Chromosome 3 Anomalies Investigated by Genome Wide SNP Analysis of Benign, Low Malignant Potential and Low Grade Ovarian Serous Tumours

Ovarian carcinomas exhibit extensive heterogeneity, and their etiology remains unknown. Histological and genetic evidence has led to the proposal that low grade ovarian serous carcinomas (LGOSC) have a different etiology than high grade carcinomas (HGOSC), arising from serous tumours of low malignant potential (LMP). Common regions of chromosome (chr) 3 loss have been observed in all types of serous ovarian tumours, including benign, suggesting that these regions contain genes important in the development of all ovarian serous carcinomas. A high-density genome-wide genotyping bead array technology, which assayed >600,000 markers, was applied to a panel of serous benign and LMP tumours and a small set of LGOSC, to characterize somatic events associated with the most indolent forms of ovarian disease. The genomic patterns inferred were related to TP53, KRAS and BRAF mutations. An increasing frequency of genomic anomalies was observed with pathology of disease: 3/22 (13.6%) benign cases, 40/53 (75.5%) LMP cases and 10/11 (90.9%) LGOSC cases. Low frequencies of chr3 anomalies occurred in all tumour types. Runs of homozygosity were most commonly observed on chr3, with the 3p12-p11 candidate tumour suppressor region the most frequently homozygous region in the genome. An LMP harboured a homozygous deletion on chr6 which created a GOPC-ROS1 fusion gene, previously reported as oncogenic in other cancer types. Somatic TP53, KRAS and BRAF mutations were not observed in benign tumours. KRAS-mutation positive LMP cases displayed significantly more chromosomal aberrations than BRAF-mutation positive or KRAS and BRAF mutation negative cases. Gain of 12p, which harbours the KRAS gene, was particularly evident. A pathology review reclassified all TP53-mutation positive LGOSC cases, some of which acquired a HGOSC status. Taken together, our results support the view that LGOSC could arise from serous benign and LMP tumours, but does not exclude the possibility that HGOSC may derive from LMP tumours

Research use in children's mental health policy in Canada: Maintaining vigilance amid ambiguity

Many researchers hope to see the best available research evidence used in policy-making to address important public problems. However, policy often appears to be based on anything but the research evidence, as the problem of conduct disorder (or severe antisocial behaviour in children) shows. In Canada, few children receive effective prevention or treatment programs, and incarceration is overused, despite evidence that it is ineffective and potentially harmful. Using the example of conduct disorder, we investigated why policy-making has not reflected the research evidence, examining research use in the context of competing influences on the policy process. Qualitative methods were used to analyze data from interviews with thirty-two politicians and senior civil servants. Our allegiance to rationality wavered as we listened to policy-makers who contended with the inherent ambiguity in the policy process. They told us that they managed institutional constraints including fragmentation across levels and sectors of government, and the long-term effects of fiscal restraint. They also reconciled the competing interests of stakeholders' priorities, the public's response to negative events involving children and the media's role in shaping this response. Ideas about youth violence were morally charged, but policy-makers remained committed to improving children's lives. Day-to-day, policy-makers obtained most of their information internally and informally. Research evidence was valued and used, but as just one source of ideas and information among many. In this environment of ambiguity, creative civil servants formed partnerships with trusted researchers in order to change policy. Our findings suggest that the use of research evidence in policy-making could be enhanced if researchers learned about the competing influences on the policy process, formed research-policy partnerships, challenged the incentives within research institutions, and engaged in public debates about important problems, such as child antisocial behaviour.Health policy Knowledge transfer Knowledge utilization Children's mental health Antisocial behaviour Canada

Mitochondrial proteome disruption in the diabetic heart through targeted epigenetic regulation at the mitochondrial heat shock protein 70 (mtHsp70) nuclear locus

Greater than 99% of the mitochondrial proteome is nuclear-encoded. The mitochondrion relies on a coordinated multi-complex process for nuclear genome-encoded mitochondrial protein import. Mitochondrial heat shock protein 70 (mtHsp70) is a key component of this process and a central constituent of the protein import motor. Type 2 diabetes mellitus (T2DM) disrupts mitochondrial proteomic signature which is associated with decreased protein import efficiency. The goal of this study was to manipulate the mitochondrial protein import process through targeted restoration of mtHsp70, in an effort to restore proteomic signature and mitochondrial function in the T2DM heart. A novel line of cardiac-specific mtHsp70 transgenic mice on the db/db background were generated and cardiac mitochondrial subpopulations were isolated with proteomic evaluation and mitochondrial function assessed. MicroRNA and epigenetic regulation of the mtHsp70 gene during T2DM were also evaluated. MtHsp70 overexpression restored cardiac function and nuclear-encoded mitochondrial protein import, contributing to a beneficial impact on proteome signature and enhanced mitochondrial function during T2DM. Further, transcriptional repression at the mtHSP70 genomic locus through increased localization of H3K27me3 during T2DM insult was observed. Our results suggest that restoration of a key protein import constituent, mtHsp70, provides therapeutic benefit through attenuation of mitochondrial and contractile dysfunction in T2DM

Reactive oxygen species damage drives cardiac and mitochondrial dysfunction following acute nano-titanium dioxide inhalation exposure

<p>Nanotechnology offers innovation in products from cosmetics to drug delivery, leading to increased engineered nanomaterial (ENM) exposure. Unfortunately, health impacts of ENM are not fully realized. Titanium dioxide (TiO₂) is among the most widely produced ENM due to its use in numerous applications. Extrapulmonary effects following pulmonary exposure have been identified and may involve reactive oxygen species (ROS). The goal of this study was to determine the extent of ROS involvement on cardiac function and the mitochondrion following nano-TiO₂ exposure. To address this question, we utilized a transgenic mouse model with overexpression of a novel mitochondrially-targeted antioxidant enzyme (phospholipid hydroperoxide glutathione peroxidase; mPHGPx) which provides protection against oxidative stress to lipid membranes. MPHGPx mice and littermate controls were exposed to nano-TiO₂ aerosols (Evonik, P25) to provide a calculated pulmonary deposition of 11 µg/mouse. Twenty-four hours following exposure, we observed diastolic dysfunction as evidenced by E/A ratios greater than 2 and increased radial strain during diastole in wild-type mice (<i>p</i> < 0.05 for both), indicative of restrictive filling. Overexpression of mPHGPx mitigated the contractile deficits resulting from nano-TiO₂ exposure. To investigate the cellular mechanisms associated with the observed cardiac dysfunction, we focused our attention on the mitochondrion. We observed a significant increase in ROS production (<i>p</i> < 0.05) and decreased mitochondrial respiratory function (<i>p</i> < 0.05) following nano-TiO₂ exposure which were attenuated in mPHGPx transgenic mice. In summary, nano-TiO₂ inhalation exposure is associated with cardiac diastolic dysfunction and mitochondrial functional alterations, which can be mitigated by the overexpression of mPHGPx, suggesting ROS contribution in the development of contractile and bioenergetic dysfunction.</p

Microvascular and mitochondrial dysfunction in the female F1 generation after gestational TiO₂ nanoparticle exposure

<div><p></p><p>Due to the ongoing evolution of nanotechnology, there is a growing need to assess the toxicological outcomes in under-studied populations in order to properly consider the potential of engineered nanomaterials (ENM) and fully enhance their safety. Recently, we and others have explored the vascular consequences associated with gestational nanomaterial exposure, reporting microvascular dysfunction within the uterine circulation of pregnant dams and the tail artery of fetal pups. It has been proposed (<i>via</i> work derived by the Barker Hypothesis) that mitochondrial dysfunction and subsequent oxidative stress mechanisms as a possible link between a hostile gestational environment and adult disease. Therefore, in this study, we exposed pregnant Sprague-Dawley rats to nanosized titanium dioxide aerosols after implantation (gestational day 6). Pups were delivered, and the progeny grew into adulthood. Microvascular reactivity, mitochondrial respiration and hydrogen peroxide production of the coronary and uterine circulations of the female offspring were evaluated. While there were no significant differences within the maternal or litter characteristics, endothelium-dependent dilation and active mechanotransduction in both coronary and uterine arterioles were significantly impaired. In addition, there was a significant reduction in maximal mitochondrial respiration (state 3) in the left ventricle and uterus. These studies demonstrate microvascular dysfunction and coincide with mitochondrial inefficiencies in both the cardiac and uterine tissues, which may represent initial evidence that prenatal ENM exposure produces microvascular impairments that persist throughout multiple developmental stages.</p></div