Publications by authors named "Paul Sinclair"

Reported herein is the first total synthesis of the poly-pseudoindoxyl natural product baphicacanthcusine A. The synthesis leverages the oxidative rearrangement of indoles to pseudoindoxyls to install vicinal pseudoindoxyl heterocycles in a diastereoselective manner. Key steps include an acid-mediated cyclization/indole transposition, two diastereoselective oxidative ring contractions, and a site-selective C-H oxygenation.

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We report the modular preparation of dihydro-1,2,5-thiodiazole dioxide heterocycles starting from methyl ketones and primary amines. This one-pot, three-component coupling employs 2,3-dimethylimidazole-1-sulfonyl azide triflate as a coupling reagent and oxidant. The transformation is scalable and various ketones and amines can be used, yielding thiodiazole dioxide products in up to 89% yield.

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Background: Access to care for children with kidney disease is limited in less well-resourced regions of the world and paediatric nephrology (PN) workforce development with good practical skills is critical.

Methods: Retrospective review of a PN training program and trainee feedback from 1999 to 2021, based at Red Cross War Memorial Children's Hospital (RCWMCH), University of Cape Town.

Results: A regionally appropriate 1-2-year training program enrolled 38 fellows with an initial 100% return rate to their country of origin.

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Article Synopsis
  • Intrachromosomal amplification of chromosome 21 is a specific subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) that involves complex genetic changes on chromosome 21, contributing to its development.
  • A study of 124 iAMP21-ALL patients revealed distinct subgroups based on their genetic alterations and identified a common amplified region containing 71 genes, many of which are linked to leukemia.
  • The research also highlighted early genetic changes in the disease, illustrated clonal diversity, and emphasized the need for improved diagnostic methods to better manage iAMP21-ALL cases.
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Article Synopsis
  • - A study on B-cell acute lymphoblastic leukaemia (B-ALL) identifies the transcription factors FOXO3 and PRDM1 as potential tumor suppressor genes through the analysis of genomic and transcriptomic data linked to large deletions in the chromosome.
  • - FOXO3 and PRDM1 work together to promote cell cycle exit in pre-B cells, while FOXO1 has a distinct role by inducing specific gene expressions that support pre-B cell development and suppress B-ALL growth.
  • - CRISPR-Cas9 research reveals FOXO3 as a tumor suppressor in B-ALL; further findings show that the pan-FOXO agonist Selinexor can inhibit glycolysis and reduce B-
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Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies.

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Background: Refractory reflux-like symptoms have a substantial impact on patients and healthcare providers. The aim of the survey was to qualitatively assess the needs and attitudes of practicing clinicians around the management of refractory reflux symptoms and refractory gastroesophageal reflux disease (rGERD).

Methods: An International Working Group for the Classification of Oesophagitis (IWGCO) steering committee invited clinicians to complete an online survey including 17 questions.

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Objectives: We estimated and compared the travel related carbon emissions of the annual meeting of the Canadian Association of Gastroenterology between the two most common geographical locations of the meeting.

Methods: We modelled the car, train and flight travel journey of each registrant to two annual meetings. One was held in Toronto, close to where the majority of Gastroenterogists live, the other in Banff in the west of the country.

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Total synthesis has long been depicted as the quest to conquer the structures created by nature, requiring an unflinching, single-minded devotion to the task. The goal is achieved by chemists with grit, strength of will, and a competitive spirit. While there is some truth to this viewpoint, it does not fully capture the rich experiences gained in this research realm.

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Background And Aim: The value of a multidisciplinary group and patient engagement in guideline groups is uncertain. We compared the recommendations of two guidelines that used the same data during the same time frame but with different participants to obtain a "real world" perspective on influence of the composition of guideline groups.

Methods: The Canadian Association of Gastroenterology (CAG) and the American College of Gastroenterology (ACG) recently updated their clinical practice guidelines for the management of Irritable Bowel Syndrome (IBS).

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Objective: Delays in triage processes in the emergency department (ED) can compromise patient safety. The aim of this study was to provide proof-of-concept that a self-check-in kiosk could decrease the time needed to identify ambulatory patients arriving in the ED. We compared the use of a novel automated self-check-in kiosk to identify patients on ED arrival to routine nurse-initiated patient identification.

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Article Synopsis
  • * Researchers discovered that a specific genetic change known as copy number neutral loss of heterozygosity (CN-LOH) on chromosome 12q occurred frequently in iAMP21-ALL cases, leading to mutations in the SH2B3 gene, which plays a role in tumor suppression.
  • * Analysis suggested that these chromosome 12q abnormalities could be linked to poorer patient outcomes in iAMP21-ALL cases, and further investigations indicated that the JAK/STAT signaling pathway
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Introduction: Uganda remains seismically vulnerable to earthquakes, which constitute one of the most deadly naturally triggered disasters in the world. This is not surprising given the country's location in the East African Rift Valley System.

Method: This paper draws mainly on the authors' live event experience and some media reports to narratively outline the nature of a sizable earthquake, which measured a magnitude of 5.

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Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of cases of childhood precursor B-cell acute lymphoblastic leukemia. These abnormalities are too complex to engineer faithfully in animal models and are unrepresented in leukemia cell lines. As a resource for future functional and preclinical studies, we have created xenografts from the leukemic blasts of patients with intrachromosomal amplification of chromosome 21 and characterized them by and luminescent imaging, flow immunophenotyping, and histological and ultrastructural analyses of bone marrow and the central nervous system.

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This paper presents the results of a consensus-driven process identifying 50 priority research questions for historical ecology obtained through crowdsourcing, literature reviews, and in-person workshopping. A deliberative approach was designed to maximize discussion and debate with defined outcomes. Two in-person workshops (in Sweden and Canada) over the course of two years and online discussions were peer facilitated to define specific key questions for historical ecology from anthropological and archaeological perspectives.

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Relapsed acute lymphoblastic leukemia is the most common cause of cancer-related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, , are particularly frequent in relapsed childhood acute lymphoblastic leukemia and associated with a hyperdiploid karyotype and mutations. To study the functional impact of haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells.

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Clinical handovers of patient care among healthcare professionals is vulnerable to the loss of important clinical information. A verbal report is typically provided by paramedics and documented by emergency department (ED) triage nurses. Paramedics subsequently complete a patient care report which is submitted electronically.

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Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.

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An important mandate of the Canadian Association of Gastroenterology (CAG), as documented in the Association's governance policies, is to optimize the care of patients with digestive disorders. Clinical practice guidelines are one means of achieving this goal. The benefits of timely, high-quality and evidenced-based recommendations include: Enhancing the professional development of clinical members through education and dissemination of synthesized clinical research; Improving patient care provided by members by providing focus on quality and evidence; Creating legislative environments that favour effective clinical practice; Enhancing the clinical care provided to patients with digestive disease by nongastroenterologists; and Identifying areas that require further information or research to improve clinical care.

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Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL.

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Background: Funders of health research in Canada seek to determine how their funding programs impact research capacity and knowledge creation.

Objective: To evaluate the impact of a focused grants and award program that was cofunded by the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes, and the Canadian Association of Gastroenterology; and to measure the impact of the Program on the career paths of funded researchers and assess the outcomes of research supported through the Program.

Methods: A survey of the recipients of grants and awards from 2000 to 2008 was conducted in 2012.

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