Somatic LKB1 Mutations Promote Cervical Cancer Progression

Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence

ProsCan for Men: Randomised controlled trial of a decision support intervention for men with localised prostate cancer

Background: Prostate cancer is the most common male cancer in the Western world but is highly heterogeneous in disease progression and outcomes. Consequently, the most substantial morbidity may actually arise from the adverse psychosocial impact of distress in decision-making and long term quality of life effects such as impotence. This paper presents the design of a randomised controlled trial of a decision support/psychosocial intervention for men newly diagnosed with localised prostate cancer. Methods/Design: 350 men per condition (700 men in total) have been recruited after diagnosis and before treatment through urology private practices and hospital outpatient clinics and randomised to 1) a tele-based nurse delivered five session decision support/psychosocial intervention or 2) a usual care control group. Two intervention sessions are delivered before treatment that address decision support, stress management and preparation for treatment. Three further sessions are provided three weeks, seven weeks and five months after treatment that focus on adjustment to cancer, problem solving and coping with treatment side effects. Participants are assessed at baseline (before treatment) and 2, 6, 12, 24 and 36 months post-treatment. Outcome measures include: cancer threat appraisal; decision-related distress and bother from treatment side effects; involvement in decision making; satisfaction with health care; heath care utilisation; use of health care resources; and a return to previous activities. Discussion: The study will provide recommendations about the efficacy of early decision support to facilitate adjustment after prostate cancer. As well the study will identify men diagnosed with localised prostate cancer at risk of poorer long term psychosocial adjustment

Gene Expression in a Drosophila Model of Mitochondrial Disease

Background A point mutation in the Drosophila gene technical knockout (tko), encoding mitoribosomal protein S12, was previously shown to cause a phenotype of respiratory chain deficiency, developmental delay, and neurological abnormalities similar to those presented in many human mitochondrial disorders, as well as defective courtship behavior. Methodology/Principal Findings Here, we describe a transcriptome-wide analysis of gene expression in tko25t mutant flies that revealed systematic and compensatory changes in the expression of genes connected with metabolism, including up-regulation of lactate dehydrogenase and of many genes involved in the catabolism of fats and proteins, and various anaplerotic pathways. Gut-specific enzymes involved in the primary mobilization of dietary fats and proteins, as well as a number of transport functions, were also strongly up-regulated, consistent with the idea that oxidative phosphorylation OXPHOS dysfunction is perceived physiologically as a starvation for particular biomolecules. In addition, many stress-response genes were induced. Other changes may reflect a signature of developmental delay, notably a down-regulation of genes connected with reproduction, including gametogenesis, as well as courtship behavior in males; logically this represents a programmed response to a mitochondrially generated starvation signal. The underlying signalling pathway, if conserved, could influence many physiological processes in response to nutritional stress, although any such pathway involved remains unidentified. Conclusions/Significance These studies indicate that general and organ-specific metabolism is transformed in response to mitochondrial dysfunction, including digestive and absorptive functions, and give important clues as to how novel therapeutic strategies for mitochondrial disorders might be developed.Public Library of Scienc

Interactions between tidal turbine wakes: experimental study of a group of three-bladed rotors

It is well known that a wake will develop downstream of a tidal stream turbine owing to extraction of axial momentum across the rotor plane. To select a suitable layout for an array of horizontal axis tidal stream turbines, it is important to understand the extent and structure of the wakes of each turbine. Studies of wind turbines and isolated tidal stream turbines have shown that the velocity reduction in the wake of a single device is a function of the rotor operating state (specifically thrust), and that the rate of recovery of wake velocity is dependent on mixing between the wake and the surrounding flow. For an unbounded flow, the velocity of the surrounding flow is similar to that of the incident flow. However, the velocity of the surrounding flow will be increased by the presence of bounding surfaces formed by the bed and free surface, and by the wake of adjacent devices. This paper presents the results of an experimental study investigating the influence of such bounding surfaces on the structure of the wake of tidal stream turbines. © 2013 The Author(s) Published by the Royal Society. All rights reserved

Development of Tetravalent, Bispecific CCR5 Antibodies with Antiviral Activity against CCR5 Monoclonal Antibody-Resistant HIV-1 Strains▿

In this study, we describe novel tetravalent, bispecific antibody derivatives that bind two different epitopes on the HIV coreceptor CCR5. The basic protein formats that we applied were derived from Morrison-type bispecific antibodies: whole IgGs to which we connected single-chain antibodies (scFvs) via (Gly4Ser)n sequences at either the C or N terminus of the light chain or heavy chain. By design optimization, including disulfide stabilization of scFvs or introduction of 30-amino-acid linkers, stable molecules could be obtained in amounts that were within the same range as or no less than 4-fold lower than those observed with monoclonal antibodies in transient expression assays. In contrast to monospecific CCR5 antibodies, bispecific antibody derivatives block two alternative docking sites of CCR5-tropic HIV strains on the CCR5 coreceptor. Consequently, these molecules showed 18- to 57-fold increased antiviral activities compared to the parent antibodies. Most importantly, one prototypic tetravalent CCR5 antibody had antiviral activity against virus strains resistant to the single parental antibodies. In summary, physical linkage of two CCR5 antibodies targeting different epitopes on the HIV coreceptor CCR5 resulted in tetravalent, bispecific antibodies with enhanced antiviral potency against wild-type and CCR5 antibody-resistant HIV-1 strains