HPMA copolymer - aminoellipticine conjugates: mechanism of action.

Over the past two decades cancer chemotherapy has resulted in a small number of previously fatal cancers becoming curable. Many cancers, particularly the so-called solid tumours, do not respond well to conventional chemotherapy. To maximise tumour targeting and minimize host tissue toxicity a large number of drug delivery systems have been proposed. Polymer anticancer conjugates based on N-(2- hydroxypropyl) methacrylamide (HPMA) have recently entered early clinical trial. It has been shown that HPMA copolymer conjugates preferentially extravasate into solid tumours and are retained there by a process known as the 'enhanced permeability and retention' (EPR) effect. A natural anticancer agent, derived from ellipticine, namely 6-(3-aminopropyl) ellipticine (APE) was selected for conjugation to HPMA copolymers. In this study a series of HPMA copolymer-APE conjugates were synthesised, containing a variety of drug loadings (1.07-6.10%w/w) conjugated via the tetrapeptide linker (Gly-Phe-Leu- Gly). These conjugates were designed to be localised in tumours following injection and to be taken up by tumour cells via the process of endocytosis before liberating APE, mediated by cathepsin B present in the lysosome. These conjugates were shown to form complex intramolecular micelles in solution which resulted in the conjugates of a high drug loading showing reduced APE release in vitro (20%/5h) compared to the medium and low drug loading conjugates (55%/5h), suggesting hindered enzyme access. All conjugates showed a marked reduction in haemolysis, a common problem with ellipticines, compared to APE alone. Anti-tumour activity was observed in the s.c. B16F10 murine melanoma model and also in the CORL-23 human non small cell lung carcinoma xenograft in mice, particularly for the conjugate of medium APE loading. This thesis also examined the extravasation and intratumoural distribution of HPMA copolymer-anticancer conjugates using HPMA copolymer doxorubicin (PK1) as a model conjugate in the rat dorsal window chamber model

Stochastic parameterization: uncertainties from convection

In 2005, the ECMWF held a workshop on stochastic parameterisation, at which the convection was seen as being a key issue. That much is clear from the working group reports and particularly the statement from working group 1 that “it is clear that a stochastic convection scheme is desirable”. The present note aims to consider our current status in comparison with some of the issues raised and hopes expressed in that working group report

Uniform Computer Information Transactions Act: Bringing Commercial Law into the 21st Century

The e-commerce revolution has redefined the way business is transacted everywhere. Meanwhile, the body of commercial law lags behind the fast pace of technological changes and has yet to effectively address the numerous issues presented by radical changes in the world of commerce such as electronic contracts, electronic signatures, shrinkwrap agreements, and click-wrap agreements. In an effort to establish the Commonwealth of Virginia as a national leader on this subject, in 2000 the Virginia General Assembly passed the Uniform Computer Information Transactions Act ( UCITA ). UCITA legislation has been introduced in a handful of other states but the only other state that has passed UCITA is Maryland. By all accounts it is too early to tell whether these laws will meet the needs of the business community in this era of high technology and whether they will be effective if only passed by a limited number of states

Evaluation of the Plant–Craig stochastic convection scheme (v2.0) in the ensemble forecasting system MOGREPS-R (24 km) based on the Unified Model (v7.3)

The Plant–Craig stochastic convection parameterization (version 2.0) is implemented in the Met Office Regional Ensemble Prediction System (MOGREPS-R) and is assessed in comparison with the standard convection scheme with a simple stochastic scheme only, from random parameter variation. A set of 34 ensemble forecasts, each with 24 members, is considered, over the month of July 2009. Deterministic and probabilistic measures of the precipitation forecasts are assessed. The Plant–Craig parameterization is found to improve probabilistic forecast measures, particularly the results for lower precipitation thresholds. The impact on deterministic forecasts at the grid scale is neutral, although the Plant–Craig scheme does deliver improvements when forecasts are made over larger areas. The improvements found are greater in conditions of relatively weak synoptic forcing, for which convective precipitation is likely to be less predictable

FUEL POVERTY IN IRELAND: EXTENT, AFFECTED GROUPS AND POLICY ISSUES. ESRI WP262. October 2008

This paper provides updated estimates for the scale of fuel poverty in the Republic of Ireland using two measures: one based on fuel expenditure as a share of income and the other based on self-reported deprivation. It also presents modeling results as to the characteristics of households most vulnerable to fuel poverty, examines the potential effects of future fuel price changes, outlines policies in place in Ireland and other countries, and discusses policy issues

Multi-tiered distributed computing platform

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Upper‐level midlatitude troughs in boreal winter have an amplified low‐latitude linkage over Africa

In boreal winter, strong upper-level midlatitude troughs across the Atlantic–Africa–southwestern Asia sector generate substantial tropical–extratropical interaction and have become recognized as important factors in some extreme weather events. As such, they represent important dynamic features to understand and capture in weather forecasts, as well as in climate models for projections on longer timescales. Here, we empirically study the 20% of winter days with strongest trough signatures during 1982–2020 at each longitude across the sector, and show that the trough impact over northern Africa, most notably in central parts, is particularly strong in magnitude, low-latitude extent and persistence, leading to the characterization of a northern Africa mode of several-days weather fluctuation. Weather conditions that follow strong troughs from the eastern Atlantic to the Central Mediterranean include: (i) a warming tendency across much of northern Africa, generally of several Celsius magnitude ahead of the trough, and >1°C even extending to the south of 10° N in central parts and continuing eastward until the Ethiopian Highlands; (ii) precipitation development further north than normal across northern tropical Africa, especially strong over longitudes corresponding to a northward extension of the main Congo rain belt. The intertropical discontinuity and low-level heat low are also shifted significantly north, with the complex of anomalies persisting for several days, beyond the timescale of the trough. For context, at all other trough longitudes across the sector, a warming signal does emerge (statistically significant), but with much shorter persistence (2–3 days), smaller magnitude and extending southward clearly only to 15–20° N. Mid-level tropical plumes of moisture are also typically present for strong troughs from the eastern Atlantic to southwestern Asia, and these alone can lead to weather extremes. However, low-level warming and mid-level moistening are uniquely juxtaposed at low latitudes over central Africa, where a near-equatorial signature develops