The role of epigenetics in resistance to cisplatin chemotherapy in lung cancer

Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20-30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

The potential role of lycopene for the prevention and therapy of prostate cancer : from molecular mechanisms to clinical evidence

Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red, lipophilic and naturally occurring in many fruits and vegetables, with tomatoes and tomato-based products containing the highest concentrations of bioavailable lycopene. Several epidemiological studies have linked increased lycopene consumption with decreased prostate cancer risk. These findings are supported by in vitro and in vivo experiments showing that lycopene not only enhances the antioxidant response of prostate cells, but that it is even able to inhibit proliferation, induce apoptosis and decrease the metastatic capacity of prostate cancer cells. However, there is still no clearly proven clinical evidence supporting the use of lycopene in the prevention or treatment of prostate cancer, due to the only limited number of published randomized clinical trials and the varying quality of existing studies. The scope of this article is to discuss the potential impact of lycopene on prostate cancer by giving an overview about its molecular mechanisms and clinical effects. © 2013 by the authors; licensee MDPI, Basel, Switzerland.

Hydrogel microwell arrays allow the assessment of protease-associated enhancement of cancer cell aggregation and survival

Current routine cell culture techniques are only poorly suited to capture the physiological complexity of tumor microenvironments, wherein tumor cell function is affected by intricate three-dimensional (3D), integrin-dependent cell-cell and cell-extracellular matrix (ECM) interactions. 3D cell cultures allow the investigation of cancer-associated proteases like kallikreins as they degrade ECM proteins and alter integrin signaling, promoting malignant cell behaviors. Here, we employed a hydrogel microwell array platform to probe using a high-throughput mode how ovarian cancer cell aggregates of defined size form and survive in response to the expression of kallikreins and treatment with paclitaxel, by performing microscopic, quantitative image, gene and protein analyses dependent on the varying microwell and aggregate sizes. Paclitaxel treatment increased aggregate formation and survival of kallikrein-expressing cancer cells and levels of integrins and integrin-related factors. Cancer cell aggregate formation was improved with increasing aggregate size, thereby reducing cell death and enhancing integrin expression upon paclitaxel treatment. Therefore, hydrogel microwell arrays are a powerful tool to screen the viability of cancer cell aggregates upon modulation of protease expression, integrin engagement and anti-cancer treatment providing a micro-scaled yet high-throughput technique to assess malignant progression and drug-resistance.

In vitro assessment of migratory behavior of two cell populations in a simple multichannel microdevice

Recent literature suggests that mesenchymal stem/stromal cells (MSC) could be used as Trojan Horses to deliver “death-signals” to cancer cells. Herein, we describe the development of a novel multichannel cell migration device, and use it to investigate the relative migration rates of bone marrow-derived MSC and breast cancer cells (MCF-7) towards each other. Confluent monolayers of MSC and MCF-7 were established in adjacent chambers separated by an array of 14 microchannels. Initially, culture chambers were isolated by air bubbles (air-valves) contained within each microchannel, and then bubbles were displaced to initiate the assay. The MCF-7 cells migrated preferentially towards MSC, whilst the MSC did not migrate preferentially towards the MCF-7 cells. Our results corroborate previous literature that suggests MSC migration towards cancer cells in vivo is in response to the associated inflammation rather than directly to signals secreted by the cancer cells themselves.

Engraftment outcomes after HPC co-culture with mesenchymal stromal cells and osteoblasts

Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co-culture on monolayers of either undifferentiated mesenchymal stromal cells (MSCs) or osteoblasts. Sorted Lineage− Sca-1+ c-kit+ (LSK) haematopoietic stem/progenitor cells (HPC) demonstrated proliferative capacity on both stromal monolayers with the greatest expansion of LSK shown in cultures supported by osteoblast monolayers. After transplantation, both types of bulk-expanded cultures were capable of engrafting and repopulating lethally irradiated primary and secondary murine recipients. LSKs co-cultured on MSCs showed comparable, but not superior, reconstitution ability to that of freshly isolated LSKs. Surprisingly, however, osteoblast co-cultured LSKs showed significantly poorer haematopoietic reconstitution compared to LSKs co-cultured on MSCs, likely due to a delay in short-term reconstitution. We demonstrated that stromal monolayers can be used to maintain, but not expand, functional HSCs without a need for additional haematopoietic growth factors. We also demonstrated that despite apparently superior in vitro performance, co-injection of bulk cultures of osteoblasts and LSKs in vivo was detrimental to recipient survival and should be avoided in translation to clinical practice.

Direct Detection of a Persistent Carbonyloxyl Radical in the Gas Phase

Long lived: Carbonyloxyl radicals (RCO2 .) are reactive intermediates that play key roles in initiating polymerization reactions. This reactivity also makes their direct observation difficult. For the first time a persistent organic RCO2 . radical is detected in the gas phase, its extraordinary longevity is attributed to the high barrier towards fragmentation owing to the endothermicity of the decarboxylation products. Grant Numbers ARC/DP0986738, ARC/DP120102922, ARC/DE120100467

Bisresorcinols and arbutin derivatives from Grevillea banksii R. Br

This work is part of a series of chemical investigations of the genus Grevillea. Two new arbutin derivatives, seven new bisresorcinols, including a mixture of two isomers, three known flavonol glycosides, and four known resorcinols, including a mixture of two homologous compounds, were isolated from the ethyl acetate extract of the leaves and methanol extract of the stems of Grevillea banksii. The new compounds were identified, on the basis of spectroscopic data, as 6'-O-(3-(2(hydroxymethyl)acryloyloxy)-2-methylpropanoyl)arbutin (1), 6'-O-(2-methylacryloyl)arbutin (2), 5,5'-(4(Z)-dodecen-1,12diyl)bisresorcinol (6), 2'-methyl-5,5'-(4(Z)-tetradecen-1,14-diyl)bisresorcinol (8), 2,2'-di(4-hydroxyprenyl)-5,5'-(6(Z)-tetradecen-1,14-diyl)bisresorcinol (9), 2-(4-acetoxyprenyl)-2'-(4-hydroxyprenyl) 5,5'-(6(Z)-tetradecen-1,14-diyl)bisresorcinol (10), 2-(4-acetoxyprenyl)-2'-(4-hydroxyprenyl)5,5'-(8(Z)-tetradecen-l,14-diyl)bisresorcinol (11), 5,5'-(10(Z)-tetradecen-1-on-diyl)bisresorcinol (12) and 5,5'-(4(Z)-tetradecen-1-on-diyl)bisresorcinol (13).

Bisresorcinol Derivatives from Grevillea glauca

Seven new and three known bisresorcinols, grevirobstol A(=5,5'-((6Z,9Z)-hexadeca-6,9-diene-1,16-diyl)bisresorcinol; 8), 5,5'-[(8Z)-hexadec-8-ene-1,16-diyl]bisresorcinol (9), and 2-methyl-5,5'-[8Z)-hexadec-8-ene-1,16-diyl] bisresorcinol (10) were isolated from the stems of Grevillea glauca. The new compounds were identified on the basis of spectroscopic data as (Z)-6,7-didehydroglaucone A (1), glaucones A and B (2 and 3, resp.), 2-(3-hydroxyisopentyl)bisnorstriatol (4), 2-(3-methylbut-2-en-1-yl)bisnorstriatol (5), 2'-methylgrebustol A (6), and glaucane (7).

The body in grief : death investigations, objections to autopsy, and the religious and cultural 'other'

Sudden, violent and otherwise unexplained deaths are investigated in most western jurisdictions through a Coronial or medico-legal process. A crucial element of such an investigation is the legislative requirement to remove the body for autopsy and other medical interventions, processes which can disrupt traditional religious and cultural grieving practices. While recent legislative changes in an increasing number of jurisdictions allow families to raise objections based on religious and cultural grounds, such concerns can be over-ruled, often exacerbating the trauma and grief of families. Based on funded research which interviews a range of Coronial staff in one Australian jurisdiction, this paper explores the disjuncture between medico-legal discourses, which position the body as corpse, and the rise of more ‘therapeutic’ discourses which recognise the family’s wishes to reposition the body as beloved and lamented.

Reactions of simple and peptidic alpha-carboxylate radical anions with dioxygen in the gas phase

alpha-Carboxylate radical anions are potential reactive intermediates in the free radical oxidation of biological molecules (e. g., fatty acids, peptides and proteins). We have synthesised well-defined alpha-carboxylate radical anions in the gas phase by UV laser photolysis of halogenated precursors in an ion-trap mass spectrometer. Reactions of isolated acetate ((center dot)CH(2)CO(2)) and 1-carboxylatobutyl (CH(3)CH(2)CH(2)(center dot)CHCO(2)(-)) radical anions with dioxygen yield carbonate (CO(3)(center dot-)) radical anions and this chemistry is shown to be a hallmark of oxidation in simple and alkyl-substituted cross-conjugated species. Previous solution phase studies have shown that C(alpha)-radicals in peptides, formed from free radical damage, combine with dioxygen to form peroxyl radicals that subsequently decompose into imine and keto acid products. Here, we demonstrate that a novel alternative pathway exists for two alpha-carboxylate C(alpha)-radical anions: the acetylglycinate radical anion (CH(3)C(O)NH(center dot)CHCO(2)(-)) and the model peptide radical anion, YGGFG(center dot-). Reaction of these radical anions with dioxygen results in concerted loss of carbon dioxide and hydroxyl radical. The reaction of the acetylglycinate radical anion with dioxygen reveals a two-stage process involving a slow, followed by a fast kinetic regime. Computational modelling suggests the reversible formation of the C(alpha) peroxyl radical facilitates proton transfer from the amide to the carboxylate group, a process reminiscent of, but distinctive from, classical proton-transfer catalysis. Interestingly, inclusion of this isomerization step in the RRKM/ME modelling of a G3SX level potential energy surface enables recapitulation of the experimentally observed two-stage kinetics.

Prenylated Alkylbisphenols from Grevillea whiteana

Eleven new bisresorcinols including four mixtures each of two isomers and one resorcinol/phloroglucinol derivative, together with five known resorcinols have been isolated from the ethyl acetate extract of sterns of Grevillea whiteana. The new Compounds were identified as 4-(3-hydroxy-3-methylbutyl)grebustol-B (10a), 4'-(3-hydroxy-3-methylbutyl)grebustol-B (10b), 4-(4-hydroxy-3-methylbutyl)grebustol-B (2a) and 4'-(4-hydroxy-3-methylbutyl) rebustol-B (2b), 2,2-dimethyldihydropyrano grebustol-B (11a) and iso-2,2-dimethyldihydropyranogrebustol-B (11b), 2,2-dimethyl-3 xi-hydroxydihydropyranogrebustol-B (7a) and iso-2,2-dimethyl-3 xi-hydroxydihydropyranogrebustol-B (7b), 15-(2-(4-hydroxy-3-methylbutyl)-resorcinol-5-yl)-1-(phloroglucinolyl )-9(Z)pentadecen-one (whiteanone) (4), 5,5'-(hexadecan-diyl)bisresorcinol (12) and 2-methyl-5,5'-(8(Z)hexadecen-1,16-diyl)bisresorcinol (9). This is the first record of pyranobisresorcinols in the genus and the first report of a phloroglucinol terminal Phenolic unit in any Grevillea species.

Prenylated bisresorcinols from Grevillea floribunda

Seven new bisresorcinol derivatives, together with four known resorcinols. have been isolated from the ethyl acetate extract of the sterns of Grevillea floribunda. Five of the new compounds (floribol A-E) were characterized as bisnorstriatol derivatives Substituted at C-2 of both resorcinol units with variously modified prenyl (3-methylbut-2-enyl) units. The remaining two new compounds are similarly Substituted derivatived of grebustol-B. (c) 2008 Phytochemical Society of Europe Published by Elsevier B.V. All rights reserved.

Synthesis of MgB2 at low temperature and autogenous pressure

High quality, micron-sized interpenetrating grains of MgB2 with high density are produced at low temperatures (~420oC < T < ~500oC) under autogenous pressure by pre-mixing Mg powder and NaBH4 and heating in an Inconel 601 alloy reactor for 5−15 hours. Optimum production of MgB2 with yields greater than 75% occurs for autogenous pressure in the range 1.0 MPa to 2.0 MPa with the reactor at ~500oC. Autogenous pressure is induced by the decomposition of NaBH4 in the presence of Mg and/or other Mg-based compounds. The morphology, transition temperature and magnetic properties of MgB2 are dependent on the heating regime. Significant improvement in physical properties accrues when the reactor temperature is held at 250oC for >20minutes prior to a hold at 500oC.

The effect of exercise on the skeletal muscle phospholipidome of rats fed a high-fat diet

The aim of this study was to examine the effect of endurance training on skeletal muscle phospholipid molecular species from high-fat fed rats. Twelve female Sprague-Dawley rats were fed a high-fat diet (78.1% energy). The rats were randomly divided into two groups, a sedentary control group and a trained group (125 min of treadmill running at 8 m/min, 4 days/wk for 4 weeks). Forty-eight hours after their last training bout phospholipids were extracted from the red and white vastus lateralis and analyzed by electrospray-ionization mass spectrometry. Exercise training was associated with significant alterations in the relative abundance of a number of phospholipid molecular species. These changes were more prominent in red vastus lateralis than white vastus lateralis. The largest observed change was an increase of similar to 30% in the abundance of 1-palmitoyl-2-linoleoyl phosphatidylcholine ions in oxidative fibers. Reductions in the relative abundance of a number of phospholipids containing long-chain n-3 polyunsaturated fatty acids were also observed. These data suggest a possible reduction in phospholipid remodeling in the trained animals. This results in a decrease in the phospholipid n-3 to n-6 ratio that may in turn influence endurance capacity.

The lag effects and vulnerabilities of temperature effects on cardiovascular disease mortality in a subtropical climate zone in China

This research quantifies the lag effects and vulnerabilities of temperature effects on cardiovascular disease in Changsha—a subtropical climate zone of China. A Poisson regression model within a distributed lag nonlinear models framework was used to examine the lag effects of cold- and heat-related CVD mortality. The lag effect for heat-related CVD mortality was just 0–3 days. In contrast, we observed a statistically significant association with 10–25 lag days for cold-related CVD mortality. Low temperatures with 0–2 lag days increased the mortality risk for those ≥65 years and females. For all ages, the cumulative effects of cold-related CVD mortality was 6.6% (95% CI: 5.2%–8.2%) for 30 lag days while that of heat-related CVD mortality was 4.9% (95% CI: 2.0%–7.9%) for 3 lag days. We found that in Changsha city, the lag effect of hot temperatures is short while the lag effect of cold temperatures is long. Females and older people were more sensitive to extreme hot and cold temperatures than males and younger people.