Photodynamic therapy for inflammatory choroidal neovascularisation unresponsive to immunosuppression

Aim: To report on visual and angiographic outcomes of a consecutive series of patients with inflammatory choroidal neovascular membranes (CNV) unresponsive to systemic immunosuppression treated with photodynamic therapy (PDT). Methods: The medical records of six consecutive patients with inflammatory CNVs that failed to respond to systemic immunosuppression and that later underwent PDT were retrospectively reviewed. Patient demographics, visual acuity, and fluorescein angiographic findings were evaluated. Results: There were five females and one male with a mean age of 40.8 years (range 35-58 years). Four patients had clinical features consistent with punctate inner choroidopathy and two with presumed ocular histoplasmosis. In all cases clinical signs of CNV activity, including subretinal fluid, subretinal blood, hard exudates, and/or recent decrease in visual acuity were present prior to PDT. All patients had been treated with high dose systemic immunosuppressants, which failed to induce regression of the CNV and/or to improve vision. The CNVs were subfoveal in five patients and juxtafoveal in one; all were classified as predominantly classic. Following PDT an improvement in vision occurred in all cases (median improvement of 18 letters, range 3-42 letters). At last follow up, signs of decreased activity in the CNV were detected in all cases. Patients were followed for a median of 10 months (range 9-20 months). Conclusion: PDT appears to be a useful option in the management of patients with inflammatory CNVs unresponsive to immunosuppressive therapies.

Proteomic analysis of colorectal cancer metastasis:stathmin-1 revealed as a player in cancer cell migration and prognostic marker

Metastasis accounts largely for the high mortality rate of colorectal cancer (CRC) patients. In this study, we performed comparative proteome analysis of primary CRC cell lines HCT-116 and its metastatic derivative E1 using 2-D DIGE. We identified 74 differentially expressed proteins, many of which function in transcription, translation, angiogenesis signal transduction, or cytoskeletal remodeling pathways, which are indispensable cellular processes involved in the metastatic cascade. Among these proteins, stathmin-1 (STMN1) was found to be highly up-regulated in E1 as compared to HCT-116 and was thus selected for further functional studies. Our results showed that perturbations in STMN1 levels resulted in significant changes in cell migration, invasion, adhesion, and colony formation. We further showed that the differential expression of STMN1 correlated with the cells' metastatic potential in other paradigms of CRC models. Using immunohistochemistry, we also showed that STMN1 was highly expressed in colorectal primary tumors and metastatic tissues as compared to the adjacent normal colorectal tissues. Furthermore, we also showed via tissue microarray analyses of 324 CRC tissues and Kaplan-Meier survival plot that CRC patients with higher expression of STMN1 have poorer prognosis.

A Compact V-band power detector

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A compact V-band active power detector using Infineon 0.35 µm SiGe HBT process (fT/fmax =170/250 GHz) is described. The total chip area is only 0.35×0.8 mm2 including all pads. This design exhibits a dynamic range larger than 20 dB over the frequency range from 55 GHz to 67 GHz. It also offers a simple and low-power application potential as an envelop detector in multi-Gbps high data rate demodulators for OOK/ASK etc.

Tumour necrosis factor-alpha (TNF-alpha) increases nuclear factor kappaB (NFkappaB) activity in and interleukin-8 (IL-8) release from bovine mammary epithelial cells

Epithelia play important immunological roles at a variety of mucosal sites. We examined NFkappaB activity in control and TNF-alpha treated bovine mammary epithelial monolayers (BME-UV cells). A region of the bovine IL-8 (bIL-8) promoter was sequenced and a putative kappaB consensus sequence was identified bioinformatically. We used this sequence to analyse nuclear extracts for IL-8 specific NFkappaB activity. As a surrogate marker of NFkappaB activation, we investigated IL-8 release in two models. Firstly in BME-UV monolayers, IL-8 release in the presence of pro- and anti-inflammatory agents was determined by enzyme-linked immunosorbent assay (ELISA). Secondly, we measured IL-8 secretion from a novel model of intact mucosal sheets of bovine teat sinus. IL-8 release into bathing solutions was assessed following treatment with pro- and anti-inflammatory agents. TNF-alpha enhanced NFkappaB activity in bovine mammary epithelial monolayers. p65 NFkappaB homodimer was identified in both control and TNF-alpha treated cells. Novel sequencing of the bovine IL-8 promoter identified a putative kappaB consensus sequence, which specifically bound TNF-alpha inducible p50/p65 heterodimer. TNF-alpha induced primarily serosal IL-8 release in the cell culture model. Pre-treatment with anti-TNF or dexamethasone inhibited TNF-alpha induced IL-8 release. High dose interleukin-1beta (IL-1beta) induced IL-8 release, however significantly less potently than TNF-alpha. Bovine mammary mucosal tissue released high basal levels of IL-8 which were unaffected by TNF-alpha or IL-1beta but inhibited by both dexamethasone and anti-TNF. These data support a role for TNF-alpha in activation of NFkappaB and release of IL-8 from bovine mammary epithelial cells.

First results on cell irradiation with laser-driven protons on the TARANIS system

The ultra short duration of laser-driven multi-MeV ion bursts offers the possibility of radiobiological studies at extremely high dose rates. Employing the TARANIS Terawatt laser at Queen's University, the effect of proton irradiation at MeV-range energies on live cells has been investigated at dose rates exceeding 10 Gy/s as a single exposure. A clonogenic assay showed consistent lethal effects on V-79 live, cells, which, even at these dose rates, appear to be in line with previously published results employing conventional sources. A Relative Biological Effectiveness (RBE) of 1.4±0.2 at 10% survival is estimated from a comparison with a 225 kVp X-ray source.

The host galaxy of the super-luminous SN 2010gx and limits on explosive nickel-56 production

Super-luminous supernovae have a tendency to occur in faint host galaxies which are likely to have low mass and low metallicity. While these extremely luminous explosions have been observed from z=0.1 to 1.55, the closest explosions allow more detailed investigations of their host galaxies. We present a detailed analysis of the host galaxy of SN 2010gx (z=0.23), one of the best studied super-luminous type Ic supernovae. The host is a dwarf galaxy (M_g=-17.42+/-0.17) with a high specific star formation rate. It has a remarkably low metallicity of 12+log(O/H)=7.5+/-0.1 dex as determined from the detection of the [OIII] 4363 Angs line. This is the first reliable metallicity determination of a super-luminous stripped-envelope supernova host. We collected deep multi-epoch imaging with Gemini + GMOS between 240-560 days after explosion to search for any sign of radioactive nickel-56, which might provide further insights on the explosion mechanism and the progenitor's nature. We reach griz magnitudes of m_AB~26, but do not detect SN 2010gx at these epochs. The limit implies that any nickel-56 production was similar to or below that of SN 1998bw (a luminous type Ic SN that produced around 0.4 M_sun of nickel-56). The low volumetric rates of these supernovae (~10^-4 of the core-collapse population) could be qualitatively matched if the explosion mechanism requires a combination of low-metallicity (below 0.2 Z_sun), high progenitor mass (>60 M_sun) and high rotation rate (fastest 10% of rotators).

Octavius 4D characterization for flattened and flattening filter free rotational deliveries

Purpose: In this study the Octavius detector 729 ionization chamber (IC) array with the Octavius 4D phantom was characterized for flattening filter (FF) and flattening filter free (FFF) static and rotational beams. The device was assessed for verification with FF and FFF RapidArc treatment plans.

Methods: The response of the detectors to field size, dose linearity, and dose rate were assessed for 6 MV FF beams and also 6 and 10 MV FFF beams. Dosimetric and mechanical accuracy of the detector array within the Octavius 4D rotational phantom was evaluated against measurements made using semiflex and pinpoint ionization chambers, and radiochromic film. Verification FF and FFF RapidArc plans were assessed using a gamma function with 3%/3 mm tolerances and 2%/2 mm tolerances and further analysis of these plans was undertaken using film and a second detector array with higher spatial resolution.

Results: A warm-up dose of >6 Gy was required for detector stability. Dose-rate measurements were stable across a range from 0.26 to 15 Gy/min and dose response was linear, although the device overestimated small doses compared with pinpoint ionization chamber measurements. Output factors agreed with ionization chamber measurements to within 0.6% for square fields of side between 3 and 25 cm and within 1.2% for 2 x 2 cm(2) fields. The Octavius 4D phantom was found to be consistent with measurements made with radiochromic film, where the gantry angle was found to be within 0.4. of that expected during rotational deliveries. RapidArc FF and FFF beams were found to have an accuracy of >97.9% and >90% of pixels passing 3%/3 mm and 2%/2 mm, respectively. Detector spatial resolution was observed to be a factor in determining the accurate delivery of each plan, particularly at steep dose gradients. This was confirmed using data from a second detector array with higher spatial resolution and with radiochromic film.

Conclusions: The Octavius 4D phantom with associated Octavius detector 729 ionization chamber array is a dosimetrically and mechanically stable device for pretreatment verification of FF and FFF RapidArc treatments. Further improvements may be possible through use of a detector array with higher spatial resolution (detector size and/or detector spacing). (C) 2013 American Association of Physicists in Medicine.

Multi-standard sub-pixel interpolation architecture for video motion estimation

A new domain-specific reconfigurable sub-pixel interpolation architecture for multi-standard video Motion Estimation (ME) is presented. The mixed use of parallel and serial-input FIR filters achieves high throughput rate and efficient silicon utilisation. Flexibility has been achieved by using a multiplexed reconfigurable data-path controlled by a selection signal. Silicon design studies show that this can be implemented using 34.8K gates with area and performance that compares very favourably with existing fixed solutions based solely on the H.264 standard. ©2008 IEEE.

The impact of peer review on the radiotherapy treatment planning process in the treatment of lung cancer

Background:
Advanced radiotherapy techniques permit accurate delivery of radiotherapy to lung tumours. Improved accuracy increases the possibility of radiotherapy field geographic miss of the tumour. One source of error is the accuracy of target volume (TV) delineation by the clinical oncologist. Colleague peer review of all curative intent lung cancer plans has been mandatory in our institution since May 2013. At least 2 clinical oncologists review plans checking treatment paradigm, TV delineated, dose to tumour and dose to critical organs. We report the impact of peer review on the radiotherapy planning process for lung cancer.

Methods:
The radiotherapy treatment plans of all patients receiving radical radiotherapy were presented at weekly peer review meetings after their TVs volumes were provisionally signed off by the treating consultant or post-fellowship registrar. All cases and any resultant change to the treatment plan were recorded in our prospective peer review database. We present the summary of changes agreed following the peer review process for a 6 month period.

Results:
Fifteen peer review sessions, including 46 patients (36 NSCLC, 10 SCLC) were analysed. An average of 3 cases were discussed per meeting (range 1 5). 24% of treatment courses were changed. In 4% there was a complete change in paradigm
of treatment (1 patient proceeded to induction chemotherapy, 1 patient had high dose palliative radiotherapy). In 16% there was a change in TV delineated and in 9% a change in dose (2 dose reductions and 2 alterations to post-operative dose fractionations).

Conclusions:
Consultant led peer review resulted in a change in a component of the treatment plan for 28% of patients that would not otherwise have taken place. Given this impact, consultant led peer review should be considered as an essential component in the radiotherapy planning process for all patients treated with curative radiotherapy.

Freeze-Dried Strawberries Lower Serum Cholesterol and Lipid Peroxidation in Adults with Abdominal Adiposity and Elevated Serum Lipids

Dietary flavonoid intake, especially berry flavonoids, has been associated with reduced risks of cardiovascular disease (CVD) in large prospective cohorts. Few clinical studies have examined the effects of dietary berries on CVD risk factors. We examined the hypothesis that freeze-dried strawberries (FDS) improve lipid and lipoprotein profiles and lower biomarkers of inflammation and lipid oxidation in adults with abdominal adiposity and elevated serum lipids. In a randomized dose-response controlled trial, 60 volunteers [5 men and 55 women; aged 49 ± 10 y; BMI: 36 ± 5 kg/m2 (means ± SDs)] were assigned to consume 1 of the following 4 beverages for 12 wk: 1) low-dose FDS (LD-FDS; 25 g/d); 2) low-dose control (LD-C); 3) high-dose FDS (HD-FDS; 50 g/d); and 4) high-dose control (HD-C). Control beverages were matched for calories and total fiber. Blood draws, anthropometrics, blood pressure, and dietary data were collected at screening (0 wk) and after 12-wk intervention. Dose-response analyses revealed significantly greater decreases in serum total and LDL cholesterol and nuclear magnetic resonance (NMR)–derived small LDL particle concentration in HD-FDS [33 ± 6 mg/dL, 28 ± 7 mg/dL, and 301 ± 78 nmol/L, respectively (means ± SEMs)] vs. LD-FDS (−3 ± 11 mg/dL, −3 ± 9 mg/dL, and −28 ± 124 nmol/L, respectively) over 12 wk (0–12 wk; all P < 0.05). Compared with controls, only the decreases in total and LDL cholesterol in HD-FDS remained significant vs. HD-C (0.7 ± 12 and 1.4 ± 9 mg/dL, respectively) over 12 wk (0–12 wk; all P < 0.05). Both doses of strawberries showed a similar decrease in serum malondialdehyde at 12 wk (LD-FDS: 1.3 ± 0.2 μmol/L; HD-FDS: 1.2 ± 0.1 μmol/L) vs. controls (LD-C: 2.1 ± 0.2 μmol/L; HD-C: 2.3 ± 0.2 μmol/L) (P < 0.05). In general, strawberry intervention did not affect any measures of adiposity, blood pressure, glycemia, and serum concentrations of HDL cholesterol and triglycerides, C-reactive protein, and adhesion molecules. Thus, HD-FDS exerted greater effects in lowering serum total and LDL cholesterol and NMR-derived small LDL particles vs. LD-FDS in the 12-wk study. These findings warrant additional investigation in larger trials. This trial was registered at clinicaltrials.gov as NCT01883401.

A New Mechanism for Hydroxyl Radical Production in Irradiated Nanoparticle Solutions

The absolute yield of hydroxyl radicals per unit of deposited X-ray energy is determined for the first time for irradiated aqueous solutions containing metal nanoparticles based on a “reference” protocol. Measurements are made as a function of dose rate and nanoparticle concentration. Possible mechanisms for hydroxyl radical production are considered in turn: energy deposition in the nanoparticles followed by its transport into the surrounding environment is unable to account for observed yield whereas energy deposition in the water followed by a catalytic-like reaction at the water-nanoparticle interface can account for the total yield and its dependence on dose rate and nanoparticle concentration. This finding is important because current models used to account for nanoparticle enhancement to radiobiological damage only consider the primary interaction with the nanoparticle, not with the surrounding media. Nothing about the new mechanism appears to be specific to gold, the main requirements being the formation of a structured water layer in the vicinity of the nanoparticle possibly through the interaction of its charge and the water dipoles. The massive hydroxyl radical production is relevant to a number of application fields, particularly nanomedicine since the hydroxyl radical is responsible for the majority of radiation-induced DNA damage.

The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy

A new efficient type of gadolinium-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy (RT). These new particles consist of a polysiloxane network surrounded by a number of gadolinium chelates, usually 10. Owing to their small size (<5 nm), AGuIX typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes. For example, although a significant proportion of these particles accumulate in tumours, the remainder is rapidly eliminated by the renal route. In addition, in the absence of irradiation, the nanoparticles are well tolerated even at very high dose (10 times more than the dose used for mouse treatment). AGuIX particles have been proven to act as efficient radiosensitizers in a large variety of experimental in vitro scenarios, including different radioresistant cell lines, irradiation energies and radiation sources (sensitizing enhancement ratio ranging from 1.1 to 2.5). Pre-clinical studies have also demonstrated the impact of these particles on different heterotopic and orthotopic tumours, with both intratumoural or intravenous injection routes. A significant therapeutical effect has been observed in all contexts. Furthermore, MRI monitoring was proven to efficiently aid in determining a RT protocol and assessing tumour evolution following treatment. The usual theoretical models, based on energy attenuation and macroscopic dose enhancement, cannot account for all the results that have been obtained. Only theoretical models, which take into account the Auger electron cascades that occur between the different atoms constituting the particle and the related high radical concentrations in the vicinity of the particle, provide an explanation for the complex cell damage and death observed.

Hydrogel-Forming Microneedles Prepared from ‘‘Super Swelling’’ Polymers Combined with Lyophilised Wafers for Transdermal Drug Delivery

We describe, for the first time, hydrogel-forming microneedle arrays prepared from "super swelling" polymeric compositions. We produced a microneedle formulation with enhanced swelling capabilities from aqueous blends containing 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000 and 3% w/w Na2CO3 and utilised a drug reservoir of a lyophilised wafer-like design. These microneedle-lyophilised wafer compositions were robust and effectively penetrated skin, swelling extensively, but being removed intact. In in vitro delivery experiments across excised neonatal porcine skin, approximately 44 mg of the model high dose small molecule drug ibuprofen sodium was delivered in 24 h, equating to 37% of the loading in the lyophilised reservoir. The super swelling microneedles delivered approximately 1.24 mg of the model protein ovalbumin over 24 h, equivalent to a delivery efficiency of approximately 49%. The integrated microneedle-lyophilised wafer delivery system produced a progressive increase in plasma concentrations of ibuprofen sodium in rats over 6 h, with a maximal concentration of approximately 179 µg/ml achieved in this time. The plasma concentration had fallen to 71±6.7 µg/ml by 24 h. Ovalbumin levels peaked in rat plasma after only 1 hour at 42.36±17.01 ng/ml. Ovalbumin plasma levels then remained almost constant up to 6 h, dropping somewhat at 24 h, when 23.61±4.84 ng/ml was detected. This work represents a significant advancement on conventional microneedle systems, which are presently only suitable for bolus delivery of very potent drugs and vaccines. Once fully developed, such technology may greatly expand the range of drugs that can be delivered transdermally, to the benefit of patients and industry. Accordingly, we are currently progressing towards clinical evaluations with a range of candidate molecules.

Evaluation of a partnership between primary and secondary care providing an accessible Level 1 sexual health service in the community

Comprehensive testing for asymptomatic sexually transmitted infections in Northern Ireland has traditionally been provided by genitourinary medicine clinics. As patient demand for services has increased while budgets have remained limited, there has been increasing difficulty in accommodating this demand. In May 2013, the newly commissioned specialist Sexual Health service in the South Eastern Trust sought to pilot a new model of care working alongside a GP partnership of 12 practices. A training programme to enable GPs and practice nurses to deliver Level 1 sexual health care to heterosexual patients aged >16 years, in accordance with the standards of BASHH, was developed. A comprehensive care pathway and dedicated community health advisor supported this new model with close liaison between primary and secondary care. Testing for Chlamydia, gonorrhoea, HIV and syphilis was offered. The aims of the pilot were achieved, namely to provide accessible, cost-effective sexual health care within a framework of robust clinical governance. Furthermore, it uncovered a high positivity rate for Chlamydia, especially in young men attending their general practice, and demonstrated a high level of patient satisfaction. Moreover the capacity of secondary care to deliver Levels 2 and 3 services was increased.

The Impact of Colleague Peer Review on the Radiotherapy Treatment Planning Process in the Radical Treatment of Lung Cancer

AIMS: Modern radiotherapy uses techniques to reliably identify tumour and reduce target volume margins. However, this can potentially lead to an increased risk of geographic miss. One source of error is the accuracy of target volume delineation (TVD). Colleague peer review (CPR) of all curative-intent lung cancer plans has been mandatory in our institution since May 2013. At least two clinical oncologists review plans, checking treatment paradigm, TVD, prescription dose tumour and critical organ tolerances. We report the impact of CPR in our institution.

MATERIALS AND METHODS: Radiotherapy treatment plans of all patients receiving radical radiotherapy were presented at weekly CPR meetings after their target volumes were reviewed and signed off by the treating consultant. All cases and any resultant change to TVD (including organs at risk) or treatment intent were recorded in our prospective CPR database. The impact of CPR over a 13 month period from May 2013 to June 2014 is reported.

RESULTS: One hundred and twenty-two patients (63% non-small cell lung carcinoma, 17% small cell lung carcinoma and 20% 'clinical diagnosis') were analysed. On average, 3.2 cases were discussed per meeting (range 1-8). CPR resulted in a change in treatment paradigm in 3% (one patient proceeded to induction chemotherapy, two patients had high-dose palliative radiotherapy). Twenty-one (17%) had a change in TVD and one (1%) patient had a change in dose prescription. In total, 6% of patients had plan adjustment after review of dose volume histogram.

CONCLUSION: The introduction of CPR in our centre has resulted in a change in a component of the treatment plan for 27% of patients receiving curative-intent lung radiotherapy. We recommend CPR as a mandatory quality assurance step in the planning process of all radical lung plans.