Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery

Patients with anaplastic thyroid carcinoma can rarely be cured, but every effort should be made to prevent death due to suffocation. Between 1984 and 1999, 55 consecutive patients with anaplastic thyroid carcinoma were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin, and when feasible surgery. Radiotherapy was carried out for 5 days a week. The daily fraction until 1988 was 1.0 Gy×2 (A) and 1989–92 1.3 Gy×2 (B) . Thereafter 1.6 Gy×2 (C) was administered. Radiotherapy was administered to a total target dose of 46 Gy; of which 30 Gy was administered preoperatively in the first two protocols (A and B), while the whole dose was given preoperatively in the third protocol (C). The therapy was otherwise identical. Twenty mg doxorubicin was administered intravenously weekly. Surgery was possible in 40 patients. No patient failed to complete the protocol due to toxicity. In only 13 cases (24%) was death attributed to local failure. Five patients (9%) ‘had a survival’ exceeding 2 years. No signs of local recurrence were seen in 33 patients (60%); 5 out of 16 patients in Protocol A, 11 out of 17 patients in Protocol B, 17 out of 22 patients in Protocol C (P=0.017). In the 40 patients undergoing additional surgery, no signs of local recurrence were seen in 5 out of 9 patients, 11 out of 14 patients and 17 out of 17 patients, respectively (P=0.005)

Interaction Between Convection and Pulsation

This article reviews our current understanding of modelling convection dynamics in stars. Several semi-analytical time-dependent convection models have been proposed for pulsating one-dimensional stellar structures with different formulations for how the convective turbulent velocity field couples with the global stellar oscillations. In this review we put emphasis on two, widely used, time-dependent convection formulations for estimating pulsation properties in one-dimensional stellar models. Applications to pulsating stars are presented with results for oscillation properties, such as the effects of convection dynamics on the oscillation frequencies, or the stability of pulsation modes, in classical pulsators and in stars supporting solar-type oscillations.Comment: Invited review article for Living Reviews in Solar Physics. 88 pages, 14 figure

YK-4-279 Inhibits ERG and ETV1 Mediated Prostate Cancer Cell Invasion

Background: Genomic rearrangements involving the ETS family of transcription factors occur in 40–70 % of prostate cancer cases. ERG and ETV1 are the most common ETS members observed in these genetic alterations. The high prevalence of these rearrangements and their biological significance represents a novel therapeutic target for the treatment of prostate cancer. Methods and Findings: We recently reported the development of YK-4-279, a small molecule inhibitor of EWS-FLI1 oncoprotein in Ewing’s Sarcoma. Since ERG and ETV1 belong to the same class of ETS factors as FLI1, we tested the ability of YK-4-279 to inhibit biological functions of ERG and ETV1 proteins in prostate cancer. YK-4-279 inhibited ERG and ETV1 mediated transcriptional activity in a luciferase assay. YK-4-279 also decreased ERG and ETV1 downstream target mRNA and protein expression in ETV1-fusion positive LNCaP and ERG fusion positive VCaP cells. YK-4-279 reduced the motility of LNCaP cells in a scratch assay and the invasive phenotype of both LNCaP and VCaP cells in a HUVEC invasion assay. Fusion-negative PC3 cells were unresponsive to YK-4-279. SiRNA mediated ERG knockdown in VCaP cells resulted in a loss of drug responsiveness. Concurrently, transient ERG expression in PC-3 cells resulted in increased invasive potential, which was reduced by YK-4-279. Conclusion: These data demonstrate that YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostat

Ultrasound-Enhanced Drug Transport and Distribution in the Brain

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm2. In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage

GWAS Meets Microarray: Are the Results of Genome-Wide Association Studies and Gene-Expression Profiling Consistent? Prostate Cancer as an Example

Genome-wide association studies (GWASs) and global profiling of gene expression (microarrays) are two major technological breakthroughs that allow hypothesis-free identification of candidate genes associated with tumorigenesis. It is not obvious whether there is a consistency between the candidate genes identified by GWAS (GWAS genes) and those identified by profiling gene expression (microarray genes).We used the Cancer Genetic Markers Susceptibility database to retrieve single nucleotide polymorphisms from candidate genes for prostate cancer. In addition, we conducted a large meta-analysis of gene expression data in normal prostate and prostate tumor tissue. We identified 13,905 genes that were interrogated by both GWASs and microarrays. On the basis of P values from GWASs, we selected 1,649 most significantly associated genes for functional annotation by the Database for Annotation, Visualization and Integrated Discovery. We also conducted functional annotation analysis using same number of the top genes identified in the meta-analysis of the gene expression data. We found that genes involved in cell adhesion were overrepresented among both the GWAS and microarray genes.We conclude that the results of these analyses suggest that combining GWAS and microarray data would be a more effective approach than analyzing individual datasets and can help to refine the identification of candidate genes and functions associated with tumor development

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?

Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds

Capturing the cloud of diversity reveals complexity and heterogeneity of MRSA carriage, infection and transmission.

Genome sequencing is revolutionizing clinical microbiology and our understanding of infectious diseases. Previous studies have largely relied on the sequencing of a single isolate from each individual. However, it is not clear what degree of bacterial diversity exists within, and is transmitted between individuals. Understanding this 'cloud of diversity' is key to accurate identification of transmission pathways. Here, we report the deep sequencing of methicillin-resistant Staphylococcus aureus among staff and animal patients involved in a transmission network at a veterinary hospital. We demonstrate considerable within-host diversity and that within-host diversity may rise and fall over time. Isolates from invasive disease contained multiple mutations in the same genes, including inactivation of a global regulator of virulence and changes in phage copy number. This study highlights the need for sequencing of multiple isolates from individuals to gain an accurate picture of transmission networks and to further understand the basis of pathogenesis.Thanks to Dr Alex O’Neill, University of Leeds and Dr Matthew Ellington, Public Health England for provision of RN4220 and RN4200mutS. We thank the core sequencing and informatics team at the Wellcome Trust Sanger Institute for sequencing of the isolates described in this study. This work was supported by a Medical Research Council Partnership grant (G1001787/1) held between the Department of Veterinary Medicine, University of Cambridge (M.A.H.), the School of Clinical Medicine, University of Cambridge (S.J.P.), the Moredun Research Institute, and the Wellcome Trust Sanger Institute (J.P. and S.J.P). S.J.P. receives support from the NIHR Cambridge Biomedical Research Centre. M.T.G.H., S.R.H. and J.P. were funded by Wellcome Trust grant no. 098051. G.G.R.M. was funded by an MRC studentship.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms756

Drop-out and mood improvement: a randomised controlled trial with light exposure and physical exercise [ISRCTN36478292]

BACKGROUND: Combining bright light exposure and physical exercise may be an effective way of relieving depressive symptoms. However, relatively little is known about individual factors predicting either a good response or treatment failure. We explored background variables possibly explaining the individual variation in treatment response or failure in a randomised trial. METHODS: Participants were volunteers of working-age, free from prior mental disorders and recruited via occupational health centres. The intervention was a randomised 8-week trial with three groups: aerobics in bright light, aerobics in normal room lighting, and relaxation/stretching in bright light. Good response was defined as a 50% decrease in the symptom score on either the Hamilton Depression Rating Scale (HDRS) or 8-item scale of atypical symptoms. Background variables for the analysis included sex, age, body-mass index, general health habits, seasonal pattern, and sleep disturbances. RESULTS: Complete data were received from 98 subjects (11 men, 87 women). Of them, 42 (5 men, 37 women) were classified as responders on the HDRS. Overall, light had a significant effect on the number of responders, as assessed with the HDRS (X(2 )= .02). The number needed to treat (NNT) for light was 3.8. CONCLUSIONS: We investigated the effect of bright light and exercise on depressive symptoms. Problems with sleep, especially initial insomnia, may predict a good response to treatment using combined light and exercise. Bright light exposure and physical exercise, even in combination, seem to be well tolerated and effective on depressive symptoms