European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy.

PURPOSE:
Treatment options for older patients with acute myeloid leukemia (AML) who are not considered suitable for intensive chemotherapy are limited. We assessed the second-generation purine nucleoside analog, clofarabine, in two similar phase II studies in this group of patients.
PATIENTS AND METHODS:
Two consecutive studies, UWCM-001 and BIOV-121, recruited untreated older patients with AML to receive up to four or six 5-day courses of clofarabine. Patients in UWCM-001 were either older than 70 years or 60 to 69 years of age with poor performance status (WHO > 2) or with cardiac comorbidity. Patients in BIOV-121 were >or= 65 years of age and deemed unsuitable for intensive chemotherapy.
RESULTS:
A total of 106 patients were treated in the two monotherapy studies. Median age was 71 years (range, 60 to 84 years), 30% had adverse-risk cytogenetics, and 36% had a WHO performance score >or= 2. Forty-eight percent had a complete response (32% complete remission, 16% complete remission with incomplete peripheral blood count recovery), and 18% died within 30 days. Interestingly, response and overall survival were not inferior in the adverse cytogenetic risk group. The safety profile of clofarabine in these elderly patients with AML who were unsuitable for intensive chemotherapy was manageable and typical of a cytotoxic agent in patients with acute leukemia. Patients had similar prognostic characteristics to matched patients treated with low-dose cytarabine in the United Kingdom AML14 trial, but had significantly superior response and overall survival.
CONCLUSION:
Clofarabine is active and generally well tolerated in this patient group. It is worthy of further evaluation in comparative trials and might be of particular use in patients with adverse cytogenetics.

Designing photosensitizers for photodynamic therapy: strategies, challenges and promising developments

Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) are techniques that combine the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitizing drug (possessing no dark toxicity) to cause destruction of selected cells. Despite its still widespread clinical use, Photofrin (R) has several drawbacks that limit its general clinical use. Consequently, there has been extensive research into the design of improved alternative photosensitizers aimed at overcoming these drawbacks. While there are many review articles on the subject of PDT and PACT, these have focused on the photosensitizers that have been used clinically, with little emphasis placed on how the chemical aspects of the molecule can affect their efficacy as PDT agents. Indeed, many of the PDT/PACT agents used clinically may not even be the most appropriate within a given class. As such, this review aims to provide a better understanding of the factors that have been investigated, while aiming at improving the efficacy of a molecule intended to be used as a photosensitizer. Recent publications, spanning the last 5 years, concerning the design, synthesis and clinical usage of photosensitizers for application in PDT and PACT are reviewed, including 5-aminolevulinic acid, porphyrins, chlorins, bacteriochlorins, texaphyrins, phthalocyanines and porphycenes. It has been shown that there are many important considerations when designing a potential PDT/PACT agent, including the influence of added groups on the lipophilicity of the molecule, the positioning and nature of these added groups within the molecule, the presence of a central metal ion and the number of charges that the molecule possesses. The extensive ongoing research within the field has led to the identification of a number of potential lead molecules for application in PDT/PACT. The development of the second-generation photosensitizers, possessing shorter periods of photosensitization, longer activation wavelengths and greater selectivity for diseased tissue provides hope for attaining the ideal photosensitizer that may help PDT and PACT move from laboratory investigation to clinical practice.

Proteasome inhibitors in cancer therapy

The ubiquitin proteasome pathway plays a critical role in regulating many processes in the cell which are important for tumour cell growth and survival. Inhibition of proteasome function has emerged as a powerful strategy for anti-cancer therapy. Clinical validation of the proteasome as a therapeutic target was achieved with bortezomib and has prompted the development of a second generation of proteasome inhibitors with improved pharmacological properties. This review summarises the main mechanisms of action of proteasome inhibitors in cancer, the development of proteasome inhibitors as therapeutic agents and the properties and progress of next generation proteasome inhibitors in the clinic.

Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection

Pseudomonas elastase (LasB), a metalloprotease virulence factor, is known to play a pivotal role in pseudomonal infection. LasB is secreted at the site of infection, where it exerts a proteolytic action that spans from broad tissue destruction to subtle action on components of the host immune system. The former enhances invasiveness by liberating nutrients for continued growth, while the latter exerts an immunomodulatory effect, manipulating the normal immune response. In addition to the extracellular effects of secreted LasB, it also acts within the bacterial cell to trigger the intracellular pathway that initiates growth as a bacterial bio?lm. The key role of LasB in pseudomonal virulence makes it a potential target for the development of an inhibitor as an antimicrobial agent. The concept of inhibition of virulence is a recently established antimicrobial strategy, and such agents have been termed “second-generation” antibiotics. This approach holds promise in that it seeks to attenuate virulence processes without bactericidal action and, hence, without selection pressure for the emergence of resistant strains. A potent inhibitor of LasB,N-mercaptoacetyl-Phe-Tyr-amide (Ki 41 nM) has been developed, and its ability to block these virulence processes has been assessed. It has been demonstrated that thes compound can completely block the action of LasB on protein targets that are instrumental in bio?lm formation and immunomodulation. The novel LasB inhibitor has also been employed in bacterial-cell-based assays, to reduce the growth of pseudomonal bio?lms, and to eradicate bio?lm completely when used in combination with conventional antibiotics.

Dimerisation of cyclooctene using Grubbs' catalysts

The dimerisation of cyclooctene (COE) to 1,9-cyclohexadecadiene, a molecule of interest to the fragrance industry, has been achieved using ruthenium catalysts in organic solvents with significantly better selectivities (47-74%) and yields (39-60%) than previously reported (34% and 30%, respectively). Grubbs' first and second generation catalysts, the Hoveyda-Grubbs' catalyst and a phosphonium alkylidene catalyst were tested in a range of organic solvents and ionic liquids (ILs), including 1:1 IL/dichloromethane mixtures and biphasic IL + pentane systems. The best results (74% selectivity, 60% yield) were obtained using Grubbs' first generation catalyst in 1,2-dichloroethane. The formation of trimer, tetramer and other higher molecular mass products were found to be favoured at low catalyst loadings (0.77 mM). Studies of metathesis reactions using 1,9-cyclohexadecadiene as substrate indicated that the monomer-dimer and monomer-trimer reactions are faster than the dimer-dimer reaction. The use of IL media allowed for the recyclability of the catalyst, although a drop in the yield of dimer generally occurred after the first run. Heterogeneized catalysts, where the IL-catalyst system was immobilised onto silica, resulted in fast reactions leading to poor yields of dimer. (C) 2011 Elsevier B.V. All rights reserved.

Connected Life Courses:Influences on and Experiences of 'Midlife' In-Migration to Rural Areas

This paper aims to contribute to the theorisation of midlife migration into rural areas. Although the factors influencing migration are known to be variable at different stages of a person's life, much less well understood is how migration decisions at different stages of the life course are connected and how post-migration experiences may be influenced by an earlier life course stage. We argue that midlife migration decisions are the product of the migrant's lifetime experiences and influences up until that stage in their life alongside their expectations and aspirations for future life course stages. Using a case study of the Glens of Antrim (Northern Ireland), this paper specifically demonstrates the role of childhood memories to explain midlife migration to a rural area. In doing so, it argues that some findings more commonly associated with second-generation transnational migration are also equally relevant to migration within the UK. Roots migration and place attachment alongside the midlife migrant's post-migration sense of belonging and permanency are found to be influenced by the migrant's earlier memories, behaviours, and experiences.

User behaviour, best practice and the risks of non-target exposure associated with anticoagulant rodenticide use

Usage of anticoagulant rodenticides (ARs) is an integral component of modern agriculture and is essential for the control of commensal rodent populations. However, the extensive deployment of ARs has led to widespread exposure of a range of non-target predatory birds and mammals to some compounds, in particular the second-generation anticoagulant rodenticides (SCARS). As a result, there has been considerable effort placed into devising voluntary best practice guidelines that increase the efficacy of rodent control and reduce the risk of non-target exposure. Currently, there is limited published information on actual practice amongst users or implementation of best practice. We assessed the behaviour of a typical group of users using an on-farm questionnaire survey. Most baited for rodents every year using SGARs. Most respondents were apparently aware of the risks of non-target exposure and adhered to some of the best practice recommendations but total compliance was rare. Our questionnaire revealed that users of first generation anticoagulant rodenticides rarely protected or checked bait stations, and so took little effort to prevent primary exposure of non-targets. Users almost never searched for and removed poisoned carcasses and many baited for prolonged periods or permanently. These factors are all likely to enhance the likelihood of primary and secondary exposure of non-target species. (C) 2010 Published by Elsevier Ltd.

Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells

Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms. Therefore understanding of the feedback mechanisms that occur with respect to specific genetic mutations may aid identification of novel biomarkers that predict patient response. In the present paper, we show that feedback between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is cell-line-specific and highly dependent on the activating mutation of K-Ras or overexpression c-Met. We found that cell lines exhibited differential signalling and apoptotic responses to PD184352, a specific MEK inhibitor, and PI103, a second-generation class I PI3K inhibitor. We reveal that feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway is present in cancer cells harbouring either K-Ras activating mutations or amplification of c-Met but not the wild-type counterparts. Moreover, we demonstrate that inhibition of protein phosphatase activity by OA (okadaic acid) restored PI103-mediated feedback in wild-type cells. Together, our results demonstrate a novel mechanism for feedback between the PI3K/Akt/mTORC1 and the Ras/MEK/ERK pathways that only occurs in K-Ras mutant and c-Met amplified cells but not the isogenic wild-type cells through a mechanism that may involve inhibition of a specific endogenous phosphatase(s) activity. We conclude that monitoring K-Ras and c-Met status are important biomarkers for determining the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy.

Targeting the ubiquitin proteasome system in haematological malignancies

The ubiquitin proteasome system (UPS) plays a central role in cellular protein homeostasis through the targeted destruction of damaged/misfolded proteins and regulatory proteins that control critical cellular functions. The UPS comprises a sequential series of enzymatic activities to covalently attach ubiquitin to proteins to target them for degradation through the proteasome. Aberrancies within this system have been associated with transformation and tumourigenesis and thus, the UPS represents an attractive target for the development of anti-cancer therapies. The use of the first-in-class proteasome inhibitor, bortezomib, in the treatment of Plasma Cell Myeloma and Mantle Cell Lymphoma has validated the UPS as a therapeutic target. Following on its success, efforts are focused on the development of second-generation proteasome inhibitors and small molecule inhibitors of other components of the UPS. This review will provide an overview of the UPS and discuss current and novel therapies targeting the UPS.

Pre-clinical development of a combination microbicide vaginal ring containing dapivirine and darunavir

Objectives: Combination microbicide vaginal rings may be more effective than single microbicide rings at reducing/preventing sexual transmission of HIV. Here, we report the preclinical development and macaque pharmacokinetics of matrix-type silicone elastomer vaginal rings containing dapivirine and darunavir.

Methods: Macaque rings containing 25 mg dapivirine, 300 mg darunavir and 100 mg dapivirine, and 300 mg darunavir were manufactured and characterised by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28-day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values calculated.

Results: Darunavir caused a concentration-dependent reduction in the dapivirine melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present, and the release medium. In macaques, serum concentrations of both microbicides were maintained between 101–102 pg/mL. Vaginal fluid levels ranged between 103–104 ng/g and 104–105 ng/g for dapivirine and darunavir, respectively. Tissue concentrations ranges for each drug were: vagina (1.8×103–3.8×103 ng/g) > cervix (9.4×101–3.9×102 ng/g) > uterus (0–108 ng/g) > rectum (0–40 ng/g). Measured IC50 values were > 2 ng/mL for both compounds.

Conclusions: Based on these results, and in light of recent clinical progress of the 25mg dapivirine ring, a combination vaginal ring containing dapivirine and darunavir is a viable second-generation HIV microbicide candidate.

A Combination Vaginal Ring Releasing Dapivirine and Darunavir

Background: Combination microbicide vaginal rings, containing two or more antiretrovirals targeting different steps in the HIV replicative process, may be more effective than single microbicide products at preventing sexual transmission of HIV. Here, we report the preclinical development, including in vitro release and macaque pharmacokinetics, of matrix-type silicone elastomer rings containing dapivirine (DPV; an experimental non-nucleoside reverse transcriptase inhibitor) and darunavir (DRV; a marketed protease inhibitor). Methods: Macaque rings containing 25 mg DPV, 300 mg DRV and 100 mg DPV, and 300 mg DRV were manufactured and characterised by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28-day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values calculated.
Results: DRV caused a concentration-dependent reduction in the DPV melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present, and the release medium. In macaques, serum concentrations of both
microbicides were maintained between 101-102 pg/mL. Vaginal fluid levels
ranged between 103-104 ng/g and 104-105 ng/g for DPV and DRV, respectively. Vaginal tissue concentrations decreased in rank order: vagina
(1.8×103-3.8×103 ng/g) > cervix (9.4×101-3.9×102 ng/g) > uterus (0-108 ng/g) > rectum (0-40 ng/g). Measured IC50 values (HIV-1 BaL) determined from macaque vaginal fluid samples were < 2 ng/mL for both compounds. Conclusions: Based on these results, and in light of the ongoing clinical progress of the 25mg DPV ring, a combination vaginal ring containing DPV and DRV is a viable second-generation HIV microbicide candidate.

Deglacial mesophotic reef demise on the Great Barrier Reef

Submerged reefs are important recorders of palaeo-environments and sea-level change, and provide a substrate for modern mesophotic (deep-water, light-dependent) coral communities. Mesophotic reefs are rarely, if ever, described from the fossil record and nothing is known of their long-term record on Great Barrier Reef (GBR). Sedimentological and palaeo-ecological analyses coupled with 67 14C AMS and U–Th radiometric dates from dredged coral, algae and bryozoan specimens, recovered from depths of 45 to 130 m, reveal two distinct generations of fossil mesophotic coral community development on the submerged shelf edge reefs of the GBR. They occurred from 13 to 10 ka and 8 ka to present. We identified eleven sedimentary facies representing both autochthonous (in situ) and allochthonous (detrital) genesis, and their palaeo-environmental settings have been interpreted based on their sedimentological characteristics, biological assemblages, and the distribution of similar modern biota within the dredges. Facies on the shelf edge represent deep sedimentary environments, primarily forereef slope and open platform settings in palaeo-water depths of 45–95 m. Two coral–algal assemblages and one non-coral encruster assemblage were identified: 1) Massive and tabular corals including Porites, Montipora and faviids associated with Lithophylloids and minor Mastophoroids, 2) platy and encrusting corals including Porites, Montipora and Pachyseris associated with melobesioids and Sporolithon, and 3) Melobesiods and Sporolithon with acervulinids (foraminifera) and bryozoans. Based on their modern occurrence on the GBR and Coral Sea and modern specimens collected in dredges, these are interpreted as representing palaeo-water depths of < 60 m, < 80–100 m and > 100 m respectively. The first mesophotic generation developed at modern depths of 85–130 m from 13 to 10.2 ka and exhibit a deepening succession of < 60 to > 100 m palaeo-water depth through time. The second generation developed at depths of 45–70 m on the shelf edge from 7.8 ka to present and exhibit stable environmental conditions through time. The apparent hiatus that interrupted the mesophotic coral communities coincided with the timing of modern reef initiation on the GBR as well as a wide-spread flux of siliciclastic sediments from the shelf to the basin. For the first time we have observed the response of mesophotic reef communities to millennial scale environmental perturbations, within the context of global sea-level rise and environmental changes.

Supervised training approach using spiking neural networks

One of the basic aspects of some neural networks is their attempt to approximate as much as possible their biological counterparts. The goal is to achieve a simple and robust network, easy to understand and able of simulating the human brain at a computational level. Recently a third generation of neural networks (NN) [1], called Spiking Neural Networks(SNN) was appeared. This new kind of networks use the time of a electrical pulse, or spike, to encode the information. In the first and second generation of NN analog values are used in the communication between neurons.

Exploring an uncommon host-parasite interaction to unveil the uniqueness of Perkinsus sp as a model organism

We report the exploration of some unique metabolic pathways in Perkinsus olseni a marine protist parasite, responsible to significant mortalities in mollusks, especially in bivalves all around the world. In Algarve, south of Portugal carpet shell clam Ruditapes decussatus mortalities can reach up to 70%, causing social and economic losses. The objective of studying those unique pathways, is finding new therapeutic strategies capable of controlling/eliminating P. olseni proliferation in clams. In that sense metabolic pathways, were explored, and drugs affecting these cycles were tested for activity. The first step involved the identification of the genes behind those pathways, the reconstitution of the main steps, and molecular characterization of those genes and later on, the identification of possible targets within the genes studied. Metabolic cycles were screened due to the fact of not being present in host or differ in a critical way, such as the following pathways: shikimate, MEP-­‐ isoprenoids, Leloir cycle for chitin production, purine biosynthesis (unique among protists), the de novo synthesis of folates (absent in metazoa) and some unique genes like, the alternative oxidase (a branch of respiratory chain) and the hypoxia sensor HPH. All those pathways were covered and possible chemical inhibition using therapeutic drugs was tested with positive results. The relation between the common host Ruditapes decussatus and P. olseni was also explored in a dimension not possible some years ago. With the accessibility to second generation sequencers and microarray analysis platforms, genes involved in host defense or parasite virulence and resistance to the host were deciphered, allowing aiming to new targets (mechanisms and pathways), offering new possibilities for the control of Perkinsus in close environments. The thousands of genes, generated by this work, sequenced and analyzed from this commercial valuable clam and for Perkinsus olseni will be an important and value tool for the scientific community, allowing a better understanding of host-­‐parasite interactions, promoting the usage of P. olseni as an emerging model for alveolata parasites.

Cosmopolitanism and the relevance of ‘zombie concepts’: the case of anomic suicide amongst Alevi Kurd youth

Against Beck’s claims that conventional sociological concepts and categories are zombie categories, this paper argues that Durkheim’s theoretical framework in which suicide is a symptom of an anomic state of society can help us understand the diversity of trajectories that transnational migrants follow and that shape their suicide rates within a cosmopolitan society. Drawing on ethnographic data collected on eight suicides and three attempted suicide cases of second-generation male Alevi Kurdish migrants living in London, this article explains the impact of segmented assimilation/adaptation trajectories on the incidence of suicide and how their membership of a ‘new rainbow underclass’, as a manifestation of cosmopolitan society, is itself an anomic social position with a lack of integration and regulation.