Synthesis of an analogue of the bisphosphonate drug Ibandronate for targeted drug-delivery therapeutic strategies

An analogue of the bisphosphonate drug Ibandronate was prepared and coupled via a cleavable ester function to a bromoacetyl linker with specific reactivity for thiol groups. This compound should find useful applications in therapeutic strategies aiming to deliver bisphosphonate drugs specifically to cancer cells making use of proteins as vectors. The specific delivery of bisphosphonates to cancer cells instead of bone, the usual site of accumulation of these cytotoxic drugs, could greatly widen their therapeutic applications.

Evolution of elastic x-ray scattering in laser-shocked warm dense lithium

We have studied the dynamics of warm dense Li with near-elastic x-ray scattering. Li foils were heated and compressed using shock waves driven by 4-ns-long laser pulses. Separate 1-ns-long laser pulses were used to generate a bright source of 2.96 keV Cl Ly-alpha photons for x-ray scattering, and the spectrum of scattered photons was recorded at a scattering angle of 120 degrees using a highly oriented pyrolytic graphite crystal operated in the von Hamos geometry. A variable delay between the heater and backlighter laser beams measured the scattering time evolution. Comparison with radiation-hydrodynamics simulations shows that the plasma is highly coupled during the first several nanoseconds, then relaxes to a moderate coupling state at later times. Near-elastic scattering amplitudes have been successfully simulated using the screened one-component plasma model. Our main finding is that the near-elastic scattering amplitudes are quite sensitive to the mean ionization state Z and by extension to the choice of ionization model in the radiation-hydrodynamics simulations used to predict plasma properties within the shocked Li.

Radiation and the genome: from risks to opportunities for therapeutic exploitation

On 1 December 2009, the Radiation and Cancer Biology Committee of the British Institute of Radiology (BIR) held a one-day conference on the theme of radiation and the genome. Talks covered genomic instability (its importance for radiation-induced carcinogenesis and potential for exploitation in the development of novel chemoradiotherapy combinations) and the prospects of exploiting knowledge of the genome to understand how individual genetic variation can impact on a patient's likelihood of developing toxicity following radiotherapy. The meeting also provided an overview of stem cell biology and its relevance for radiotherapy in terms of both tumour (somatic) and normal tissue (germline) sensitivity to radiation. Moreover, the possibility of manipulating stem cells to reduce radiation-induced normal tissue damage was considered.

The inhibition of human cytomegalovirus (hCMV) protease by hydroxylamine derivatives.

Aryl hydroxylamine derivs. have been synthesized that are some of the most potent inhibitors of hCMV protease prepd. to date (IC50 14-60 nM). Mass spectrometry studies indicate that oxazinone derived hydroxylamines inhibit the enzyme by acylation of Ser132 whereas non-oxazinone derived hydroxylamines appear to inhibit via formation of a sulfinanilide at Cys138.

The 67-kd laminin receptor is preferentially expressed by proliferating retinal vessels in a murine model of ischemic retinopathy.

Endothelial cell association with vascular basement membranes is complex and plays a critical role in regulation of cell adhesion and proliferation. The interaction between the membrane-associated 67-kd receptor (67LR) and the basement membrane protein laminin has been studied in several cell systems where it was shown to be crucial for adhesion and attachment during angiogenesis. As angiogenesis in the pathological setting of proliferative retinopathy is a major cause of blindness in the Western world we examined the expression of 67LR in a murine model of hyperoxia-induced retinopathy that exhibits retinal neovascularization. Mice exposed to hyperoxia for 5 days starting at postnatal day 7 (P7) and returned to room air (at P12) showed closure of the central retinal vasculature. In response to the ensuing retinal ischemia, there was consistent preretinal neovascularization starting around P17, which persisted until P21, after which the new vessels regressed. Immunohistochemistry was performed on these retinas using an antibody specific for 67LR. At P12, immunoreactivity for 67LR was absent in the retina, but by P17 it was observed in preretinal proliferating vessels and also within the adjacent intraretinal vasculature. Intraretinal 67LR immunoreactivity diminished beyond P17 until by P21 immunoreactivity was almost completely absent, although it persisted in the preretinal vasculature. Control P17 mice (not exposed to hyperoxia) failed to demonstrate any 67LR immunoreactivity in their retinas. Parallel in situ hybridization studies demonstrated 67LR gene expression in the retinal ganglion cells of control and hyperoxia-exposed mice. In addition, the neovascular intra- and preretinal vessels of hyperoxia-treated P17 and P21 mice labeled strongly for 67LR mRNA. This study has characterized 67LR immunolocalization and gene expression in a murine model of ischemic retinopathy. Results suggest that, although the 67LR gene is expressed at high levels in the retinal ganglion cells, the mature receptor protein is preferentially localized to the proliferating retinal vasculature and is almost completely absent from quiescent vessels. The differential expression of 67LR between proliferating and quiescent retinal vessels suggests that this laminin receptor is an important and novel target for future chemotherapeutic intervention during proliferative vasculopathies.

The effect of patient characteristics upon uptake of the influenza vaccination: a study comparing community based older adults in two healthcare systems

Background: Uptake of influenza vaccination represents a simple marker of proactive care of older people. However, many still do not receive the vaccine. To understand this challenge better, we investigated the relationship between patient characteristics (demographic, physical and psychological health, and health service use) and vaccination uptake in a sample of community-dwelling older people in two adjacent but differently structured healthcare systems (Northern Ireland (NI) and the Republic of Ireland (RoI)). Methods: 2,033 randomly selected community-dwelling older adults (65 years and older) were interviewed in their homes. Results: Rates of uptake were 78% in NI and 72% in RoI. Uptake was greater with older age (odds ratio (OR) 1.6, 95% confidence interval (CI) = 1.3-2.1, p

Management of varicella contacts in pregnancy: VZIG or Vaccination?

Background Varicella infection during pregnancy poses a serious risk for both foetus and mother. It has been suggested that it would be more cost-effective to screen antenatally with post-partum vaccination, which occurs in the US, than the current policy of checking immune status post varicella exposure, with VZIG administration where necessary. Additionally, it is doubtful whether the current policy provides best patient care, when a vaccine is available. Objectives The study aims to retrospectively compare the cost of the current policy with a cost estimate for antenatal screening with post-partum vaccination in NI. Study design A cost estimate of antenatal screening of primigravidas, with post-partum vaccination, was calculated for two models: (1) verbal screening, with serological testing of those with no history of varicella infection and (2) serological screening of all primigravidas. Results The cost of VZIG issued to pregnant women in 2006 was £100,800; 43% of births were to primigravidas therefore the estimated cost of VZIG issued to multigravidas was £58,100. The cost of verbal screening with post-partum vaccination is estimated at £23,750 p.a., saving £34,350 over current policy. The estimated cost of screening all primigravidas with post-partum vaccination is £43,000, saving £15,100. Conclusions This retrospective study suggests that in NI either of the proposed antenatal screening strategies would be less costly than current practice. This finding supports the suggestion that varicella immunity testing should be included in the Antenatal Infectious Diseases Screening Programme, either as part of the universal vaccination programme or solely as an antenatal programme.