Decreased mitochondrial respiration in aneurysmal aortas of Fibulin-4 mutant mice is linked to PGC1A regulation

Aim Thoracic aortic aneurysms are a life-threatening condition often diagnosed too late. To discover novel robust biomarkers, we aimed to better understand the molecular mechanisms underlying aneurysm formation. Methods and results In Fibulin-4R/R mice, the extracellular matrix protein Fibulin-4 is 4-fold reduced, resulting in progressive ascending aneurysm formation and early death around 3 months of age. We performed proteomics and genomics studies on Fibulin-4R/R mouse aortas. Intriguingly, we observed alterations in mitochondrial protein composition in Fibulin-4R/R aortas. Consistently, functional studies in Fibulin-4R/R vascular smooth muscle cells (VSMCs) revealed lower oxygen consumption rates, but increased acidification rates. Yet, mitochondria in Fibulin-4R/R VSMCs showed no aberrant cytoplasmic localization. We found similar reduced mitochondrial respiration in Tgfbr-1M318R/+ VSMCs, a mouse model for Loeys-Dietz syndrome (LDS). Interestingly, also human fibroblasts from Marfan (FBN1) and LDS (TGFBR2 and SMAD3) patients showed lower oxygen consumption. While individual mitochondrial Complexes I–V activities were unaltered in Fibulin-4R/R heart and muscle, these tissues showed similar decreased oxygen consumption. Furthermore, aortas of aneurysmal Fibulin-4R/R mice displayed increased reactive oxygen species (ROS) levels. Consistent with these findings, gene expression analyses revealed dysregulation of metabolic pathways. Accordingly, blood ketone levels of Fibulin-4R/R mice were reduced and liver fatty acids were decreased, while liver glycogen was increased, indicating dysregulated metabolism at the organismal level. As predicted by gene expression analysis, the activity of PGC1α, a key regulator between mitochondrial function and organismal metabolism, was downregulated in Fibulin-4R/R VSMCs. Increased TGFβ reduced PGC1α levels, indicating involvement of TGFβ signalling in PGC1α regulation. Activation of PGC1α restored the decreased oxygen consumption in Fibulin-4R/R VSMCs and improved their reduced growth potential, emphasizing the importance of this key regulator. Conclusion Our data indicate altered mitochondrial function and metabolic dysregulation, leading to increased ROS levels and altered energy production, as a novel mechanism, which may contribute to thoracic aortic aneurysm formation

Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder

Meier–Gorlin syndrome (MGS) is a rare autosomal recessivedisorder characterized by primordial dwarfism, microtia, andpatellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic backgroundand underlying molecular cause, with ORC1 and ORC4 mutationscausing more severe short stature and microcephaly.Growth hormone therapy (n=9) was generally ineffective,though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) andmammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth

Molecular characterization of colorectal cancer related peritoneal metastatic disease

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity

Molecular characterization of colorectal cancer related peritoneal metastatic disease

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity

Molecular characterization of colorectal cancer related peritoneal metastatic disease

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity

Molecular characterization of colorectal cancer related peritoneal metastatic disease

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity

Musculoskeletal health and work ability in physically demanding occupations: study protocol for a prospective field study on construction and health care workers

Abstract Background: Musculoskeletal disorders have a profound impact on individual health, sickness absence and early retirement, particularly in physically demanding occupations. Demographics are changing in the developed countries, towards increasing proportions of senior workers. These senior workers may have particular difficulties coping with physically demanding occupations while maintaining good health. Previous studies investigating the relationship between physical work demands and musculoskeletal disorders are mainly based on self-reported exposures and lack a prospective design. The aim of this paper is to describe the background and methods and discuss challenges for a field study examining physical demands in construction and health care work and their prospective associations with musculoskeletal disorders, work ability and sickness absence. Methods and design: This protocol describes a prospective cohort study on 1200 construction and health care workers. Participants will answer a baseline questionnaire concerning musculoskeletal complaints, general health, psychosocial and organizational factors at work, work demands, work ability and physical activity during leisure. A shorter questionnaire will be answered every 6 th months for a total of two years, together with continuous sickness absence monitoring during this period. Analysis will prospectively consider associations between self-reported physical demands and musculoskeletal disorders, work ability and sickness absence. To obtain objective data on physical exposures, technical measurements will be collected from two subgroups of N = 300 (Group A) and N = 160 (Group B) during work and leisure. Both group A and B will be given a physical health examination, be tested for physical capacity and physical activity will be measured for four days. Additionally, muscle activity, ground reaction force, body positions and physical activity will be examined during one workday for Group B. Analysis of associations between objectively measured exposure data and the outcomes described above will be done separately for these subpopulations. Discussion: The field study will at baseline produce objectively measured data on physical demands in the construction and health care occupations. In combination with clinical measurements and questionnaire data during follow-up, this will provide a solid foundation to prospectively investigate relationships between physical demands at work and development of musculoskeletal disorders, work ability and sickness absence

Bias and imprecision in posture percentile variables estimated from short exposure samples

BACKGROUND: Upper arm postures are believed to be an important risk determinant for musculoskeletal disorder development in the neck and shoulders. The 10th and 90th percentiles of the angular elevation distribution have been reported in many studies as measures of neutral and extreme postural exposures, and variation has been quantified by the 10th-90th percentile range. Further, the 50th percentile is commonly reported as a measure of "average" exposure. These four variables have been estimated using samples of observed or directly measured postures, typically using sampling durations between 5 and 120 min. METHODS: The present study examined the statistical properties of estimated full-shift values of the 10th, 50th and 90th percentile and the 10th-90th percentile range of right upper arm elevation obtained from samples of seven different durations, ranging from 5 to 240 min. The sampling strategies were realized by simulation, using a parent data set of 73 full-shift, continuous inclinometer recordings among hairdressers. For each shift, sampling duration and exposure variable, the mean, standard deviation and sample dispersion limits (2.5% and 97.5%) of all possible sample estimates obtained at one minute intervals were calculated and compared to the true full-shift exposure value. RESULTS: Estimates of the 10th percentile proved to be upward biased with limited sampling, and those of the 90th percentile and the percentile range, downward biased. The 50th percentile was also slightly upwards biased. For all variables, bias was more severe with shorter sampling durations, and it correlated significantly with the true full-shift value for the 10th and 90th percentiles and the percentile range. As expected, shorter samples led to decreased precision of the estimate; sample standard deviations correlated strongly with true full-shift exposure values. CONCLUSIONS: The documented risk of pronounced bias and low precision of percentile estimates obtained from short posture samples presents a concern in ergonomics research and practice, and suggests that alternative, unbiased exposure variables should be considered if data collection resources are restricted