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Pancreatic ductal adenocarcinoma is a notoriously difficult-to-treat cancer and patients are in need of novel therapies. We have shown previously that these tumours have altered metabolic requirements, making them highly reliant on a number of adaptations including a non-canonical glutamine (Gln) metabolic pathway and that inhibition of downstream components of Gln metabolism leads to a decrease in tumour growth. Here we test whether recently developed inhibitors of glutaminase (GLS), which mediates an early step in Gln metabolism, represent a viable therapeutic strategy. We show that despite marked early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that sustain proliferation in vitro and in vivo . We use an integrated metabolomic and proteomic platform to understand this adaptive response and thereby design rational combinatorial approaches. We demonstrate that pancreatic cancer metabolism is adaptive and that targeting Gln metabolism in combination with these adaptive responses may yield clinical benefits for patients. Glutaminase inhibition (GLSi) has promising activity against certain cancers. Here, the authors show that GLSi has no effect on multiple mouse models of pancreatic cancer and characterize the metabolic pathways activated in response to GLSi whose concomitant inhibition may have therapeutic utility.

Development and comparison of spine-shaped phantoms generated by two different 3D-printing technologies, digital light processing (DLP) and Polyjet has been purposed to utilize in patient-specific quality assurance (QA) of stereotactic body radiation treatment. The developed 3D-printed spine QA phantom consisted of an acrylic body phantom and a 3D-printed spine shaped object. DLP and Polyjet 3D printers using a high-density acrylic polymer were employed to produce spine-shaped phantoms based on CT images. Image fusion was performed to evaluate the reproducibility of our phantom, and the Hounsfield units (HUs) were measured based on each CT image. Two different intensity-modulated radiotherapy plans based on both CT phantom image sets from the two printed spine-shaped phantoms with acrylic body phantoms were designed to deliver 16 Gy dose to the planning target volume (PTV) and were compared for target coverage and normal organ-sparing. Image fusion demonstrated good reproducibility of the developed phantom. The HU values of the DLP- and Polyjet-printed spine vertebrae differed by 54.3 on average. The PTV Dmax dose for the DLP-generated phantom was about 1.488 Gy higher than that for the Polyjet-generated phantom. The organs at risk received a lower dose for the 3D printed spine-shaped phantom image using the DLP technique than for the phantom image using the Polyjet technique. Despite using the same material for printing the spine-shaped phantom, these phantoms generated by different 3D printing techniques, DLP and Polyjet, showed different HU values and these differently appearing HU values according to the printing technique could be an extra consideration for developing the 3D printed spine-shaped phantom depending on the patient's age and the density of the spinal bone. Therefore, the 3D printing technique and materials should be carefully chosen by taking into account the condition of the patient in order to accurately produce 3D printed patient-specific QA phantom.

α-ketoglutarate (KG), also referred to as 2-oxoglutarate, is a key intermediate of cellular metabolism with pleiotropic functions. Cell-permeable esterified analogs are widely used to study how KG fuels bioenergetic and amino acid metabolism and DNA, RNA, and protein hydroxylation reactions, as cellular membranes are thought to be impermeable to KG. Here we show that esterified KG analogs rapidly hydrolyze in aqueous media, yielding KG that, in contrast to prevailing assumptions, imports into many cell lines. Esterified KG analogs exhibit spurious KG-independent effects on cellular metabolism, including extracellular acidification, arising from rapid hydrolysis and de-protonation of α-ketoesters, and significant analog-specific inhibitory effects on glycolysis or mitochondrial respiration. We observe that imported KG decarboxylates to succinate in the cytosol and contributes minimally to mitochondrial metabolism in many cell lines cultured in normal conditions. These findings demonstrate that nuclear and cytosolic KG-dependent reactions may derive KG from functionally distinct subcellular pools and sources. Analogues of α-ketoglutarate are used in many cellular studies but assumptions are made about cellular uptake. Here, the authors show that esterified analogues rapidly hydrolyse in aqueous medium resulting in an analogue which can be quickly taken up by many cell lines, contrary to prevailing assumptions.

Background There has been little examination of consumer attitudes towards the commercial advertising of healthcare services in Australia and how marketing is used by consumers in their health decision-making. In this research, we examined how consumers reported commercial advertising helped them to understand the health services available to them and the influence that marketing had upon their choices. Methods A survey instrument using a Likert scale to indicate agreement or disagreement with 21 questions was developed using qualitative interviews before being distributed online within Australia. Sampling of participants was stratified by age, gender and location. The results were subjected to statistical analysis with Spearman Rank Correlation test being used for bivariate analysis. Results One thousand five hundred sixty-four complete surveys were collected. The results revealed certain consumer beliefs, for example; the title of ‘Dr’ was believed to indicate skill and high levels of training (81.0%), with 80.3% agreeing incorrectly that use of the title was strictly regulated. Participants reported to have a higher confidence in their own abilities (71.2%) than the public (52.8%) in assessing health advertising. The level of self-confidence increased with higher education level and decreased by age ( p  < 0.05). Testimonials were reported to be lacking in reliability (67.7%) and that they should not be used in healthcare in the same manner as they are used in other industries. Only 44.8% of participants reported that they felt confident to spot a review that was not written by a genuine user of a service. Conclusions The data demonstrated that many health consumers felt that while commercial health advertising was helpful, it was also confusing, with many participants also holding mistaken beliefs around other elements of commercial health advertising. While the advertising of healthcare services might have educational effects and be superficially empowering, advertising is primarily intended to sell, not educate. This research demonstrates that there is significant potential for healthcare advertising to mislead. Future developments in regulatory health advertising policy, and the related ethical frameworks developed by professional healthcare associations, need to consider how the consumers of healthcare services might be better protected from misleading and predatory advertising practices.

The purpose of this phase I clinical trial was to evaluate the safety, tolerability and potential efficacy of VM202, naked DNA expressing two isoforms of hepatocyte growth factor, as an adjunct therapy to coronary artery bypass grafting (CABG) in patients with ischemic heart disease (IHD). Nine patients were assigned to receive increasing doses (0.5 to 2.0 mg) of VM202 injected into the right coronary artery (RCA) territory following completion of CABG for the left coronary artery territory. Patients were evaluated for safety and tolerability, and changes in myocardial functions were monitored via echocardiography, cardiac magnetic resonance imaging and myocardial single photon emission computed tomography throughout 6-month follow-up period. No serious complication related to VM202 was observed throughout the 6-month follow-up period. Global myocardial functions (wall motion score index, P =0.0084; stress perfusion, P =0.0002) improved during the follow-up period. In the RCA region, there was an increase in the stress perfusion (baseline vs 3-month, P =0.024; baseline vs 6-month, P =0.024) and also in the wall thickness of the diastolic and systolic phases. Intramyocardial injection of VM202 can be safely used in IHD patients with the tolerable dose of 2.0 mg. In addition, VM202 might appear to have improved regional myocardial perfusion and wall thickness in the injected region.

The current evidence on the role of the social, behavioral, and community determinants of dental caries is based on cross-sectional analyses. The available evidence has not been based on analysis of multiple determinants within the same population. This longitudinal study addresses both of these limitations. The study included data from 788 dyads of children and their caregivers (77% follow-up), who were examined in 2002–03 and 2004–05. The families were assessed by calibrated dentists for severity of caries at both time periods. Additionally, the caregivers answered questionnaires administered by trained interviewers. The caries increment was adjusted for reversals. Significant predictors of higher caries increment were higher consumption of soda drinks, older age of child, greater weight-for-age, fewer dental treatment visits, higher baseline caries levels of children and their caregivers, dental fatalism, and neighborhood disadvantage status. The selected risk factors in the final model explained about 20% of the variation in the increment.

Background Socioeconomically disadvantaged children are disproportionately affected by oral disease. Mobile dental services help underserved communities overcome barriers to accessing health care, including time, geography, and trust. The NSW Health Primary School Mobile Dental Program (PSMDP) is designed to provide diagnostic and preventive dental services to children at their schools. The PSMDP is mainly targeted toward high-risk children and priority populations. This study aims to evaluate the program’s performance across five local health districts (LHDs) where the program is being implemented. Methods The evaluation will use routinely collected administrative data, along with other program-specific data sources, from the district public oral health services to conduct a statistical analysis that determines the reach and uptake of the program, its effectiveness, and the associated costs and cost-consequences. The PSMDP evaluation program utilises data from Electronic Dental Records (EDRs) and other data sources, including patient demographics, service mix, general health, oral health clinical data and risk factor information. The overall design includes cross-sectional and longitudinal components. The design combines comprehensive output monitoring across the five participating LHDs and investigates the associations between socio-demographic factors, service patterns and health outcomes. Time series analysis using difference-in-difference estimation will be conducted across the four years of the program, involving services, risk factors, and health outcomes. Comparison groups will be identified via propensity matching across the five participating LHDs. An economic analysis will estimate the costs and cost-consequences for children who participate in the program versus the comparison group. Discussion The use of EDRs for oral health services evaluation research is a relatively new approach, and the evaluation works within the limitations and strengths of utilising administrative datasets. The study will also provide avenues to improve the quality of data collected and system-level improvements to better enable future services to be aligned with disease prevalence and population needs.

The very long baseline interferometry (VLBI) technique offers angular resolutions superior to any other instruments at other wavelengths, enabling unique science applications of high-resolution imaging of radio sources and high-precision astrometry. The East Asia VLBI Network (EAVN) is a collaborative effort in the East Asian region. The EAVN currently consists of 21 telescopes with diverse equipment configurations and frequency setups, allowing flexible subarrays for specific science projects. The EAVN provides the highest resolution of 0.5 mas at 22 GHz, allowing the fine imaging of jets in active galactic nuclei, high-accuracy astrometry of masers and pulsars, and precise spacecraft positioning. The soon-to-be-operational Five-hundred-meter Aperture Spherical radio Telescope (FAST) will open a new era for the EAVN. This state-of-the-art VLBI array also provides easy access to and crucial training for the burgeoning Asian astronomical community. This Perspective summarizes the status, capabilities and prospects of the EAVN. The East Asia Very Long Baseline Interferometry Network (EAVN) consists of 21 radio telescopes whose equipment and frequency setup allow fine imaging of jets in active galaxies, high-accuracy astrometry of masers and pulsars, and spacecraft positioning.

Bone-marrow stem-cell transplantation has been shown to improve cardiac function in patients with myocardial infarction. We examined the feasibility and efficacy of granulocyte-colony stimulating factor (G-CSF) therapy and subsequent intracoronary infusion of collected peripheral blood stem-cells (PBSCs) in such patients. We prospectively randomised 27 patients with myocardial infarction who underwent coronary stenting for the culprit lesion of infarction into three groups; cell infusion (n=10), G-CSF alone (n=10), and control group (n=7). Changes in left ventricular systolic function and perfusion were assessed after 6 months. By December, 2003, seven patients from the cell infusion group, three from the G-CSF group, and one from the control group had been assessed. G-CSF injection and intracoronary infusion of the mobilised PBSC did not aggravate inflammation and ischaemia during the periprocedural period. Exercise capacity (mean treadmill exercise time: 450 s [SD 178] at baseline vs 578 s [168] at 6 months' follow-up, p=0·004), myocardial perfusion (perfusion defect 11·6% [9·6] vs 5·3% [5·0], p=0·020) and systolic function (left ventricular ejection fraction 48·7% [8·3] vs 55·1% [7·4], p=0·005) improved significantly in patients who received cell infusion. However, we noted an unexpectedly high rate of in-stent restenosis at culprit lesion in patients who received G-CSF, and therefore we stopped enrolment. G-CSF therapy with intracoronary infusion of PBSC showed improved cardiac function, and promoted angiogenesis in patients with myocardial infarction. However, aggravation of restenosis could be a serious problem. In future studies with G-CSF based stem-cell therapy, patients should be carefully monitored for unexpected effects. Published online March 2, 2004 http://image.thelancet.com/extras/04art1325web.pdf

Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with 18 O 2 or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with 18 O 2 to identify the polar oxy-metabolome, defined as polar metabolites labelled with 18 O under different physiological O 2 tensions. The most highly 18 O-labelled feature was 4-hydroxymandelate (4-HMA). We demonstrate that 4-HMA is produced by hydroxyphenylpyruvate dioxygenase-like (HPDL), a protein of previously unknown function in human cells. We identify 4-HMA as an intermediate involved in the biosynthesis of the coenzyme Q10 (CoQ10) headgroup in human cells. The connection of HPDL to CoQ10 biosynthesis provides crucial insights into the mechanisms underlying recently described neurological diseases related to HPDL deficiencies 1 – 4 and cancers with HPDL overexpression 5 . 18 O 2 labelling is used to identify metabolites in human cells that incorporate gaseous oxygen, including 4-hydroxymandelate, an intermediate in the synthesis of the coenzyme Q10 head group.