Epigenome engineering in cancer: fairytale or a realistic path to the clinic?

Epigenetic modifications such as histone post-transcriptional modifications, DNA methylation, and non-protein-coding RNAs organize the DNA in the nucleus of eukaryotic cells and are critical for the spatio-temporal regulation of gene expression. These epigenetic modifications are reversible and precisely regulated by epigenetic enzymes. In addition to genetic mutations, epigenetic modifications are highly disrupted in cancer relative to normal tissues.

Stable oncogenic silencing in vivo by programmable and targeted de novo DNA methylation in breast cancer.

With the recent comprehensive mapping of cancer genomes, there is now a need for functional approaches to edit the aberrant epigenetic state of key cancer drivers to reprogram the epi-pathology of the disease. In this study we utilized a programmable DNA-binding methyltransferase to induce targeted incorporation of DNA methylation (DNAme) in the SOX2 oncogene in breast cancer through a six zinc finger (ZF) protein linked to DNA methyltransferase 3A (ZF-DNMT3A). We demonstrated long-lasting oncogenic repression, which was maintained even after suppression of ZF-DNMT3A expression in tumor cells.

Paracrine communication modulates production of Wnt antagonists and COX1-mediated prostaglandins in a decidual-trophoblast co-culture model.

Wnt signalling has important roles in decidualisation, implantation and placentation. We investigated the role of decidua-trophoblast communication and Wnt signalling in the placenta using a co-culture model. Expression of a wide range of Wnt-related genes was observed in both decidual and trophoblast cells using PCR array, with remarkably similar expression profiles.

Selective brain cooling reduces water turnover in dehydrated sheep.

In artiodactyls, arterial blood destined for the brain can be cooled through counter-current heat exchange within the cavernous sinus via a process called selective brain cooling. We test the hypothesis that selective brain cooling, which results in lowered hypothalamic temperature, contributes to water conservation in sheep. Nine Dorper sheep, instrumented to provide measurements of carotid blood and brain temperature, were dosed with deuterium oxide (D2O), exposed to heat for 8 days (40 ◦C for 6-h per day) and deprived of water for the last five days (days 3 to 8).

Abacavir-reactive memory T cells are present in drug naïve individuals.

Background: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.

Methods: To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.

Activation of protease-activated receptors (PARs)-1 and -2 promotes alpha-smooth muscle actin expression and release of cytokines from human lung fibroblasts.

Previous studies have shown that protease-activated receptors (PARs) play an important role in various physiological processes. In the present investigation, we determined the expression of PARs on human lung fibroblasts (HLF-1) and whether they were involved in cellular differentiation and pro-inflammatory cytokine and prostaglandin (PGE2) secretion. PAR-1, PAR-2, PAR-3, and PAR-4 were detected in fibroblasts using RT-PCR, immunocytochemistry, and flow cytometry.

Effects of loaded voluntary wheel exercise on performance and muscle hypertrophy in young and old male C57Bl/6J mice.

This study compared the capacity of young and old male C57Bl/6J mice to exercise with increasing resistance over 10 weeks, and its impact on muscle mass. Young mice (aged 15-25 weeks) were subjected to low (LR) and high (HR) resistance exercise, whereas only LR was used for old mice (107-117 weeks). Weekly patterns of voluntary wheel activity, food consumption and body weights were measured.

Haplosufficient genomic androgen receptor signaling is adequate to protect female mice from induction of polycystic ovary syndrome features by prenatal hyperandrogenization.

Polycystic ovary syndrome (PCOS) is associated with reproductive, endocrine, and metabolic abnormalities. Because hyperandrogenism is the most consistent PCOS feature, we used wild-type (WT) and androgen receptor (AR) knockout (ARKO) mice, together with a mouse model of PCOS, to investigate the contribution of genomic AR-mediated actions in the development of PCOS traits. PCOS features were induced by prenatal exposure to dihydrotestosterone (250 μg) or oil vehicle (control) on days 16-18 of gestation in WT, heterozygote, and homozygote ARKO mice.

Pressure-limited sustained inflation vs. gradual tidal inflations for resuscitation in preterm lambs.

Support of the mechanically complex preterm lung needs to facilitate aeration while avoiding ventilation heterogeneities: whether to achieve this gradually or quickly remains unclear. We compared the effect of gradual vs. constant tidal inflations and a pressure-limited sustained inflation (SI) at birth on gas exchange, lung mechanics, gravity-dependent lung volume distribution, and lung injury in 131-day gestation preterm lambs.

Plasma cholinesterase activity of rats, western grey kangaroos, alpacas, sheep, cattle, and horses.

Introduction: Plasma cholinesterase activity levels of various species may be of interest to toxicologists or pathologists working with chemicals that interfere with the activity of plasma cholinesterase.

Methods: We used a pH titration method to measure the plasma cholinesterase activity of six mammalian species.

Results: Plasma cholinesterase activity varied up to 50-fold between species: sheep (88 ± 45 nM acetylcholine degraded per ml of test plasma per minute), cattle (94 ± 35), western grey kangaroos (126 ± 92), alpaca (364 ± 70), rats (390 ± 118) and horses (4539 ± 721).

A qualitative study exploring counselling for release of information to participants of a donor-assisted conception programme.

Worldwide, donor-assisted conceptions are increasing with legislative reforms in some countries providing opportunities for participants of a donor-assisted conception programme, i.e. recipients, donors, donor-conceived adults and their genetically related siblings and half-siblings, to access information.

Evidence for lymphatics in the developing and adult human choroid.

Purpose: Lymphatics subserve many important functions in the human body including maintenance of fluid homeostasis, immune surveillance, and tumor metastasis. Our aim was to provide structural and phenotypic evidence of lymphatic-like structures in the human choroid, including details of its development.

Methods: Using multiple-marker immunohistochemistry (IHC), choroids from human fetal eyes (8-26 weeks gestation) and adults (17-74 years) were examined with lymphatic- and vascular-specific markers: prospero homeobox-1 (PROX-1), lymphatic vascular endothelium receptor-1 (LYVE-1), podoplanin, D2-40, endomucin, VEGF-C, vascular endothelial growth factor receptor-3 (VEGFR-3 or Flt4), UEA lectin, platelet endothelial cell adhesion molecule-1 (PECAM-1), CD34, and CD39.

Ten years of hospitalisation for oral health-related conditions in Western Australia: an unjust dichotomy.

The objective of this study was: (1) to examine the demographics of in-patient oral health care by Aboriginal status; (2) to identify the mix of oral conditions by Aboriginal status; and (3) to describe trends over a 10-year period, comparing Aboriginal and non-Aboriginal groups. Hospitalisation data were obtained from the Western Australian Morbidity Data System (HMDS). The principal diagnosis, as classified by the International Classification of Disease (ICD-10AM), was obtained for every episode for adult patients who were discharged from all hospitals in Western Australia (WA) for the financial years 1999-2000 to 2008-09.

Social integration confers thermal benefits in a gregarious primate.

Sociality has been shown to have adaptive value for gregarious species, with more socially integrated animals within groups experiencing higher reproductive success and longevity. The value of social integration is often suggested to derive from an improved ability to deal with social stress within a group; other potential stressors have received less attention. We investigated the relationship between environmental temperature, an important non-social stressor, and social integration in wild female vervet monkeys (Chlorocebus pygerythrus), using implanted data loggers to obtain direct measures of core body temperature.

A Comprehensive Evaluation of a Two-Channel Portable Monitor to "Rule in" Obstructive Sleep Apnea.

Study Objectives: We hypothesized that a dual-channel portable monitor (PM) device could accurately identify patients who have a high pretest probability of obstructive sleep apnea (OSA), and we evaluated factors that may contribute to variability between PM and polysomnography (PSG) results.

Methods: Consecutive clinic patients (N = 104) with possible OSA completed a home PM study, a PM study simultaneous with laboratory PSG, and a second home PM study. Uniform data analysis methods were applied to both PM and PSG data.

High follicle density does not decrease sweat gland density in Huacaya alpacas.

When exposed to high ambient temperatures, mammals lose heat evaporatively by either sweating from glands in the skin or by respiratory panting. Like other camelids, alpacas are thought to evaporate more water by sweating than panting, despite a thick fleece, unlike sheep which mostly pant in response to heat stress. Alpacas were brought to Australia to develop an alternative fibre industry to sheep wool.

Heterothermy in large mammals: inevitable or implemented?

Advances in biologging techniques over the past 20 years have allowed for the remote and continuous measurement of body temperatures in free-living mammals. While there is an abundance of literature on heterothermy in small mammals, fewer studies have investigated the daily variability of body core temperature in larger mammals. Here we review measures of heterothermy and the factors that influence heterothermy in large mammals in their natural habitats, focussing on large mammalian herbivores.

Nanoparticle-mediated dual delivery of an antioxidant and a peptide against the L-Type Ca2+ channel enables simultaneous reduction of cardiac ischemia-reperfusion injury.

Increased reactive oxygen species (ROS) production and elevated intracellular Ca(2+) following cardiac ischemia-reperfusion injury are key mediators of cell death and the development of cardiac hypertrophy. The L-type Ca(2+) channel is the main route for calcium influx in cardiac myocytes. Activation of the L-type Ca(2+) channel leads to a further increase in mitochondrial ROS production and metabolism.

Effects of omega-3 and omega-6 fatty acids on human placental cytokine production.

Introduction: Dietary supplementation with omega-3 long chain polyunsaturated fatty acids (n-3 PUFAs) may exert benefits in pregnancy through inhibition of placental inflammation. However, studies on the anti-inflammatory effects of n-3 PUFAs in the placenta are lacking. We compared the cytokine responses of human placental explants in vitro after 4 days pre-incubation with either: a) individual n-3 or n-6 PUFAs (20 μM), or b) physiologically relevant combinations of low, medium or high n-3 or n-6 PUFA concentrations.

Choline kinase β mutant mice exhibit reduced phosphocholine, elevated osteoclast activity, and low bone mass.

The maintenance of bone homeostasis requires tight coupling between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the precise molecular mechanism(s) underlying the differentiation and activities of these specialized cells are still largely unknown. Here, we identify choline kinase β (CHKB), a kinase involved in the biosynthesis of phosphatidylcholine, as a novel regulator of bone homeostasis.

Neurotrophic factors for spinal cord repair: Which, where, how and when to apply, and for what period of time?

A variety of neurotrophic factors have been used in attempts to improve morphological and behavioural outcomes after experimental spinal cord injury (SCI). Here we review many of these factors, their cellular targets, and their therapeutic impact on spinal cord repair in different, primarily rodent, models of SCI. A majority of studies report favourable outcomes but results are by no means consistent, thus a major aim of this review is to consider how best to apply neurotrophic factors after SCI to optimize their therapeutic potential.

Cellular and molecular changes to cortical neurons following low intensity repetitive magnetic stimulation at different frequencies.

Background: Repetitive transcranial magnetic stimulation is increasingly used as a treatment for neurological dysfunction. Therapeutic effects have been reported for low intensity rTMS (LI-rTMS) although these remain poorly understood.

Objective: Our study describes for the first time a systematic comparison of the cellular and molecular changes in neurons in vitro induced by low intensity magnetic stimulation at different frequencies.

Variable responses of benthic communities to anomalously warm sea temperatures on a high-latitude coral reef.

High-latitude reefs support unique ecological communities occurring at the biogeographic boundaries between tropical and temperate marine ecosystems. Due to their lower ambient temperatures, they are regarded as potential refugia for tropical species shifting poleward due to rising sea temperatures. However, acute warming events can cause rapid shifts in the composition of high-latitude reef communities, including range contractions of temperate macroalgae and bleaching-induced mortality in corals.

Home range overlap as a driver of intelligence in primates.

Various socioecological factors have been suggested to influence cognitive capacity in primates, including challenges associated with foraging and dealing with the complexities of social life. Alexander [Alexander, 1989]. Evolution of the human psyche.

Three-dimensional optical coherence micro-elastography of skeletal muscle tissue.

In many muscle pathologies, impairment of skeletal muscle function is closely linked to changes in the mechanical properties of the muscle constituents. Optical coherence micro-elastography (OCME) uses optical coherence tomography (OCT) imaging of tissue under a quasi-static, compressive mechanical load to map variations in tissue mechanical properties on the micro-scale. We present the first study of OCME on skeletal muscle tissue.