Novel anti-endothelial therapeutic strategies in malignant melanoma : the metronomic approach.

Treatment strategies for advanced malignancy remain limited in their success, despite major advances in the understanding of cancer aetiology and molecular biology. The incidence of many cancers, including melanoma, continues to rise, with a huge demand for therapies even if treatment goals are purely cytostatic. One particular therapeutic strategy is the metronomic (continuous and low) dosing of conventional chemotherapy. There is evidence to suggest that tumour vasculature is the main target of this dosing schedule resulting in an overall ‘non specific’ anti-angiogenic effect. It is now being studied in clinical trials alone and in combination with specific antiangiogenic agents.This thesis had two main aims: firstly to investigate the additive or synergistic antiendothelial effects of a number of conventional cytotoxic agents (Temozolomide, Paclitaxel, Vinorelbine, Etoposide, Carboplatin) in vitro given in a metronomic schedule in combination with a specific anti-angiogenic compound (Sorafenib) and a non-specific sompound (Combretastatin). The anti-proliferative, cytotoxic activities of the metronomic combinatorial schedules were assessed on microvascular endothelial cells and cancer cells using an MTT proliferation assay. Results confirmed significant (

The Effect of Retro-Cueing on an ERP Marker of VSTM Maintenance

Previous research has found that Contralateral Delay Activity (CDA) is correlated with the number of items maintained in Visual Short Term Memory from one visual field (VF) (Vogel & Machizawa, 2004). CDA is usually elicited by a to-be-remembered array after a prospective cue (pro-cue) signalling the relevant side of the visual display, and is interpreted as a putative electrophysiological signature of WM maintenance. Attention can also be directed to the contents of VSTM, after the presentation of a visual array, using a retroactive cue (retro-cue) (Nobre, Griffin, & Rao, 2008). Because retro-cueing directs attention within a memory trace, potentially reducing the load of items to be maintained, we hypothesised that this would significantly attenuate the CDA. Participants were initially presented with a spatial pro-cue which reduced the number of to-be-remembered items to one side. After a delay, a memory array of either four (low load) or eight (high load) items was displayed. A retro-cue then cued participants to one location within the relevant VF, further reducing the load of to-be-remembered items; or provided no information, requiring participants to hold all items in the relevant VF. At the end of the trial, participants performed a same/different judgement on a test stimulus. Retro-cues significantly improved VSTM performance. Unexpectedly, the CDA was found to be abolished by the presentation of both spatially predictive and neutral cues, independently of the VSTM load participants had to maintain

Markers of preparatory attention predict visual short-term memory performance

AbstractVisual short-term memory (VSTM) is limited in capacity. Therefore, it is important to encode only visual information that is most likely to be relevant to behaviour. Here we asked which aspects of selective biasing of VSTM encoding predict subsequent memory-based performance. We measured EEG during a selective VSTM encoding task, in which we varied parametrically the memory load and the precision of recall required to compare a remembered item to a subsequent probe item. On half the trials, a spatial cue indicated that participants only needed to encode items from one hemifield. We observed a typical sequence of markers of anticipatory spatial attention: early attention directing negativity (EDAN), anterior attention directing negativity (ADAN), late directing attention positivity (LDAP); as well as of VSTM maintenance: contralateral delay activity (CDA). We found that individual differences in preparatory brain activity (EDAN/ADAN) predicted cue-related changes in recall accuracy, indexed by memory-probe discrimination sensitivity (d′). Importantly, our parametric manipulation of memory-probe similarity also allowed us to model the behavioural data for each participant, providing estimates for the quality of the memory representation and the probability that an item could be retrieved. We found that selective encoding primarily increased the probability of accurate memory recall; that ERP markers of preparatory attention predicted the cue-related changes in recall probability

Further studies on the pyrolytic domino cyclization of stabilized phosphonium ylides bearing an ortho-aminophenyl group

The authors thank the EPSRC (UK) for a DTA studentship (Grant No. EP/P501768/1).Four new stabilized phosphonium ylides containing a 2-(benzyl(methyl)amino)phenyl group have been prepared and characterized and are found, upon pyrolysis under gas-phase flow conditions, to lose Ph3PO and benzyl radical to afford new heterocyclic products resulting from domino cyclization of both C- and N-centred radicals. Most products arise from processes of the former type and have quinoline, phenanthridine or ring-fused phenanthridine structures, while in one case a process of the latter type leads to a benzocarbazole product. The X-ray structure of a 2-(methyl(tosyl)amino)phenyl ylide is also reported.Publisher PDFPublisher PDFPeer reviewe

Typical 22q11.2 deletion syndrome appears to confer a reduced risk of schwannoma

Purpose: The LZTR1 gene has been associated with schwannomatosis tumor predisposition and is located in a region that is deleted in the great majority (89%) of patients with 22q11.2 deletion syndrome (22q11.2DS). Since it is known that approximately 1 in 500 people in the general population will develop a sporadic schwannoma and there are no reports of the occurrence of schwannoma in 22q11.2DS, we investigated whether whole-gene deletion of LZTR1 occurs in schwannomatosis and assessed the risk of schwannoma in 22q11.2DS. Methods: We assessed the genetic testing results for LZTR1-associated schwannomatosis and the clinical phenotypes of patients with 22q11.2DS. Results: There were no reports of schwannoma in over 1,500 patients with 22q11.2DS. In addition, no patients meeting clinical diagnostic criteria for schwannomatosis had a whole-gene deletion in LZTR1. Only 1 patient in 110 with an apparently sporadic vestibular schwannoma had a constitutional whole-gene deletion of LZTR1. Conclusion: People with a large 22q11.2 deletion may have a reduced risk of developing a schwannoma compared to the general population

Quantifying the burden of rhodesiense sleeping sickness in Urambo district, Tanzania

Sleeping sickness (human African trypanosomiasis - HAT) is a disease transmitted by tsetse flies and is always fatal if left untreated. The disease occurs in foci affecting poor communities with limited access to health service provision and as such the disease is often left undiagnosed, mistaken for more common afflictions. Even if diagnosed, sleeping sickness is costly to treat, both for health services and patients and their families in terms of costs of diagnosis, transport, hospital care, and the prolonged period of convalescence. Here we estimate the health burden of the acute form T. b. rhodesiense sleeping sickness in Urambo District, Tanzania in terms of Disability Adjusted Life Years (DALYs), the yardstick commonly used by policy makers to prioritize disease management practices, representing a year of healthy life lost to disease. In this single district, the burden of the disease over one year was estimated at 979 DALYs and the estimated monetary costs to health services for the 143 treated patients at US$11,841 and to the patients themselves at US$ 3,673 for direct medical costs and US$ 9,781 for indirect non-medical costs. Sleeping sickness thus places a considerable burden on the affected rural communities and health services

A Novel Bacterium Associated with Lymphadenitis in a Patient with Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system causing defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections. We identified a novel gram-negative rod in excised lymph nodes from a patient with CGD. Gram-negative rods grew on charcoal-yeast extract, but conventional tests could not identify it. The best 50 matches of the 16S rRNA (using BLAST) were all members of the family Acetobacteraceae, with the closest match being Gluconobacter sacchari. Patient serum showed specific band recognition in whole lysate immunoblot. We used mouse models of CGD to determine whether this organism was a genuine CGD pathogen. Intraperitoneal injection of gp91(phox) (−/−) (X-linked) and p47 (phox −/−) (autosomal recessive) mice with this bacterium led to larger burdens of organism recovered from knockout compared with wild-type mice. Knockout mouse lymph nodes had histopathology that was similar to that seen in our patient. We recovered organisms with 16S rRNA sequence identical to the patient's original isolate from the infected mice. We identified a novel gram-negative rod from a patient with CGD. To confirm its pathogenicity, we demonstrated specific immune reaction by high titer antibody, showed that it was able to cause similar disease when introduced into CGD, but not wild-type mice, and we recovered the same organism from pathologic lesions in these mice. Therefore, we have fulfilled Koch's postulates for a new pathogen. This is the first reported case of invasive human disease caused by any of the Acetobacteraceae. Polyphasic taxonomic analysis shows this organism to be a new genus and species for which we propose the name Granulobacter bethesdensis

Success Factors of European Syndromic Surveillance Systems: A Worked Example of Applying Qualitative Comparative Analysis

Introduction: Syndromic surveillance aims at augmenting traditional public health surveillance with timely information. To gain a head start, it mainly analyses existing data such as from web searches or patient records. Despite the setup of many syndromic surveillance systems, there is still much doubt about the benefit of the approach. There are diverse interactions between performance indicators such as timeliness and various system characteristics. This makes the performance assessment of syndromic surveillance systems a complex endeavour. We assessed if the comparison of several syndromic surveillance systems through Qualitative Comparative Analysis helps to evaluate performance and identify key success factors. Materials and Methods: We compiled case-based, mixed data on performance and characteristics of 19 syndromic surveillance systems in Europe from scientific and grey literature and from site visits. We identified success factors by applying crisp-set Qualitative Comparative Analysis. We focused on two main areas of syndromic surveillance application: seasonal influenza surveillance and situational awareness during different types of potentially health threatening events. Results: We found that syndromic surveillance systems might detect the onset or peak of seasonal influenza earlier if they analyse non-clinical data sources. Timely situational awareness during different types of events is supported by an automated syndromic surveillance system capable of analysing multiple syndromes. To our surprise, the analysis of multiple data sources was no key success factor for situational awareness. Conclusions: We suggest to consider these key success factors when designing or further developing syndromic surveillance systems. Qualitative Comparative Analysis helped interpreting complex, mixed data on small-N cases and resulted in concrete and practically relevant findings

Monetary Cost of the MyPlate Diet in Young Adults: Higher Expenses Associated with Increased Fruit and Vegetable Consumption

Background. Cost is a commonly reported barrier to healthy eating. This is a secondary research analysis designed to examine the food expenditures of young adults on a university campus following the United States Department of Agriculture (USDA) MyPlate guidelines for fruits and vegetables. Methods. Meal receipts and dietary intake were recorded weekly. Anthropometrics and clinical assessments were recorded before intervention. Researchers rated compliance based on the participant’s dietary food log, receipt matching, food pictures, and reports during weekly 1-hour consultations. Results. Fifty-three young adults (18–30 years old) at-risk of, or diagnosed with, metabolic syndrome (MetS) were enrolled in the study, with 10 excluded (n = 43) from analyses due to enrollment in a fixed cost university campus dining meal plan. A two sample t-test assessed differences in food costs and regression analysis determined associations between food cost and diet compliance while controlling for confounding factors of age, sex, and body mass index (BMI). Diet compliant subjects (n = 38) had higher weekly food cost at $95.73 compared to noncompliant subjects (n = 5) who spent$66.24 (). A regression analysis controlling for age, sex, BMI, and geographical region also indicated cost differences based on diet compliance (). Conclusion. Results indicate an ∼$29.00 per week increase in food cost when eating the recommended amount of fruit and vegetables. These findings can contribute to research incentive design, program planning cost, and determining effective interventions to improve diet in this population