Reduced Expression of miRNA-27a Modulates Cisplatin Resistance in Bladder Cancer by Targeting the Cystine/Glutamate Exchanger SLC7A11

Purpose: Resistance to cisplatin-based chemotherapy is a major obstacle to bladder cancer treatment. We aimed to identify microRNAs (miRNA) that are dysregulated in cisplatin-resistant disease, ascertain how these contribute to a drug-resistant phenotype, and how this resistance might be overcome. Experimental Design: miRNA expression in paired cisplatin-resistant and -sensitive cell lines was measured. Dysregulated miRNAs were further studied for their ability to mediate resistance. The nature of the cisplatin-resistant phenotype was established by measurement of cisplatin/DNA adducts and intracellular glutathione (GSH). Candidate miRNAs were examined for their ability to (i) mediate resistance and (ii) alter the expression of a candidate target protein (SLC7A11); direct regulation of SLC7A11 was confirmed using a luciferase assay. SLC7A11 protein and mRNA, and miRNA-27a were quantified in patient tumor material. Results: A panel of miRNAs were found to be dysregulated in cisplatin-resistant cells. miRNA-27a was found to target the cystine/glutamate exchanger SLC7A11 and to contribute to cisplatin resistance through modulation of GSH biosynthesis. In patients, SLC7A11 expression was inversely related to miRNA-27a expression, and those tumors with high mRNA expression or high membrane staining for SLC7A11 experienced poorer clinical outcomes. Resistant cell lines were resensitized by restoring miRNA-27a expression or reducing SLC7A11 activity with siRNA or with sulfasalazine. Conclusion: Our findings indicate that miRNA-27a negatively regulates SLC7A11 in cisplatin-resistant bladder cancer, and shows promise as a marker for patients likely to benefit from cisplatin-based chemotherapy. SLC7A11 inhibition with sulfasalazine may be a promising therapeutic approach to the treatment of cisplatin-resistant disease

The UKIDSS Galactic Plane Survey

'The definitive version is available at www.blackwell-synergy.com .' Copyright Blackwell Publishing DOI: 10.1111/j.1365-2966.2008.13924.xThe UKIDSS Galactic Plane Survey (GPS) is one of the five near-infrared Public Legacy Surveys that are being undertaken by the UKIDSS consortium, using the Wide Field Camera on the United Kingdom Infrared TelescopePeer reviewe

Spin and energy transfer in nanocrystals without transport of charge

We describe a mechanism of spin transfer between individual quantum dots that does not require tunneling. Incident circularly-polarized photons create inter-band excitons with non-zero electron spin in the first quantum dot. When the quantum-dot pair is properly designed, this excitation can be transferred to the neighboring dot via the Coulomb interaction with either {\it conservation} or {\it flipping} of the electron spin. The second dot can radiate circularly-polarized photons at lower energy. Selection rules for spin transfer are determined by the resonant conditions and by the strong spin-orbit interaction in the valence band of nanocrystals. Coulomb-induced energy and spin transfer in pairs and chains of dots can become very efficient under resonant conditions. The electron can preserve its spin orientation even in randomly-oriented nanocrystals.Comment: 13 pages, 3 figure

Intersecting 6-branes from new 7-manifolds with G_2 holonomy

We discuss a new family of metrics of 7-manifolds with G_2 holonomy, which are R^3 bundles over a quaternionic space. The metrics depend on five parameters and have two Abelian isometries. Certain singularities of the G_2 manifolds are related to fixed points of these isometries; there are two combinations of Killing vectors that possess co-dimension four fixed points which yield upon compactification only intersecting D6-branes if one also identifies two parameters. Two of the remaining parameters are quantized and we argue that they are related to the number of D6-branes, which appear in three stacks. We perform explicitly the reduction to the type IIA model.Comment: 25 pages, 1 figure, Latex, small changes and add refs, version appeared in JHE

Automorphism groups of polycyclic-by-finite groups and arithmetic groups

We show that the outer automorphism group of a polycyclic-by-finite group is an arithmetic group. This result follows from a detailed structural analysis of the automorphism groups of such groups. We use an extended version of the theory of the algebraic hull functor initiated by Mostow. We thus make applicable refined methods from the theory of algebraic and arithmetic groups. We also construct examples of polycyclic-by-finite groups which have an automorphism group which does not contain an arithmetic group of finite index. Finally we discuss applications of our results to the groups of homotopy self-equivalences of K(\Gamma, 1)-spaces and obtain an extension of arithmeticity results of Sullivan in rational homotopy theory

Critical point network for drainage between rough surfaces

In this paper, we present a network method for computing two-phase flows between two rough surfaces with significant contact areas. Low-capillary number drainage is investigated here since one-phase flows have been previously investigated in other contributions. An invasion percolation algorithm is presented for modeling slow displacement of a wetting fluid by a non wetting one between two rough surfaces. Short-correlated Gaussian process is used to model random rough surfaces.The algorithm is based on a network description of the fracture aperture field. The network is constructed from the identification of critical points (saddles and maxima) of the aperture field. The invasion potential is determined from examining drainage process in a flat mini-channel. A direct comparison between numerical prediction and experimental visualizations on an identical geometry has been performed for one realization of an artificial fracture with a moderate fractional contact area of about 0.3. A good agreement is found between predictions and observations

The Complexity of the Empire Colouring Problem

We investigate the computational complexity of the empire colouring problem (as defined by Percy Heawood in 1890) for maps containing empires formed by exactly $r > 1$ countries each. We prove that the problem can be solved in polynomial time using $s$ colours on maps whose underlying adjacency graph has no induced subgraph of average degree larger than $s/r$. However, if $s \geq 3$, the problem is NP-hard even if the graph is a forest of paths of arbitrary lengths (for any $r \geq 2$, provided $s < 2r - \sqrt(2r + 1/4+ 3/2)$. Furthermore we obtain a complete characterization of the problem's complexity for the case when the input graph is a tree, whereas our result for arbitrary planar graphs fall just short of a similar dichotomy. Specifically, we prove that the empire colouring problem is NP-hard for trees, for any $r \geq 2$, if $3 \leq s \leq 2r-1$ (and polynomial time solvable otherwise). For arbitrary planar graphs we prove NP-hardness if $s<7$ for $r=2$, and $s < 6r-3$, for $r \geq 3$. The result for planar graphs also proves the NP-hardness of colouring with less than 7 colours graphs of thickness two and less than $6r-3$ colours graphs of thickness $r \geq 3$.Comment: 23 pages, 12 figure

Appraising empirical applications of Structuration Theory in management and organization studies

There is an increasing interest in the application of Structuration Theory in the fields of management and organization studies. Based upon a thorough literature review, we have come up with a data-set to assess how Structuration Theory has been used in empirical research. We use three key concepts of this theory (duality of structure, knowledgeability, and time-space) as sensitizing concepts for our analysis. We conclude that the greatest potential of Structuration Theory for management and organization studies is to view it as a process theory that offers a distinct building block for explaining intra and interorganizational change, as exemplified through concepts such as routine, script, genre, practice, and discourse

The environmental impacts of land transformation in the coastal perimeter of the Mar Menor lagoon (Spain)

Assigned to WIT Press all rights under copyright that may exist in and to the Work and any associated written or multimedia components or other enhancements accompanying the Work.The distinctive environment of the lagoon has long been attractive for visitors. A surge in touristic activities has taken place in the area since the early 1960s, characterised by intense urban development along the lagoon s perimeter to accommodate the growing seasonal population. This phenomenon has particularly affected La Manga, a sandy bar which is 20 km in length. La Manga acts as a barrier between the lagoon and the Mediterranean Sea, crossed by five, more or less functional channels called golas . The urbanization process has changed the water flow system between the inside and seawater through the channels. The changes have affected coastal dynamics, the longitudinal profile of the coast and the lagoon s ecosystem. The coastal lagoon is also highly threatened by other pollution variables derived from agricultural lands. The water derived from the Tajo-Segura transfer generated a profound land transformation of the adjacent agricultural areas, which changed from extensive dry crop farming to intensively irrigated crops, disturbing the lagoon dramatically. This paper analyzes both land transformations around the coastal perimeter of the Mar Menor during the last 50 years and shows the environmental impact with its consequences on the ecosystem. Although numerous biological studies have been carried out in the Mar Menor, a better understanding of the consequences of land transformation in the perimeter of the lagoon is still necessary to understand the lagoon s situation. The results of territorial management in the Mar Menor lagoon need to be addressed in order to develop successful strategies in the area to protect this valuable ecosystem and its services.García-Ayllon Veintimilla, S.; Miralles García, JL. (2014). The environmental impacts of land transformation in the coastal perimeter of the Mar Menor lagoon (Spain). International Journal of Design and Nature and Ecodynamics. 9(2):109-128. doi:10.2495/DNE-V9-N2-109-128S1091289

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer : the ProtecT three-arm RCT

Background Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments. Objectives To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50–69 years. Design A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up. Setting Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK. Participants Between 2001 and 2009, 228,966 men aged 50–69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (n = 545), radical prostatectomy (n = 553) or radical radiotherapy (n = 545) and 997 chose a treatment. Interventions The interventions were active monitoring, radical prostatectomy and radical radiotherapy. Trial primary outcome measure Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants. Secondary outcome measures Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes. Results There were no statistically significant differences between the groups for 17 prostate cancer-specific (p = 0.48) and 169 all-cause (p = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy’s impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy). Limitations A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed. Conclusions At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years. Trial registration Current Controlled Trials ISRCTN20141297