 Australian children who underwent allogeneic HSCT for non-malignant disease.

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Jul
2016

A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels-Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.

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Sep
2016

Mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBIs) lead to significant morbidity, mortality, and healthcare resource utilization in hematopoietic stem cell transplant (HSCT) patients. Determination of the healthcare burden of MBI-LCBIs and identification of patients at risk of MBI-LCBIs will allow researchers to identify strategies to reduce MBI-LCBI rates. The objective of our study was to describe the incidence, risk factors, timing, and outcomes of MBI-LCBIs in hematopoietic stem cell transplant patients.

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Oct
2016

Transcatheter aortic valve replacement (TAVR) has become an established treatment for patients with severe aortic stenosis and high surgical risk. Ten years of technological advances in valve structure and delivery systems alongside growing operator and centre experience has opened TAVR implantation to an increasingly broad range of patients. The extension to off-label use however needs careful consideration and monitoring.

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Apr
2016

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is an understudied complication of HSCT that significantly affects transplant-related morbidity and mortality. Over the past several decades, the cause of TA-TMA has remained unknown, limiting treatment options to non-specific therapies adapted from other diseases. Recent prospective studies dedicated to the study of TA-TMA have provided new insights into the pathogenesis of, and genetic susceptibility to TA-TMA, raising awareness of this important transplant complication and allowing for the identification of potentially novel therapeutic targets.

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Jun
2016

Complementary cyclisation reactions of hex-2-ene-1,6-diamine derivatives were exploited in the synthesis of alternative molecular scaffolds. The value of the synthetic approach was analysed using LLAMA, an open-access computational tool for assessing the lead-likeness and novelty of molecular scaffolds.

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Oct
2016

Cor Medusae: Giant Coronary Arteriovenous Fistula.

Rev Esp Cardiol (Engl Ed) 2016 Oct 25;69(10):976-977. Epub 2016 Apr 25.
Geoffrey R Wong, Adam J Nelson, Adil Rajwani

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Jun
2016

The trans-o-hydroxybenzylidene pyruvate aldolase-catalysed reactions between fluoropyruvate and many (hetero)aromatic aldehydes yield aldol adducts without subsequent dehydration. Treatment of the reaction products with hydrogen peroxide yields the corresponding syn-configured α-fluoro β-hydroxy carboxylic acids which have >98 % ee. The overall chemoenzymatic approach, in which fluoropyruvate serves as a fluoroacetate equivalent, may be exploited in the synthesis of polar building blocks and fragments with potential value in drug discovery.

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Jul
2016

Eculizumab inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy (TMA) in patients with atypical hemolytic uremic syndrome and is now used as a first-line therapy in these diseases. Eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) because of an increased risk of meningococcal infections in persons without adequate functional complement. Administration of meningococcal vaccine is required at least 2 weeks before administering the first dose of eculizumab, and this advice is included in the product label.

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Jul
2016

We recently reported that more than 70% of pediatric and young adult patients had a vitamin D (VD) deficiency at the time of their hematopoietic stem cell transplantation (HSCT). Moreover, VD deficiency was associated with inferior survival at 100 days after transplantation. The goal of the present study was to evaluate the VD requirements needed to maintain an optimal VD level (30 to 60 ng/mL) during the first 3 months after transplantation using real-time VD monitoring and personalized VD supplementation.

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Apr
2016

Using the HIF-1α transcription factor as a model, this manuscript illustrates how an extended sequence of α-amino acids in a polypeptide can be replaced with a non-natural topographical mimic of an α-helix comprised from an aromatic oligoamide. The resultant hybrid is capable of reproducing the molecular recognition profile of the p300 binding sequence of HIF-1α from which it is derived.

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Apr
2016

α-Helix proteomimetics represent an emerging class of ligands that can be used to inhibit an array of helix mediated protein-protein interactions. Within this class of inhibitor, aromatic oligobenzamide foldamers have been widely and successfully used. This manuscript describes alternative syntheses of these compounds that can be used to access mimetics that are challenging to synthesize using previously described methodologies, permitting access to compounds functionalized with multiple sensitive side chains and accelerated library assembly through late stage derivatisation.

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Aug
2016


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May
2016

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for progressive marrow failure, myelodysplastic syndrome, or leukemia associated with dyskeratosis congenita (DC). HSCT for DC is limited by a high incidence of treatment-related mortality, thought to be related to underlying chromosomal instability and sensitivity to chemotherapy and radiation. We report our experience in 7 patients with DC who underwent allogeneic transplantation using a reduced-intensity conditioning (RIC) preparative regimen that contained chemotherapy only (no radiation).

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Dec
1969

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy.

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Jan
2016

The catalysis of reactions involving fluoropyruvate as donor by N-acetyl neuraminic acid lyase (NAL) variants was investigated. Under kinetic control, the wild-type enzyme catalysed the reaction between fluoropyruvate and N-acetyl mannosamine to give a 90 : 10 ratio of the (3R,4R)- and (3S,4R)-configured products; after extended reaction times, equilibration occurred to give a 30 : 70 mixture of these products. The efficiency and stereoselectivity of reactions of a range of substrates catalysed by the E192N, E192N/T167V/S208V and E192N/T167G NAL variants were also studied.

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Nov
2015

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection.

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Dec
2015

Defibrillator lead endocarditis.

Eur Heart J Cardiovasc Imaging 2015 Dec 15;16(12):1407. Epub 2015 Sep 15.
Geoffrey R Wong, Ross L Roberts-Thomson, Adam J Nelson

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