Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen ...and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.
To examine the effects of infant sofa-sleeping, recent use by caregivers of alcohol, cannabis, and/or other drugs, and bed type and pillows, on the risk of sudden unexpected death in infancy (SUDI) ...in New Zealand.
A nationwide prospective case–control study was implemented between March 2012 and February 2015. Data were collected during interviews with parents/caregivers. “Hazards” were defined as infant exposure to 1 or more of sofa-sleeping and recent use by caregivers of alcohol, cannabis, and other drugs. The interaction of hazards with tobacco smoking in pregnancy and bed sharing, including for very young infants, and the difference in risk for Māori and non-Māori infants, also were assessed.
The study enrolled 132 cases and 258 controls. SUDI risk increased with infant sofa-sleeping (imputed aOR IaOR 24.22, 95% CI 1.65-356.40) and with hazards (IaOR 3.35, 95% CI 1.40-8.01). The SUDI risk from the combination of tobacco smoking in pregnancy and bed sharing (IaOR 29.0, 95% CI 10.10-83.33) increased with the addition of 1 or more hazards (IaOR 148.24, 95% CI 15.72-1398), and infants younger than 3 months appeared to be at greater risk (IaOR 450.61, 95% CI 26.84-7593.14).
Tobacco smoking in pregnancy and bed sharing remain the greatest SUDI risks for infants and risk increases further in the presence of sofa-sleeping or recent caregiver use of alcohol and/or cannabis and other drugs. Continued implementation of effective, appropriate programs for smoking cessation, safe sleep, and supplying safe sleep beds is required to reduce New Zealand SUDI rates and SUDI disparity among Māori.
IntroductionNew Zealand (NZ) has a persistently high rate of suicide, particularly among young people. Hospital presentation for self-harm (SH) is one of the strongest predictors of death by suicide. ...Improving the monitoring of SH and suicide is a key recommendation for suicide prevention by WHO. This study will establish the first ever sentinel surveillance for SH at several large hospitals and a monthly survey of all practicing paediatricians in NZ. The study will provide robust information about the epidemiology of SH, factors associated with SH and the types of interventions required for those presenting to hospital with SH.Method and analysisThis observational study will establish SH surveillance in the emergency departments of three public hospitals for the first time in NZ, where study population will include individuals of all ages who present with SH or suicidal ideation. The study methodology is in line with the WHO Best Practice guidelines and international collaborators in Australia and Europe. Electronic triage records will be reviewed manually by the research team to identify potential cases that meet inclusion criteria. For all eligible cases, variables of interest will be extracted from routine clinical records by the research team and recorded on a secure web-based survey application. Additionally, SH surveillance data for the national paediatric population (<15 years) will be obtained via the New Zealand Paediatric Surveillance Unit (NZPSU); paediatricians will report on included cases using the same variables using a secure survey application. A deidentified dataset will be produced for aggregated statistical analysis.Ethics and disseminationThe University of Otago Health Ethics Committee granted ethical approval for this study in addition to local ethics approval at participating hospital sites. The study findings will be disseminated to relevant stakeholders in NZ, in addition to international audiences through publications in peer-reviewed scientific journals and conference presentations.
The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate‐limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for ...nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.
Synopsis
This study reports that AG636, an inhibitor of the metabolic enzyme DHODH, has excellent potency against acute myeloid leukemia (AML) in pre‐clinical models.
AG636 exhibits potent activity against different AML subtypes in vivo, promoting a combination of cell death and differentiation and effectively reducing leukemic stem cells.
DHODH inhibition has a moderate impact on normal blood development, but the effects are temporary with hematopoietic populations recovering after treatment cessation.
Pyrimidine starvation limits nascent protein synthesis, in part through downregulating YY1.
Loss of CDK5, a gene recurrently deleted in a subset of patients with aggressive disease, alters the molecular response of leukemic cells to AG636 and increases their sensitivity to drug treatment.
This study reports that AG636, an inhibitor of the metabolic enzyme DHODH, has excellent potency against acute myeloid leukemia (AML) in pre‐clinical models.
Despite a major reduction in overall infant mortality, sudden unexpected death in infancy (SUDI) continues to be of concern in New Zealand, as the rate is high by international standards, and is even ...higher in indigenous Māori.
To identify modifiable risk factors for SUDI.
A three-year (1 March 2012-28 February 2015) nationwide case-control study was conducted in New Zealand.
There were 137 SUDI cases, giving a SUDI mortality rate of 0.76/1,000 live births. The rate for Māori was 1.41/1,000, Pacific 1.01/1,000 and non-Māori non-Pacific (predominantly European) 0.50/1,000. The parent(s) of 97% of the SUDI cases were interviewed. Six hundred and forty-nine controls were selected and 258 (40%) were interviewed. The two major risk factors for SUDI were: maternal smoking in pregnancy (adjusted OR=6.01, 95% CI=2.97, 12.15) and bed sharing (aOR=4.96, 95% CI=2.55, 9.64). There was a significant interaction (p=0.002) between bed sharing and antenatal maternal smoking. Infants exposed to both risk factors had a markedly increased risk of SUDI (aOR=32.8, 95% CI=11.2, 95.8) compared with infants not exposed to either risk factor. Infants not sharing the parental bedroom were also at increased risk of SUDI (aOR=2.77, 95% CI=1.45, 5.30). Just 21 cases over the three-year study were not exposed to smoking in pregnancy, bed sharing or front or side sleeping position.
This study has shown that many of the risk factors that were identified in the original New Zealand Cot Death Study (1987-1989) are still relevant today. The combination of maternal smoking in pregnancy and bed sharing is extremely hazardous for infants. Furthermore, our findings indicate that the SUDI prevention messages are still applicable today and should be reinforced. SUDI mortality could be reduced to just seven p.a. in New Zealand (approximately one in 10,000 live births).
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of pathogenic IgG antinuclear antibodies. Pathogenic IgG autoantibody production requires B‐cell activation, ...leading to the production of activation‐induced deaminase (AID) and class switching of IgM genes to IgG. To understand how and when B cells are activated to produce these IgG autoantibodies, we studied cells from 564Igi, a mouse model of SLE. 564Igi mice develop a disease profile closely resembling that found in human SLE patients, including the presence of IgG antinucleic acid Abs. We have generated 564Igi mice that conditionally express an activation‐induced cytidine deaminase transgene (Aicdatg), either in all B cells or only in mature B cells. Here, we show that class‐switched pathogenic IgG autoantibodies were produced only in 564Igi mice in which AID was functional in early‐developing B cells, resulting in loss of tolerance. Furthermore, we show that the absence of AID in early‐developing B cells also results in increased production of self‐reactive IgM, indicating that AID, through somatic hypermutation, contributes to tolerance. Our results suggest that the pathophysiology of clinical SLE might also be dependent on AID expression in early‐developing B cells.
564Igi mice have knocked-in immunoglobulin (Ig) heavy (H) and light (L) chain genes that encode an autoantibody recognizing RNA. Previously, we showed that these mice produce pathogenic IgG ...autoantibodies when activation-induced deaminase (AID) is expressed in pre-B and immature B cells but not when it is expressed only in mature B cells. AID has two functions; it is necessary for somatic hypermutation (SHM) and class switch recombination (CSR). To determine the role of each of these functions in the generation of pathogenic autoantibodies, we generated 564Igi mice that carry a mutant AID-encoding gene,
(
), which is capable of promoting CSR but not SHM. We found that 564Igi
mice secreted class-switched antibodies (Abs) at levels approximately equal to 564Igi mice. However, compared to 564Igi mice, 564Igi
mice had increased pathogenic IgG Abs and severe systemic lupus erythematosus-like disease, including, glomerulonephritis, and early death. We suggest that in 564Igi mice SHM by AID changes Ig receptors away from self reactivity, thereby mitigating the production of autoantibody, providing a novel mechanism of tolerance.
Aim
The aims of this research were to determine the mortality from sepsis and severe infection in the paediatric and adolescent populations of Aotearoa/New Zealand, and to determine the distribution ...of mortality by sub‐populations.
Methods
We used three different methods to identify deaths from sepsis and severe infection and compared the groups:
All deaths primarily coded with any ICD‐10‐AM code relating to sepsis;
The presence of A40, A41 and P36 in any cause of death field;
Deaths due to pneumonia and meningitis.
Cases were selected from a national mortality database, with cause of death as ascribed in the national mortality collection for the years 2002–2020 inclusive. Overall sepsis and severe infection rates were calculated from the sum of unique cases from all three methods for determining sepsis and severe infection cases.
Results
Substantially different results were obtained depending on the method of identifying cases. In total, 577 deaths due to sepsis and severe infection were detected, with an overall rate of 1.99/100 000 age‐specific population and statistically significant disparity by ethnic grouping. Rates were highest in post‐neonatal infants at 22.7 per 100 000, regardless of the method of identification.
Conclusions
There is a considerable opportunity to improve the mortality from sepsis and severe infection in children and young people. The ethnic disparities described in this paper show the need to ensure a high level of care for those most marginalised in society through the development and provision of systems and structures that meet, rather than fail to meet need.
The interpretation of umbilical cord gases may not be straightforward following shoulder dystocia. We reviewed Perinatal and Maternal Mortality Review Committee data from New Zealand infants with ...moderate and severe neonatal encephalopathy (NE) for 2010–2017 inclusive. If one or more of: pH of ≤7.1; base excess of ≤–12 mmol/L; or lactate of ≥6 mmol/L were present it was considered an abnormal result. One‐third (12/36) of infants born following shoulder dystocia had documented umbilical cord gases within the normal range. It is important for clinicians to be aware of this possibility when assessing newborn infants with NE.
Aim
In New Zealand, there is a paucity of information on children with chronic conditions and disabilities (CCD). One reason is that many are managed in hospital outpatients where diagnostic coding ...of health‐care events does not occur. This study explores the feasibility of coding paediatric outpatient data to provide health planners with information on children with CCD.
Methods
Thirty‐seven clinicians from six District Health Boards (DHBs) trialled coding over 12 weeks. In five DHBs, the International Classification of Diseases and Related Health Problems, 10th Edition, Australian Modification (ICD‐10‐AM) and Systematised Nomenclature of Medicine Clinical Terms (SNOMED‐CT) were trialled for 6 weeks each. In one DHB, ICD‐10‐AM was trialled for 12 weeks. A random sample (30%) of ICD‐10‐AM coded events were also coded by clinical coders. A mix of paper and electronic methods were used.
Results
In total 2,604 outpatient events were coded in ICD‐10‐AM and 693 in SNOMED‐CT. Dual coding occurred for 770 (29.6%) ICD‐10‐AM events. Overall, 34% of ICD‐10‐AM and 40% of SNOMED‐CT events were for developmental and behavioural disorders. Chronic medical conditions were also common.
Clinicians were concerned about the workload impacts, particularly for paper‐based methods. Coder's were concerned about clinician's adherence to coding guidelines and the poor quality of documentation in some notes.
Conclusion
Coded outpatient data could provide planners with a rich source of information on children with CCD. However, coding is also resource intensive. Thus its costs need to be weighed against the costs of managing a much larger health budget using very limited information.
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