Publications by authors named "Kelly A Loffler"

28 Publications

  • Page 1 of 1

The changes of AHI after long-term CPAP in patients with comorbid OSA and cardiovascular disease.

Sleep Breath 2022 May 14. Epub 2022 May 14.

Sleep Center, Department of Pulmonary and Critical Care Medicine, Guangdong Provincial People's Hospital/Guangdong Academy of Medical Sciences/Guangdong Provincial Geriatrics Institute, Guangzhou, 510080, China.

Purpose: To evaluate the effect of long-term continuous positive airway pressure (CPAP) treatment on disease severity of obstructive sleep apnea (OSA).

Methods: We analyzed results from the Sleep Apnea and Cardiovascular Events (SAVE) study involving participants recruited at the Guangdong Provincial People's Hospital, China. Participants were aged 45-75 years with a history of cardiac or cerebrovascular disease. OSA was confirmed by home sleep apnea testing (HSAT). Participants were randomized to receive CPAP plus standard cardiovascular care (CPAP group) or standard care alone (UC group) and followed for several years. At the study conclusion, surviving participants were invited to repeat HSAT. Changes in OSA indicators were compared by independent samples t-tests and subgroup analysis was implied among groups stratified by OSA severity.

Results: One hundred two adults were recruited (51 per group) and followed for 48.0 ± 14.5 months. Daily CPAP usage in the CPAP group was 4.1 ± 1.9 h. AHI decreased from baseline to end-of-study in both CPAP and UC groups (- 5.0 (- 12.5,2.0), P = 0.000; - 4.0 (- 12.5,1.5), P = 0.007, respectively), with no between-group difference (P = 0.453). An improvement in nadir SpO showed from baseline to end-of-study in the CPAP but not UC group (2.3% ± 6.1%, P = 0.011 and - 0.7% ± 7.6%, P = 0.511, respectively; between-group difference P = 0.032). Subgroup analysis shows that CPAP could improve AHI in patients with moderate OSA (- 8.0 (- 11.8, - 2.8) in CPAP group, - 2.0 (- 0.8,6.0) in UC group, P = 0.022) and improve nadir SpO in patients with severe OSA (5.0 (- 0.8, - 0.8,7.0) in CPAP group, 0.0 (- 8.5,2.5) in UC group, P = 0.032).

Conclusion: Long-term CPAP use did not result in clinically significant changes in AHI or ODI overall but showed variable effects stratified by OSA severity.

Clinical Trial Registration: Registry: Clinical Trials.gov, title: Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease (SAVE), URL: www.

Clinicaltrials: gov , identifier: NCT00738179.
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http://dx.doi.org/10.1007/s11325-022-02633-yDOI Listing
May 2022

Multinight Prevalence, Variability, and Diagnostic Misclassification of Obstructive Sleep Apnea.

Am J Respir Crit Care Med 2022 03;205(5):563-569

Adelaide Institute for Sleep Health and Flinders Health and Medical Research Institute Sleep Health, College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Recent studies suggest that obstructive sleep apnea (OSA) severity can vary markedly from night to night, which may have important implications for diagnosis and management. This study aimed to assess OSA prevalence from multinight in-home recordings and the impact of night-to-night variability in OSA severity on diagnostic classification in a large, global, nonrandomly selected community sample from a consumer database of people that purchased a novel, validated, under-mattress sleep analyzer. A total of 67,278 individuals aged between 18 and 90 years underwent in-home nightly monitoring over an average of approximately 170 nights per participant between July 2020 and March 2021. OSA was defined as a nightly mean apnea-hypopnea index (AHI) of more than 15 events/h. Outcomes were multinight global prevalence and likelihood of OSA misclassification from a single night's AHI value. More than 11.6 million nights of data were collected and analyzed. OSA global prevalence was 22.6% (95% confidence interval, 20.9-24.3%). The likelihood of misdiagnosis in people with OSA based on a single night ranged between approximately 20% and 50%. Misdiagnosis error rates decreased with increased monitoring nights (e.g., 1-night F1-score = 0.77 vs. 0.94 for 14 nights) and remained stable after 14 nights of monitoring. Multinight in-home monitoring using novel, noninvasive under-mattress sensor technology indicates a global prevalence of moderate to severe OSA of approximately 20%, and that approximately 20% of people diagnosed with a single-night study may be misclassified. These findings highlight the need to consider night-to-night variation in OSA diagnosis and management.
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http://dx.doi.org/10.1164/rccm.202107-1761OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906484PMC
March 2022

CPAP increases physical activity in obstructive sleep apnea with cardiovascular disease.

J Clin Sleep Med 2021 02;17(2):141-148

Adelaide Institute for Sleep Health - A Flinders Centre of Research Excellence, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia.

Study Objectives: Uncertainty exists over whether continuous positive airway pressure (CPAP) treatment improves moderate to vigorous physical activity levels in those with obstructive sleep apnea. We aimed to determine effects of CPAP on moderate to vigorous physical activity among participants with co-occurring cardiovascular disease and obstructive sleep apnea.

Methods: The Sleep Apnea cardioVascular Endpoints (SAVE) trial recruited participants with confirmed cardiovascular disease history and obstructive sleep apnea, 45-75 years old. The 2,687 participants (1,346 randomized to CPAP plus usual care and 1,341 to usual care alone) were followed up for a mean of 3.7 years. Self-reported physical activity was recorded at baseline, 6, 24, and 48 months using the Godin-Shepard Leisure Time Exercise Questionnaire (LTEQ). We also determined effects on any limitation of physical activity reported on the physical functioning subscale of the 36-item short form questionnaire (SF-36) and proportions of participants reaching guideline recommended physical activity levels.

Results: Among 2,601 participants with available data, those in the CPAP group reported significantly more physical activity compared to the usual care group, with approximately 20% higher reported moderate activities on the LTEQ during follow-up (adjusted mean 95% confidence interval) scores: 8.7, 7.5-9.9 vs 7.3, 6.1-8.5; P = .003). Those in the CPAP group also reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score 1.66, 95% confidence interval 0.87-2.45; P < 0.001), and more reported sufficient levels of physical activity to meet recommendations.

Conclusions: CPAP has positive effects on improving physical activity levels, consistent with long-term health benefits.

Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease (SAVE); URL: https://clinicaltrials.gov/ct2/show/NCT00738179; Identifier: NCT00738179; and Registry: Australian New Zealand Clinical Trials Registry; Name: Sleep Apnea cardioVascular Endpoints study-An investigation of continuous positive airway pressure for the treatment of obstructive sleep apnea to prevent cardiovascular disease; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=83062&isReview=true; Identifier: ACTRN12608000409370.
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http://dx.doi.org/10.5664/jcsm.8792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853210PMC
February 2021

Low Prognostic Value of Novel Nocturnal Metrics in Patients With OSA and High Cardiovascular Event Risk: Post Hoc Analyses of the SAVE Study.

Chest 2020 12 14;158(6):2621-2631. Epub 2020 Jul 14.

School of Electrical and Electronic Engineering, University of Adelaide, Adelaide, Australia.

Background: Traditional methods for the quantification of OSA severity may not encapsulate potential relationships between hypoxemia in OSA and cardiovascular risk.

Research Question: Do novel nocturnal oxygen saturation (Spo) metrics have prognostic value in patients with OSA and high cardiovascular event risk?

Study Design And Methods: We conducted post hoc analyses of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial. In 2687 individuals, Cox proportional hazards models that were stratified for treatment allocation were used to determine the associations between clinical characteristics, pulse oximetry-derived metrics that were designed to quantify sustained and episodic features of hypoxemia, and cardiovascular outcomes. Metrics included oxygen desaturation index, time <90% Spo, average Spo for the entire recording (mean Spo), average Spo during desaturation events (desaturation Spo), average baseline Spo interpolated across episodic desaturation events (baseline Spo), episodic desaturation event duration and desaturation/resaturation-time ratio, and mean and SD of pulse rate.

Results: Neither apnea-hypopnea index, oxygen desaturation index, nor any of the novel Spo metrics were associated with the primary SAVE composite cardiovascular outcome. Mean and baseline Spo were associated with heart failure (hazard ratio [HR], 0.81; 95% CI, 0.69-0.95; P = .009; and HR, 0.78; 95% CI, 0.67-0.90; P = .001, respectively) and myocardial infarction (HR, 0.86; 95% CI, 0.77-0.95; P = .003; and HR, 0.81; 95% CI, 0.73-0.90; P < .001, respectively). Desaturation duration and desaturation/resaturation time ratio, with established risk factors, predicted future heart failure (area under the curve, 0.86; 95% CI, 0.79-0.93).

Interpretation: Apnea-hypopnea index and oxygen desaturation index were not associated with cardiovascular outcomes. In contrast, the pattern of oxygen desaturation was associated with heart failure and myocardial infarction. However, concomitant risk factors remained the predominant determinants for secondary cardiovascular events and thus deserve the most intensive management.
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http://dx.doi.org/10.1016/j.chest.2020.06.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173772PMC
December 2020

Self-reported Snoring Patterns Predict Stroke Events in High-Risk Patients With OSA: Post Hoc Analyses of the SAVE Study.

Chest 2020 11 15;158(5):2146-2154. Epub 2020 Jul 15.

The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; The George Institute China at Peking University Health Science Center, Beijing, China; Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, NSW, Australia; Heart Health Research Center, Beijing, China; Universidad del Desarrollo, School of Medicine-Clínica Alemana, ICIM, Center for Clinical Studies, Santiago, Chile. Electronic address:

Background: The relation of snoring to risks of stroke and other major cardiovascular (CV) events is uncertain.

Research Question: We aimed to determine associations of snoring patterns and major CV events in relation to OSA among participants of the international Sleep Apnea cardiovascular Endpoints (SAVE) trial.

Study Design And Methods: Post hoc analyses of the SAVE trial, which involved 2,687 patients with coexisting moderate-to-severe OSA and established coronary or cerebral CV disease, who were randomly allocated to CPAP treatment plus usual care or usual care alone, and followed-up for a median 3.5 years. Associations of self-reported snoring patterns (frequency and loudness) and breathing pauses collected on the Berlin questionnaire at baseline and multiple times during follow-up, and adjudicated composites of CV outcomes (primary, CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina, heart failure, or transient ischemic attack; and separately of cardiac and cerebral events), were evaluated in time-dependent Cox proportional hazards models adjusted for various confounders including the apnea-hypopnea index.

Results: Increase (per category) of snoring frequency (adjusted hazard ratio [HR], 1.10; 95% CI, 1.02-1.20; P = .015), loudness (HR, 1.16; 95% CI, 1.06-1.27; P = .001), and breathing pauses (HR, 1.16; 95% CI, 1.08-1.25; P < .001) at any time point during follow-up were each associated with the primary composite CV outcome. These associations were driven by significant associations for cerebral rather than cardiac events, and positive interactions between the three snoring patterns for cerebral events. There was no significant interaction between CPAP treatment and snoring variables for cerebral events.

Interpretation: Snoring in patients with OSA with established CV disease is associated with greater risks of cerebral but not cardiac events, independent of CPAP treatment and frequency of apnea and hypopnea events.

Trial Registry: ClinicalTrials.gov; No.: NCT00738179; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2020.05.615DOI Listing
November 2020

Continuous Positive Airway Pressure Treatment, Glycemia, and Diabetes Risk in Obstructive Sleep Apnea and Comorbid Cardiovascular Disease.

Diabetes Care 2020 08 14;43(8):1859-1867. Epub 2020 Apr 14.

Adelaide Institute for Sleep Health, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia

Objective: Despite evidence of a relationship among obstructive sleep apnea (OSA), metabolic dysregulation, and diabetes, it is uncertain whether OSA treatment can improve metabolic parameters. We sought to determine effects of long-term continuous positive airway pressure (CPAP) treatment on glycemic control and diabetes risk in patients with cardiovascular disease (CVD) and OSA.

Research Design And Methods: Blood, medical history, and personal data were collected in a substudy of 888 participants in the Sleep Apnea cardioVascular Endpoints (SAVE) trial in which patients with OSA and stable CVD were randomized to receive CPAP plus usual care, or usual care alone. Serum glucose and glycated hemoglobin A (HbA) were measured at baseline, 6 months, and 2 and 4 years and incident diabetes diagnoses recorded.

Results: Median follow-up was 4.3 years. In those with preexisting diabetes ( = 274), there was no significant difference between the CPAP and usual care groups in serum glucose, HbA, or antidiabetic medications during follow-up. There were also no significant between-group differences in participants with prediabetes ( = 452) or new diagnoses of diabetes. Interaction testing suggested that women with diabetes did poorly in the usual care group, while their counterparts on CPAP therapy remained stable.

Conclusions: Among patients with established CVD and OSA, we found no evidence that CPAP therapy over several years affects glycemic control in those with diabetes or prediabetes or diabetes risk over standard-of-care treatment. The potential differential effect according to sex deserves further investigation.
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http://dx.doi.org/10.2337/dc19-2006DOI Listing
August 2020

Sleep duration and risk of cardiovascular events: The SAVE study.

Int J Stroke 2020 10 3;15(8):858-865. Epub 2020 Feb 3.

The 211065George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

Background And Aim: Controversy exists regarding cardiovascular risk in relation to sleep duration. We determined sleep duration and major recurrent cardiovascular event associations in patients with obstructive sleep apnoea and established cardiovascular disease.

Methods: Secondary analyses of the international, multicenter, Sleep Apnea Cardiovascular Endpoints trial. Sleep duration was estimated from overnight home oximetry (ApneaLink monitor) used for obstructive sleep apnoea diagnosis. Cox proportional hazards models were used to determine associations of categorized sleep duration (<6 h, 6-8 h (reference), and >8 h) and major cardiovascular outcomes: primary composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and any hospitalization for unstable angina, heart failure, or transient ischemic attack; secondary composite of cardiac and cerebral (stroke/transient ischemic attack) events.

Results: Oximetry-derived sleep duration estimates were available in 2687 participants (mean 61.2 years, 80.9% males) who experienced a total of 436 cardiovascular events over a mean follow-up of 3.7 years. Compared to the reference category, sleep duration was not associated with risk of the primary composite cardiovascular outcome (adjusted hazard ratio (HR) 1.00, 95% confidence interval 0.76-1.33, and HR 1.22, 95% confidence interval 0.98-1.52, for sleep duration <6 and >8 h, respectively). However, long sleep was associated with increased cerebral events (HR 1.67, 95% confidence interval 1.17-2.39;  = 0.005) and stroke alone (HR 1.79, 95% confidence interval 1.22-2.63;  = 0.003).

Conclusions: Long sleep duration is associated with an increased risk of stroke but not cardiac events in obstructive sleep apnoea patients with existing cardiovascular disease.

Clinical Trial Registration: The trial is registered at ClinicalTrials.gov (NCT00738179).
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http://dx.doi.org/10.1177/1747493020904913DOI Listing
October 2020

Predictors of long-term adherence to continuous positive airway pressure in patients with obstructive sleep apnea and cardiovascular disease.

Sleep 2019 10;42(10)

Adelaide Institute for Sleep Health: A Flinders Centre for Research Excellence, Flinders University, Adelaide, Australia.

Study Objectives: Poor adherence to continuous positive airway pressure (CPAP) commonly affects therapeutic response in obstructive sleep apnea (OSA). We aimed to determine predictors of adherence to CPAP among participants of the Sleep Apnea and cardioVascular Endpoints (SAVE) trial.

Methods: SAVE was an international, randomized, open trial of CPAP plus usual care versus usual care (UC) alone in participants (45-75 years) with co-occurring moderate-to-severe OSA (≥12 episodes/h of ≥4% oxygen desaturation) and established cardiovascular (CV) disease. Baseline sociodemographic, health and lifestyle factors, OSA symptoms, and 1-month change in daytime sleepiness, as well as CPAP side effects and adherence (during sham screening, titration week, and in the first month), were entered in univariate linear regression analyses to identify predictors of CPAP adherence at 24 months. Variables with p <0.2 were assessed for inclusion in a multivariate linear mixed model with country, age, and sex included a priori and site as a random effect.

Results: Significant univariate predictors of adherence at 24 months in 1,121 participants included: early adherence measures, improvement in daytime sleepiness at 1 month, fixed CPAP pressure, some measures of OSA severity, cardiovascular disease history, breathing pauses, and very loud snoring. While observed adherence varied between countries, adherence during sham screening, initial titration, and the first month of treatment retained independent predictive value in the multivariate model along with fixed CPAP pressure and very loud snoring.

Conclusions: Early CPAP adherence had the greatest predictive value for identifying those at highest risk of non-adherence to long-term CPAP therapy.

Clinical Trial Registration: SAVE is registered with clinicaltrials.gov (NCT00738179).
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http://dx.doi.org/10.1093/sleep/zsz152DOI Listing
October 2019

Effects of continuous positive airway pressure on depression and anxiety symptoms in patients with obstructive sleep apnoea: results from the sleep apnoea cardiovascular Endpoint randomised trial and meta-analysis.

EClinicalMedicine 2019 May-Jun;11:89-96. Epub 2019 Jun 13.

The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.

Background: Whether continuous positive airway pressure (CPAP) treatment can improve depression or anxiety symptoms in obstructive sleep apnoea (OSA) patients remains uncertain.

Methods: Secondary analysis of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial, combined with a systematic review of randomised evidence. The SAVE secondary analyses involved 2410 patients with co-existing moderate-severe OSA and established cardiovascular disease randomly allocated to CPAP treatment plus usual care or usual care alone and followed up for 3·7 (SD 1·6) years. We evaluated the effect of CPAP treatment on depression and anxiety caseness (scores ≥ 8 on the Hospital Anxiety and Depression Scale depression and anxiety subscales [HADS-D and HADS-A]) for OSA patients.

Findings: CPAP treatment was associated with reduced odds of depression caseness (adjusted odds ratio [OR] 0·80, 95% confidence interval [CI] 0·65-0·98, P = 0·031) compared to usual care in the SAVE trial and the treatment effect was greater in those with pre-existing depression symptoms. A systematic review of 20 randomised trials including 4255 participants confirmed a benefit of CPAP in reducing depression symptoms in OSA patients: the overall effect (standardised mean difference) was - 0·18 (95% CI - 0·24 to - 0·12). No effect of CPAP treatment on anxiety caseness was found both in patients of the SAVE study (adjusted OR 0·98, 95% CI 0·78-1·24, P = 0·89) and the systematic review.

Interpretation: CPAP reduces depression symptoms in patients with co-existing OSA and CVD independently of improvements in sleepiness.
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http://dx.doi.org/10.1016/j.eclinm.2019.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610775PMC
June 2019

Complex structural rearrangements are present in high-grade dysplastic Barrett's oesophagus samples.

BMC Med Genomics 2019 02 4;12(1):31. Epub 2019 Feb 4.

Surgical Oncology Group, Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals.

Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples.

Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples.

Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.
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http://dx.doi.org/10.1186/s12920-019-0476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360790PMC
February 2019

The Effects of Long-term CPAP on Weight Change in Patients With Comorbid OSA and Cardiovascular Disease: Data From the SAVE Trial.

Chest 2019 04 27;155(4):720-729. Epub 2018 Sep 27.

Flinders Centre for Epidemiology and Biostatistics (Dr Woodman), College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

Background: Although recent evidence suggests that OSA treatment may cause weight gain, the long-term effects of CPAP on weight are not well established.

Methods: This study was a post hoc analysis of the Sleep Apnea Cardiovascular Endpoints (SAVE) study, a multicenter, randomized trial of CPAP plus standard care vs standard care alone in adults with a history of cardiac or cerebrovascular events and moderate to severe OSA. Participants with weight, BMI, and neck and waist circumferences measured at baseline and during follow-up were included. Linear mixed models were used to examine sex-specific temporal differences, and a sensitivity analysis compared high CPAP adherers (≥ 4 h per night) with propensity-matched control participants.

Results: A total of 2,483 adults (1,248 in the CPAP group and 1,235 in the control group) were included (mean 6.1 ± 1.5 measures of weight available). After a mean follow-up of 3.78 years, there was no difference in weight change between the CPAP and control groups, for male subjects (mean [95% CI] between-group difference, 0.07 kg [-0.40 to 0.54]; P = .773) or female subjects (mean [95% CI] between-group difference, -0.14 kg [-0.37 to 0.09]; P = .233). Similarly, there were no significant differences in BMI or other anthropometric measures. Although male participants who used CPAP ≥ 4 h per night gained slightly more weight than matched male control subjects without CPAP (mean difference, 0.38 kg [95% CI, 0.04 to 0.73]; P = .031), there were no between-group differences in other anthropometric variables, nor were there any differences between female high CPAP adherers and matched control subjects.

Conclusions: Long-term CPAP use in patients with comorbid OSA and cardiovascular disease does not result in clinically significant weight change.

Trial Registry: ClinicalTrials.gov; No.: NCT00738179; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2018.08.1082DOI Listing
April 2019

Effect of Obstructive Sleep Apnea Treatment on Renal Function in Patients with Cardiovascular Disease.

Am J Respir Crit Care Med 2017 12;196(11):1456-1462

1 Adelaide Institute for Sleep Health: A Flinders Centre of Research Excellence and.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired renal function, but uncertainty exists over whether OSA treatment can influence renal outcomes.

Objectives: To determine the effects of continuous positive airway pressure (CPAP) on renal function in subjects with coexisting OSA and cardiovascular disease.

Methods: This was a substudy of the international SAVE (Sleep Apnea Cardiovascular Endpoints) trial, in which 2,717 patients with moderate to severe OSA and established coronary or cerebrovascular disease were randomized to receive either CPAP plus usual care or usual care alone. Renal function and adverse renal events were compared between the CPAP (n = 102) and usual care (n = 98) groups. Glomerular filtration rate was estimated at randomization and at the end of follow-up, and the urinary albumin-to-creatinine ratio was measured at study exit.

Measurements And Main Results: In 200 substudy participants (mean age, 64 yr; median, 4% oxygen desaturation index; 20 events/h; mean estimated glomerular filtration rate at baseline, 82 ml/min/1.73 m), the median (interquartile range) changes in estimated glomerular filtration rate (ml/min/1.73 m/yr) were -1.64 (-3.45 to -0.740) in the CPAP group and -2.30 (-4.53 to -0.71) in the usual care group (P = 0.21) after a median of 4.4 years. There were no between-group differences in end-of-study urinary albumin-to-creatinine ratio or in the occurrence of serious renal or urinary adverse events during the trial. The level of CPAP adherence did not influence the findings.

Conclusions: CPAP treatment of OSA in patients with cardiovascular disease does not alter renal function or the occurrence of renal adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT00738179).
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http://dx.doi.org/10.1164/rccm.201703-0603OCDOI Listing
December 2017

Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.

Carcinogenesis 2016 Apr 10;37(4):356-65. Epub 2016 Feb 10.

Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia, Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia and.

The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival.
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http://dx.doi.org/10.1093/carcin/bgw018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806711PMC
April 2016

Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

Nat Commun 2014 Oct 29;5:5224. Epub 2014 Oct 29.

QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
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http://dx.doi.org/10.1038/ncomms6224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596003PMC
October 2014

BRAF mutation status is an independent prognostic factor for resected stage IIIB and IIIC melanoma: implications for melanoma staging and adjuvant therapy.

Eur J Cancer 2014 Oct 25;50(15):2668-76. Epub 2014 Jul 25.

QIMR Berghofer Medical Research Institute, Oncogenomics Laboratory, Brisbane, QLD, Australia.

Background: 5-year survival for melanoma metastasis to regional lymph nodes (American Joint Committee on Cancer stage III) is <50%. Knowledge of outcomes following therapeutic lymphadenectomy for stage III melanoma related to BRAF status may guide adjuvant use of BRAF/MEK inhibitors along with established and future therapies.

Aims: To determine patterns of melanoma recurrence and survival following therapeutic lymph node dissection (TLND) associated with oncogenic mutations.

Methods: DNA was obtained from patients who underwent TLND and had ⩾2 positive nodes, largest node >3cm or extracapsular invasion. Mutations were detected using an extended Sequenom MelaCARTA panel.

Results: Mutations were most commonly detected in BRAF (57/124 [46%] patients) and NRAS (26/124 [21%] patients). Patients with BRAF mutations had higher 3-year recurrence rate (77%) versus 54% for BRAF wild-type patients (hazard ratio (HR) 1.8, p=0.008). The only prognostically significant mutations occurred in BRAF: median recurrence-free (RFS) and disease-specific survival (DSS) for BRAF mutation patients was 7 months and 16 months, versus 19 months and not reached for BRAF wild-type patients, respectively. Multivariate analysis identified BRAF mutant status and number of positive lymph nodes as the only independent prognostic factors for RFS and DSS.

Conclusions: Patients with BRAF mutations experienced rapid progression of metastatic disease with locoregional recurrence rarely seen in isolation, supporting incorporation of BRAF status into melanoma staging and use of BRAF/MEK inhibitors post-TLND.
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http://dx.doi.org/10.1016/j.ejca.2014.06.009DOI Listing
October 2014

Menin and p53 have non-synergistic effects on tumorigenesis in mice.

BMC Cancer 2012 Jun 18;12:252. Epub 2012 Jun 18.

Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, 4006, Australia.

Background: While it is now more than a decade since the first description of the gene mutation underlying the tumour predisposition syndrome multiple endocrine neoplasia type 1 (MEN1), the mechanism by which its protein product menin acts to prevent development of tumours is still poorly understood.

Methods: We undertook a genetic experiment to assess whether menin synergises with p53. Mice carrying various combinations of Men1 and Trp53 mutations were generated then survival and pathology assessed.

Results: While homozygous loss of Trp53 in mice resulted in early onset, aggressive tumours and profoundly reduced lifespan, heterozygous loss of either Trp53 or Men1 caused later onset disease, with a spectrum of tumours characteristic of each tumour suppressor gene. Loss of one copy of Men1 in animals also lacking both alleles of Trp53 did not exacerbate phenotype, based on survival, animal weight or sites of pathology, compared to Trp53 deletion alone. Dual heterozygous deletion of Men1 and Trp53 resulted in a small reduction in lifespan compared to the individual mutations, without new tumour sites. In the adrenal, we observed development of cortical tumours in dual heterozygous animals, as we have previously seen in Men1+/- animals, and there was loss of heterozygosity at the Men1 allele in these tumours. Median number of pathology observations per animal was increased in dual heterozygous animals compared with heterozygous loss of Trp53 alone.

Conclusions: Simultaneous heterozygous deletion of Men1 in animals with either heterozygous or homozygous deletion of Trp53 did not result in formation of tumours at any new sites, implying additive rather than synergistic effects of these pathways. Mice that were Men1+/- in addition to Trp53+/- had tumours in endocrine as well as other sites, implying that increase in total tumour burden, at sites typically associated with either Men1 or Trp53 loss, contributed to the slight decrease in survival in Men1+/-: Trp53+/- animals in comparison with their littermates.
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http://dx.doi.org/10.1186/1471-2407-12-252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433377PMC
June 2012

Alterations in gene expression in MEN1-associated insulinoma development.

Pancreas 2010 Nov;39(8):1140-6

Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Australia.

Objectives: To identify gene expression alterations associated with insulinoma formation and progression in 2 mouse models of multiple endocrine neoplasia type 1.

Methods: Mice were killed at 12 or 16 months, and pancreatic islets were isolated by enzymatic and physical disruption. Islets were separated by size representing control, normal, hyperplastic, and adenomous islets. RNA was isolated from these islets and profiled on Sentrix Mouse-6 Expression version 1 BeadChips. Array data were analyzed in GeneSpring.

Results: One hundred and one genes that were significantly (P ≤ 0.05) altered in hyperplastic islets and insulinomas compared with normal islets were identified. Of these, 64 gene elements showed reduced messenger RNA levels and 37 gene elements had increased gene expression compared with control islets. Altered expression of 3 genes, namely, Gata6, Tspan8, and s100a8, was confirmed by quantitative reverse transcription-polymerase chain reaction, and aberrant levels of Tspan8 and Lmo2 protein measured by Western blot correlated with the changes in messenger RNA levels.

Conclusions: These results suggest that alterations in gene expression of Gata6, Tspan8, S100a8, and Lmo2 may act via novel pathways that play functionally important roles in Men1-associated tumor progression.
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http://dx.doi.org/10.1097/MPA.0b013e3181dc67fcDOI Listing
November 2010

Global expression profiling of sex cord stromal tumors from Men1 heterozygous mice identifies altered TGF-beta signaling, decreased Gata6 and increased Csf1r expression.

Int J Cancer 2009 Mar;124(5):1122-32

Queensland Institute of Medical Research, QLD, Australia.

Heterozygous disruption of the Men1 gene predisposes mice to the development of multiple endocrine tumors, accurately mimicking the human MEN1 cancer predisposition syndrome. Additionally, Men1(+/-) mice frequently develop sex cord adenomas. The mechanism underlying the susceptibility of these mice to sex cord tumor development has not been fully determined, but data suggest it may involve transcriptional regulation of key growth promoting/repressing genes. To identify potential menin-regulated genes that may be important for tumor suppression in sex cord cells, we compared the global gene expression profiles of testis and ovary adenomas with other endocrine tumors of the pancreas and pituitary from Men1 heterozygous mice and with control tissues. Gonadal tumors clustered separately from pancreas and pituitary tumors with only a few genes (e.g., Cdkn2c) commonly dysregulated in all tumor types. Testis and ovary tumors displayed a higher level of transcriptional similarity to each other than they did to their respective control tissues. Among genes that had decreased expression in tumors was significant over-representation of genes associated with the TGF-beta, hedgehog and Wnt signaling, indicating that loss of menin function affects these pathways at the level of transcription. Aberrant protein expression in Leydig and granulosa cells of 2 transcriptionally dysregulated gene products, Gata6 and Csf1r were confirmed by immunohistochemistry. We propose that sex cord tumor susceptibility in Men1(+/-) mice involves deregulated cell proliferation due to dysregulation of multiple cell growth regulating genes including: reduced Cdkn2c transcription, loss of TGF-beta pathway tumor suppressor function (e.g., Gata6) and transcriptional activation of Csf1r.
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http://dx.doi.org/10.1002/ijc.24057DOI Listing
March 2009

Retinoic acid promotes the generation of pancreatic endocrine progenitor cells and their further differentiation into beta-cells.

PLoS One 2008 Jul 30;3(7):e2841. Epub 2008 Jul 30.

Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden.

The identification of secreted factors that can selectively stimulate the generation of insulin producing beta-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based beta-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of beta-cells during normal pancreatic development such putative factors may be identified. In the mouse, beta-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of beta-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when beta-cells are generated. We also provide evidence that RA induces the generation of Ngn3(+) endocrine progenitor cells and stimulates their further differentiation into beta-cells by activating a program of cell differentiation that recapitulates the normal temporal program of beta-cell differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002841PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475501PMC
July 2008

Global expression profiling of murine MEN1-associated tumors reveals a regulatory role for menin in transcription, cell cycle and chromatin remodelling.

Int J Cancer 2007 Aug;121(4):776-83

Division of Cancer Cell Biology, Queensland Institute of Medical Research, Herston, QLD, Australia.

Although the identification of menin-interacting partners and other evidence support a role for menin, the multiple endocrine neoplasia type 1 gene (MEN1) product, in regulating gene expression, little is known about the cellular pathways dysregulated by menin loss during tumorigenesis. The mouse models of MEN1 accurately mimic the human syndrome and provide an opportunity to assess the transcriptional effects of Men1 deletion in different endocrine tumor types to identify common pathway aberrations underlying tumorigenesis in MEN1-affected tissues. We compared the global gene expression profiles of pituitary adenomas and pancreatic islet tumors with control tissues from wild-type littermates. Amongst the 551 differentially expressed genes was significant over-representation of genes associated with chromatin remodelling, transcription and cell cycling, including some genes known to encode menin-binding partners, e.g., Rhox5 and Mll1. Consistent with increased cell-cycle transition from G1 to S phase was an elevation of Cdc7 expression in the tumors, which was confirmed by qRT-PCR using independent samples. In support of previous findings in islet tumors, we found down-regulation of the cell-cycle regulator, p18, in both the pancreatic islet and pituitary adenomas, suggesting that reduced p18 levels may be important for Men1-related tumorigenesis in multiple tissues. Surprisingly, we identified increased p16 transcript in pancreatic islet and pituitary tumors. This was accompanied by increased cytoplasmic localization p16 protein in tumor cells. The specific genes and general pathways we have found to be commonly dysregulated in MEN1 tumors, provide a platform for determining their roles in endocrine tumorigenesis.
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http://dx.doi.org/10.1002/ijc.22734DOI Listing
August 2007

Broad tumor spectrum in a mouse model of multiple endocrine neoplasia type 1.

Int J Cancer 2007 Jan;120(2):259-67

Queensland Institute of Medical Research, Herston, QLD, Australia.

Multiple endocrine neoplasia type 1 (MEN1) is an inherited cancer predisposition syndrome typified by development of tumors in parathyroid, pituitary and endocrine pancreas, as well as less common sites including both endocrine and nonendocrine organs. Deletion or mutation of the tumor suppressor gene MEN1 on chromosome 11 has been identified in many cases of MEN1 as well as in sporadic tumors. The molecular biology of menin, the protein encoded by MEN1, remains poorly understood. Here we describe a mouse model of MEN1 in which tumors were seen in pancreatic islets, pituitary, thyroid and parathyroid, adrenal glands, testes and ovaries. The observed tumor spectrum therefore includes types commonly seen in MEN1 patients and additional types. Pancreatic pathology was most common, evident in over 80% of animals, while other tumor types developed with lower frequency and generally later onset. Tumors of multiple endocrine organs were observed frequently, but progression to carcinoma and metastasis were not evident. Tumors in all sites showed loss of heterozygosity at the Men1 locus, though the frequency in testicular tumors was only 36%, indicating that a different molecular mechanism of tumorigenesis occurs in those Leydig tumors that do not show loss of the normal Men1 allele. Menin expression was below the level of detection in ovary, thyroid and testis, but loss of nuclear menin immunoreactivity was observed uniformly in all pancreatic islet adenomas and in some hyperplastic islet cells, suggesting that complete loss of Men1 is a critical point in islet tumor progression in this model.
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http://dx.doi.org/10.1002/ijc.22288DOI Listing
January 2007

Pisrt1, a gene implicated in XX sex reversal, is expressed in gonads of both sexes during mouse development.

Mol Genet Metab 2005 Sep-Oct;86(1-2):286-92

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.

XX sex reversal syndromes not involving Sry provide an opportunity to identify and study genes important for sexual development. The polled intersex syndrome (PIS) in goats, which shares some features with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) in humans, exemplifies such syndromes. BPES is caused by defects in the forkhead transcription factor gene FOXL2, while PIS is caused by a large deletion of goat chromosome 1q43 that affects transcription of the genes Pisrt1 and Foxl2. Pisrt1 is a non-translated gene that has a sexually dimorphic expression pattern in goats. Here, we describe the structure and expression of the mouse Pisrt1 locus, to investigate its likely role in ovarian development more broadly in mammals. This gene showed some sequence similarity, and was found in a similar genomic context, to its goat and human orthologues. Expression analyses indicated that Pisrt1 is transcribed, and its mRNA polyadenylated and exported to the cytoplasm, but no significant open reading frames were found in a 1.5kb mouse genomic region corresponding to goat Pisrt1. Pisrt1 transcripts were expressed very broadly among tissues of the developing mouse embryo, and at similar levels in male and female gonads at each stage examined, as determined by in situ hybridisation and RT-PCR. This profile of expression suggests that Pisrt1 is unlikely to contribute to sex-specific events during gonadal development in mice and that divergent pathways of ovarian development operate among different mammalian species.
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http://dx.doi.org/10.1016/j.ymgme.2005.06.013DOI Listing
January 2006

Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues.

Mol Cell Biol 2004 Apr;24(8):3125-31

Queensland Institute of Medical Research, Herston, Queensland, Australia.

Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1(-/-) genotype and leads to beta-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause beta-cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC381682PMC
http://dx.doi.org/10.1128/MCB.24.8.3125-3131.2004DOI Listing
April 2004

Etiology of ovarian failure in blepharophimosis ptosis epicanthus inversus syndrome: FOXL2 is a conserved, early-acting gene in vertebrate ovarian development.

Endocrinology 2003 Jul;144(7):3237-43

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.

Blepharophimosis ptosis epicanthus inversus syndrome (BPES) is a human disorder caused by mutations in the forkhead transcription factor gene FOXL2 and is characterized by facial dysmorphology combined in some cases with ovarian failure. To better understand the role of FOXL2 in the etiology of ovarian failure in BPES, we examined its expression in embryonic ovaries of mice, chickens, and red-eared slider turtles, representatives of three phylogenetically distant vertebrate groups that have different mechanisms of sex determination. Expression of Foxl2 was detected in early ovaries of all three species around the time of sex determination and was associated with both somatic and germ cell populations in mice. Expression was sexually dimorphic in all cases. Sequence analysis of turtle and chicken FoxL2 orthologues indicated an unusually high degree of structural conservation during evolution. FoxL2 was found to be autosomal in chickens, and therefore unlikely to represent the dominant ovarian-determining gene that has been postulated to exist as a possible explanation for female heterogamety in birds. Our observations suggest that BPES may result from early abnormalities in regulating the development of the fetal ovary, rather than premature degeneration of the postnatal or adult ovary. Further, our results suggest that FOXL2 is a highly conserved early regulator of vertebrate ovarian development.
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http://dx.doi.org/10.1210/en.2002-0095DOI Listing
July 2003

Sex determination: the fishy tale of Dmrt1.

Curr Biol 2003 Mar;13(5):R177-9

Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Australia.

The idea that the Dmrt1 gene provides a unifying sex-determining mechanism in non-mammalian vertebrates is left high and dry by recent observations in fish.
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http://dx.doi.org/10.1016/s0960-9822(03)00117-9DOI Listing
March 2003

Charting the course of ovarian development in vertebrates.

Int J Dev Biol 2002 ;46(4):503-10

Institute for Molecular Bioscience, and Department of Biochemistry and Molecular Biology, University of Queensland, Brisbane, Australia.

The decision of the embryonic gonad to differentiate as either a testis or an ovary is a critical step in vertebrate development. The molecular basis of this decision has been the focus of much study, particularly over the past decade. Here we contrast the knowledge of early gonadal development and the switch to testis differentiation with the lack of molecular understanding of ovarian development at early stages. We review current knowledge regarding mechanisms of ovarian morphogenesis and propose a model for the hierarchical control of development of the fetal ovary, incorporating the few genes already known to be important and several signals or factors that are hypothesised to exist in the early ovary.
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February 2003

The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2.

J Biol Chem 2002 Feb 16;277(6):4324-33. Epub 2001 Nov 16.

Center for Molecular and Cellular Biology, Institute for Molecular Bioscience, University of Queensland, St. Lucia 4072, Queensland, Australia.

Studies with the myogenic basic helix-loop-helix and MADS box factors suggest that efficient transactivation is dependent on the recruitment of the steroid receptor coactivator (SRC) and the cofactors p300 and p300/CBP-associated factor. SRCs have been demonstrated to recruit CARM1 (coactivator-associated arginine methyltransferase-1), a member of the S-adenosyl-l-methionine-dependent PRMT1-5 (protein-arginine N-methyltransferase-1-5) family, which catalyzes the methylation of arginine residues. This prompted us to investigate the functional role of CARM1/PRMT4 during skeletal myogenesis. We demonstrate that CARM1 and the SRC cofactor GRIP-1 cooperatively stimulate the activity of myocyte enhancer factor-2C (MEF2C). Moreover, there are direct interactions among MEF2C, GRIP-1, and CARM1. Chromatin immunoprecipitation demonstrated the in vivo recruitment of MEF2 and CARM1 to the endogenous muscle creatine kinase promoter in a differentiation-dependent manner. Furthermore, CARM1 is expressed in somites during embryogenesis and in the nuclei of muscle cells. Treatment of myogenic cells with the methylation inhibitor adenosine dialdehyde or tet-regulated CARM1 "antisense" expression did not affect expression of MyoD. However, inhibition of CARM1 inhibited differentiation and abrogated the expression of the key transcription factors (myogenin and MEF2) that initiate the differentiation cascade. This work clearly demonstrates that the arginine methyltransferase CARM1 potentiates myogenesis and supports the positive role of arginine methylation in mammalian differentiation.
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http://dx.doi.org/10.1074/jbc.M109835200DOI Listing
February 2002
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