Tackling breast cancer chemoresistance with nano-formulated siRNA.

Breast cancer is the leading cancer diagnosed in women and the second leading cause of cancer-related deaths in women. Current limitations to standard chemotherapy in the clinic are extensively researched, including problems arising from repeated treatments with the same drugs. The phenomenon that cancer cells become resistant toward certain chemo drugs is called chemotherapy resistance. In this review, we are focusing on nanoformulation of siRNA for the fight against breast cancer chemoresistance.

Lift vs. drag based mechanisms for vertical force production in the smallest flying insects.

We used computational fluid dynamics to determine whether lift- or drag-based mechanisms generate the most vertical force in the flight of the smallest insects. These insects fly at Re on the order of 4-60 where viscous effects are significant. Detailed quantitative data on the wing kinematics of the smallest insects is not available, and as a result both drag- and lift-based strategies have been suggested as the mechanisms by which these insects stay aloft. We used the immersed boundary method to solve the fully-coupled fluid-structure interaction problem of a flexible wing immersed in a two-dimensional viscous fluid to compare three idealized hovering kinematics: a drag-based stroke in the vertical plane, a lift-based stroke in the horizontal plane, and a hybrid stroke on a tilted plane. Our results suggest that at higher Re, a lift-based strategy produces more vertical force than a drag-based strategy. At the Re pertinent to small insect hovering, however, there is little difference in performance between the two strategies. A drag-based mechanism of flight could produce more vertical force than a lift-based mechanism for insects at Re<5; however, we are unaware of active fliers at this scale.

Simulation of nitrous oxide emissions at field scale using the SPACSYS model.

Nitrous oxide emitted to the atmosphere via the soil processes of nitrification and denitrification plays an important role in the greenhouse gas balance of the atmosphere and is involved in the destruction of stratospheric ozone. These processes are controlled by biological, physical and chemical factors such as growth and activity of microbes, nitrogen availability, soil temperature and water availability. A comprehensive understanding of these processes embodied in an appropriate model can help develop agricultural mitigation strategies to reduce greenhouse gas emissions, and help with estimating emissions at landscape and regional scales. A detailed module to describe the denitrification and nitrification processes and nitrogenous gas emissions was incorporated into the SPACSYS model to replace an earlier module that used a simplified first-order equation to estimate denitrification and was unable to distinguish the emissions of individual nitrogenous gases. A dataset derived from a Scottish grassland experiment in silage production was used to validate soil moisture in the top 10 cm soil, cut biomass, nitrogen offtake and N2O emissions. The comparison between the simulated and observed data suggested that the new module can provide a good representation of these processes and improve prediction of N2O emissions. The model provides an opportunity to estimate gaseous N emissions under a wide range of management scenarios in agriculture, and synthesises our understanding of the interaction and regulation of the processes.

Occurrence and impact of negative behaviour, including domestic violence and abuse, in men attending UK primary care health clinics: a cross-sectional survey.

OBJECTIVE: To measure the experience and perpetration of negative behaviour, including domestic violence and abuse (DVA), and investigate its associations with health conditions and behaviours in men attending general practice. DESIGN: Cross-sectional questionnaire-based study conducted between September 2010 and June 2011. SETTING: 16 general practices in the south west of England. PARTICIPANTS: Male patients aged 18 or older, attending alone, who could read and write English. A total of 1403 of eligible patients (58%) participated in the survey and 1368 (56%) completed the questions relevant to this paper. 97% of respondents reported they were heterosexual. MAIN OUTCOME MEASURES: Lifetime occurrence of negative behaviour consistent with DVA, perceived health impact of negative behaviours, associations with anxiety and depression symptoms, and cannabis use in the past 12 months and binge drinking. RESULTS: 22.7% (95% CI 20.2% to 24.9%) of men reported ever experiencing negative behaviour (feeling frightened, physically hurt, forced sex, ask permission) from a partner. All negative behaviours were associated with a twofold to threefold increased odds of anxiety and depression symptoms in men experiencing or perpetrating negative behaviours or both. 34.9% (95% CI 28.7% to 41.7%) of men who reported experiencing negative behaviour from a partner, and 30.8% (95% CI 23.7% to 37.8%) of men who perpetrated negative behaviours said they had been in a domestically violent or abusive relationship. No associations with problematic drinking were found; there was a weak association with cannabis use. CONCLUSIONS: DVA is experienced or perpetrated by a large minority of men presenting to general practice, and these men were more likely to have current symptoms of depression and anxiety. Presentation of anxiety or depression to clinicians may be an indicator of male experience or perpetration of DVA victimisation.

No effect of short-term exposure to high-fibre diets on the gastrointestinal morphology of layer hens (Gallus gallus domesticus): body reserves are used to manage energy deficits in favour of phenotypic plasticity.

Using layer hens, Gallus gallus domesticus, we compared the digestive capabilities of birds on a low-fibre diet (LF, 8.49% neutral detergent fibre; NDF), with those fed a high-fibre diet balanced for energy and protein to match the LF diet (high fibre balanced, HFB; NDF = 15.61%) and those fed a high fibre unbalanced (HFU) diet (NDF = 16.68%). The HFU diet had the lowest apparent dry matter (DM) metabolisability at 58.14 ± 6.46%, followed by HFB, 65.87 ± 3.50 and the LF diet, 70.49 ± 7.07%. Despite significant differences between apparent DM metabolisabilities of LF and HFU diets, no morphometric changes in the gastrointestinal tract (GIT) of layer hens were observed (including crop, gizzard, proventriculus, liver, large intestine, paired caeca and small intestine). Conversely, body mass losses were recorded for animals on HFU diet, while those on the LF and HFB diets actually gained body mass over the 14-day trials. We suggest that the body mass losses seen in the animals fed HFU diets were attributed to losses in adipose tissue, but this was not quantified. Assuming body mass losses were mainly in adipose tissue, we propose that adipose may act to buffer environmental challenges like shortfalls in nutrient acquisition when dietary energy requirements are not met. Compared with smaller birds (e.g. quail), the larger body size of the layer hens may offer them a greater safety margin in terms of body energy reserves before changes in the GIT might be needed to redress energy deficits associated with hard-to-digest, high-fibre diets.

UK emissions of the greenhouse gas nitrous oxide.

Signatories of the Kyoto Protocol are obliged to submit annual accounts of their anthropogenic greenhouse gas emissions, which include nitrous oxide (N(2)O). Emissions from the sectors industry (3.8 Gg), energy (14.4 Gg), agriculture (86.8 Gg), wastewater (4.4 Gg), land use, land-use change and forestry (2.1 Gg) can be calculated by multiplying activity data (i.e. amount of fertilizer applied, animal numbers) with simple emission factors (Tier 1 approach), which are generally applied across wide geographical regions. The agricultural sector is the largest anthropogenic source of N(2)O in many countries and responsible for 75 per cent of UK N(2)O emissions. Microbial N(2)O production in nitrogen-fertilized soils (27.6 Gg), nitrogen-enriched waters (24.2 Gg) and manure storage systems (6.4 Gg) dominate agricultural emission budgets. For the agricultural sector, the Tier 1 emission factor approach is too simplistic to reflect local variations in climate, ecosystems and management, and is unable to take into account some of the mitigation strategies applied. This paper reviews deviations of observed emissions from those calculated using the simple emission factor approach for all anthropogenic sectors, briefly discusses the need to adopt specific emission factors that reflect regional variability in climate, soil type and management, and explains how bottom-up emission inventories can be verified by top-down modelling.

Spontaneous frequency of rabbit atrioventricular node myocytes depends on SR function.

Spontaneous Ca(2+) release from the sarcoplasmic reticulum (SR) appears to play an important role in cardiac sinoatrial node pacemaking. However, comparatively little is known about the role of intracellular Ca(2+) in the atrioventricular node (AVN). Intracellular Ca(2+) was therefore monitored in cells isolated from the rabbit AVN, using fluo-3 in conjunction with confocal microscopy. These cells displayed spontaneous Ca(2+) transients and action potentials. Ca(2+) transients were normally preceded by a small, slow increase (ramp) of intracellular Ca(2+) which was sometimes, but not always, accompanied by Ca(2+) sparks. During the Ca(2+) transient, intracellular [Ca(2+)] increased initially at the cell periphery and propagated inhomogeneously to the cell centre. The rate of spontaneous activity was decreased by ryanodine (1muM) and increased by isoprenaline (500nM); these changes were accompanied by a decrease and increase, respectively, in the slope of the preceding Ca(2+) ramp, with no significant change in Ca(2+) spark characteristics. Rapidly reducing bathing [Na(+)] inhibited spontaneous activity. These findings provide the first information on Ca(2+) handling at the sub-cellular level and link cellular Ca(2+) cycling to the genesis of spontaneous activity in the AVN.

Modelling heating of liver tumours with heterogeneous magnetic microsphere deposition.

Ferromagnetic embolization hyperthermia (FEH) is a novel treatment for liver cancer. Magnetic microspheres are injected into the hepatic artery and cluster in the periphery of tumours and are heated with externally applied magnetic fields. In order to more accurately simulate FEH, we modelled a three-dimensional heterogeneous distribution of heat sources. We constructed a fractal model of the vasculature in the periphery of a tumour. We used this model to compute the spatial distribution of the microspheres that lodge in capillaries. We used the distribution model as input to a finite-element heat transfer model of the FEH treatment. The overall appearance of the vascular tree is subjectively similar to that of the disorganized vascular network which encapsulates tumours. The microspheres are distributed in the tumour periphery in similar patterns to experimental observations. We expect the vasculature and microsphere deposition models to also be of interest to researchers of any targeted cancer therapies such as localized intra-arterial chemotherapy and selective internal radiotherapy. Our results show that heterogeneous microsphere distributions give significantly different results to those for a homogeneous model and thus are preferable when accurate results are required.

Mathematical models for the early detection and treatment of colorectal cancer.

Colorectal cancer is a major cause of death for men and women in the Western world. When the cancer is detected through an awareness of the symptoms by a patient, typically it is at an advanced stage. It is possible to detect cancer at an early stage through screening and the marked differences in survival for early and late stages provide the incentive for the primary prevention or early detection of colorectal cancer. This paper considers mathematical models for colorectal cancer screening together with models for the treatment of patients. Illustrative results demonstrate that detailed attention to the processes involved in diseases, interventions and treatment enable us to combine data and expert knowledge from various sources. Thus a detailed operational model is a very useful tool in helping to make decisions about screening at national and local levels.

A randomised clinical trial of nicotine patches for treatment of spit tobacco addiction among adolescents.

BACKGROUND: This study tested the efficacy of nicotine patches in combination with behavioural therapy for the treatment of adolescent spit tobacco addiction. Prior interventions had resulted in mean cessation rates below 15% at one year. METHODS: This study, the PATCH Project, used a three group, placebo controlled, randomised clinical trial design. The control group received a standard 3-5 minute counselling followed by a two week follow up phone call. The two intervention groups received a six week behavioural intervention; in addition, one group received active nicotine patches while the other group received placebo patches. Both groups received quarterly stage based telephone counselling. RESULTS: At one year, the usual care group's spit tobacco cessation rate was 11.4% (exact 95% confidence interval (CI) 6.1% to 19.1%), placebo patch 25.0% (95% CI 16.9% to 34.7%), and the active patch 17.3% (95% CI 10.4% to 26.3%). When both patch groups were combined, the cessation rate was 21.2% (95% CI 15.7% to 27.6%). The cessation rates for active and placebo patch were not significantly different (exact two sided p = 0.22), while the combined patch groups had a significantly greater cessation rate than usual care (exact two sided p = 0.04). CONCLUSIONS: The behavioural intervention proved to be about twice as successful as previous interventions, but the nicotine patch offered no improvement in cessation rates. The behavioural intervention is based on publicly available materials and can be easily adapted for widespread use, particularly in high schools.

A magnetic resonance imaging based method for measurement of tissue iron concentration in liver arterially embolized with ferrimagnetic particles designed for magnetic hyperthermia treatment of tumors.

Rabbit liver was loaded with ferrimagnetic particles of gamma -Fe2 O3 (designed for magnetic hyperthermia treatment of liver tumors) by injecting various doses of a suspension of the particles into the hepatic artery in vivo. Proton transverse relaxation rate (R(2)) images of the livers in vivo, excised, and dissected were generated from a series of single spin-echo images. Mean R(2) values for samples of ferrimagnetic-particle-loaded liver dissected into approximate 1 cm cubes were found to linearly correlate with tissue iron concentration over the range from approximately 0.1 to at least 2.7 mg Fe/g dry tissue when measured at room temperature. Changing the temperature of ferrimagnetic-particle-loaded samples of liver from 1 degrees C to 37 degrees C had no observable effect on tissue R(2) values. However, a small but significant decrease in R(2) was found for control samples containing no ferrimagnetic material on raising the temperature from 1 degrees C to 37 degrees C. Both chemically measured iron concentrations and mean R(2) values for rabbit livers with implanted tumors tended to be higher than those measured for tumor-free liver. This study indicates that tissue R(2) measurement and imaging by nuclear magnetic resonance may have a useful role in magnetic hyperthermia therapy protocols for the treatment of liver cancer.

Detection of Dientamoeba fragilis by culture.

Symptoms associated with Dientamoeba fragilis include diarrhoea, abdominal pain, nausea, vomiting, epigastric pain and weight loss. A possible link between D. fragilis and irritable bowel syndrome (IBS)-like symptoms has been reported, and therefore the presence of this parasite should be excluded before making a diagnosis of IBS. Over a six-month period, 976 faecal samples were submitted to NPHS Microbiology Aberystwyth for routine microbiological analysis. All samples were also cultured for parasites using Robinson's xenic medium. Trichrome staining was undertaken whenever practicable, but many stools had insufficient material. D. fragilis was isolated from 25 (2.6%) patients, whereas Cryptosporidium spp. was detected in 16 (1.6%) patients. D. fragilis was only detected in nine (1.3%) out of 685 specimens stained with trichrome, although four of the 25 culture-positive stools had insufficient sample for staining. Parasite culture proved to be less laborious than trichrome staining and dramatically increased D. fragilis detection rate.

Nonsynchronized segmented heterochromia in black scalp hair.

Nonsynchronized segmented heterochromia in black scalp hair is a rarely reported entity, the only previous report being described in association with iron deficiency anaemia. A 14-year-old girl presented with a 2-year history of nonsynchronized segmented heterochromia. She was otherwise well and her serum iron, copper, zinc and protein levels were all within the normal range. She had no clinical evidence of vitiligo or alopecia areata. This patient is believed to represent the first reported case of nonsynchronized segmented heterochromia in black scalp hair as a presentation of premature greying of the hair.

Hepatic clearance of arterially infused ferromagnetic particles.

OBJECTIVE: Arterial embolization hyperthermia (AEH) consists of arterially embolizing tumours with ferromagnetic particles that generate hysteretic heating on exposure to an alternating magnetic field. It was the objective of this study to determine if such particles are cleared from the liver. METHOD: A lobe of normal liver in three pigs was arterially embolized with 300 mg of gamma-Fe2O3 particles (150 nm) suspended in lipiodol. The same liver lobe of three other pigs was embolized with 300 mg of ferromagnetic polymer matrix-encapsulated microspheres (32 microm) suspended in 1% tween-water. Samples of liver and blood were obtained before infusion, and at 60 min and 28 days after arterial infusion. At 28 days, samples of lung and other abdominal viscera were also obtained. The tissue samples were chemically analysed for iron content, and submitted to histopathological examination. RESULTS: There was no significant reduction in the hepatic iron concentration in either treatment group 28 days after infusion. Both types of particles illicited an immunogenic response and were extensively phagocytosed in the liver. The particle/lipiodol suspension caused extensive necrosis of liver, while the microsphere/tween-water suspension was well tolerated. Small amounts of both types of ferromagnetic particles embolized in the lungs, but there was no evidence of embolization into other organs. There were no haematological or biochemical changes and all subjects experienced uneventful 28-day survivals. CONCLUSION: This study has shown that, although arterially infused ferromagnetic particles were extensively phagocytosed, there was no significant hepatic clearance 28 days after infusion. It also determined that the suspension of 150 nm ferromagnetic particles in lipiodol was too vaso-occlusive for use in hepatic tissue. However, the suspension of 32 microm microspheres containing ferromagnetic particles in tween-water was safe and well tolerated.

Incidence of Blastocystis hominis in faecal samples submitted for routine microbiological analysis.

Over a one-year period, 1390 faecal samples were submitted to Aberystwyth Public Health Laboratory for routine microbiological examination. All were stained using a commercial trichrome method. Blastocystis hominis was detected in 96 (6.9%), making it the most common parasite found in the study. Of the B. hominis-positive specimens, 73% were missed on direct microscopy. Molecular typing of B. hominis has revealed extensive genetic diversity in morphologically identical strains and thus detection by microscopy alone may not be sufficient to confirm the role of this organism in human disease.

Magnetically mediated hyperthermia: current status and future directions.

The use of hyperthermia in the treatment of cancers is appealing because, as a physical therapy, hyperthermia would have far fewer restrictive side effects than chemotherapy and radiotherapy, and it could be used in combination with these therapies. However, the currently available modalities of hyperthermia are often limited by their inability to selectively target tumour tissue and, hence, they carry a high risk of collateral organ damage or they deposit heat in a very localized manner which can result in under-treatment of a tumour. Magnetically mediated hyperthermia (MMH) has the potential to address these shortcomings. MMH consists of the localization of magnetic particles or seeds within tumour tissue followed by exposure to an externally applied alternating magnetic field to cause them to heat. Since this concept was introduced (over 40 years ago), MMH has evolved into four general sub-classes: arterial embolization hyperthermia (AEH), direct injection hyperthermia (DIH), intracellular hyperthermia (IH) and interstitial implant hyperthermia (IIH). It is the purpose of this article to review these four sub-classes in terms of experimental or clinical results, advantages, limitations and current status.

Treatment of experimental rabbit liver tumours by selectively targeted hyperthermia.

Experimental rabbit liver tumours were preferentially heated to therapeutic temperatures without compromising the surrounding normal hepatic parenchyma. This was achieved by the use of hepatic arterially infused ferromagnetic microspheres that heat as a result of magnetic hysteresis loss when exposed to an alternating magnetic field. Treatment sessions involving a single 20-min exposure to the alternating field resulted in total suppression of tumour growth at 14 days compared to controls, in which tumour sizes increased dramatically over the same period. Histopathological examination of treated tumour sections showed total tumour destruction in some cases. Separate animal groups used to control for the effects of the embolized microspheres alone and for the effect of the applied magnetic field yielded similar tumour growth responses to a control group with no intervention whatsoever. The achievement of positive temperature differentials between tumour and normal liver and the consequent therapeutic responses encourages further development of this technology for the treatment of liver cancer in humans.

The effect of tumour size on ferromagnetic embolization hyperthermia in a rabbit liver tumour model.

OBJECTIVE: Ferromagnetic Embolization Hyperthermia (FEH) consists of arterially embolizing tumours with ferromagnetic particles to cause hysteretic heating upon subsequent exposure to an alternating magnetic field. The objective was to determine the effect of tumour size during FEH using a rabbit liver tumour model. METHOD: Thirty-three rabbits containing implanted hepatic VX2 carcinomas received a hepatic arterial infusion of ferromagnetic particles suspended in lipiodol. Following hysteretic heating, tumour and normal hepatic tissues were chemically analysed for iron content. Tumours were classed as small if their mass was less than the median mass for the whole group of subjects (2.1 g), and as large if their mass was greater than or equal to the median. To control for variability in tumour iron concentration, 13 small tumours were matched to 13 large tumours by iron concentration, and their heating characteristics compared. RESULTS: The heating rate in large tumours (median = 5.0 degrees C/min) was significantly greater than that in the matched small tumours (median = 2.8 degrees C/min), p = 0.006. Regression analysis determined that the slope of the heating rate vs iron concentration curve for large tumours was 1.5 times greater than that for the matched small tumours, p < 0.001. After cessation of heating in large tumours, there was continued heat dissipation into surrounding tissues, which led to anomalous temperature increases. There was an inverse linear relationship between tumour size and tumour iron concentration for a given dose of particles. CONCLUSION: For a given tumour iron concentration, larger tumours heat at a greater rate than small tumours, due to the poorer tissue cooling and better heat conduction in the necrotic regions of large tumours. This warrants further investigation as this finding could confer a significant advantage on FEH over other hyperthermic modalities in the treatment of hepatic malignancies.

Targeting liver tumors with hyperthermia: ferromagnetic embolization in a rabbit liver tumor model.

BACKGROUND AND OBJECTIVES: Ferromagnetic embolization hyperthermia (FEH) consists of arterially embolizing liver tumors with ferromagnetic particles, and then applying an external alternating magnetic field to generate hysteretic heating within the embolized particles. The objective of this study was to assess the ability of FEH to selectively target liver tumors with hyperthermia. METHODS: Twenty rabbits containing hepatic VX2 carcinomas were arterially infused with ferromagnetic particles suspended in lipiodol, and then exposed to an external alternating magnetic field. Temperatures in the tumor, normal hepatic parenchyma (NHP), and rectum were recorded. Tumour and NHP were chemically analyzed for iron content, which was then correlated with the observed heating rates. RESULTS: The mean tumor-to-NHP iron concentration ratio was 5.3:1 (P < 0.001, N = 20). The mean tumor heating rates were 3.0-11.5 times greater than those in the NHP (P < 0.001, N = 20). After 5 min of heating, the greatest increase in mean tumor temperature was 11.0 degrees C and the greatest increase in mean NHP temperature was 1.3 degrees C. There was a positive relationship between tumor iron concentration and heating rate (correlation coefficient = 0.82, P < 0.001, N = 20). A tumor iron concentration of 2-3 mg/g resulted in tumor heating rates of 0.5-1.0 degrees C/min. CONCLUSIONS: Hepatic arterial infusion of lipiodol containing ferromagnetic particles can result in excellent targeting of liver tumors with hyperthermia on the subsequent application of an external alternating magnetic field. The promising results of this study warrant further investigation of FEH as a potential treatment for advanced liver cancer.