bluuebunny/crossref_metadata_2025 huggingface dataset:
Can analyses of electronic patient records be independently and externally validated? Study 2—the effect of β-adrenoceptor blocker therapy on cancer survival: a retrospective cohort study
Authors: Springate David A , Ashcroft Darren M , Kontopantelis Evangelos , Doran Tim , Ryan Ronan , Reeves David
Published: April 2015

Objectives

To conduct a fully independent, external validation of a research study based on one electronic health record database using a different database sampling from the same population.

Design

Retrospective cohort analysis of β-blocker therapy and all-cause mortality in patients with cancer.

Setting

Two UK national primary care databases (PCDs): the Clinical Practice Research Datalink (CPRD) and Doctors’ Independent Network (DIN).

Participants

CPRD data for 11 302 patients with cancer compared with published results from DIN for 3462 patients; study period January 1997 to December 2006.

Primary and secondary outcome measures

All-cause mortality: overall; by treatment subgroup (β-blockers only, β-blockers plus other blood pressure lowering medicines (BPLM), other BPLMs only); and by cancer site.

Results

Using CPRD, β-blocker use was not associated with mortality (HR=1.03, 95% CI 0.93 to 1.14, vs patients prescribed other BPLMs only), but DIN β-blocker users had significantly higher mortality (HR=1.18, 95% CI 1.04 to 1.33). However, these HRs were not statistically different (p=0.063), but did differ for patients on β-blockers alone (CPRD=0.94, 95% CI 0.82 to 1.07; DIN=1.37, 95% CI 1.16 to 1.61; p<0.001). Results for individual cancer sites differed by study, but only significantly for prostate and pancreas cancers. Results were robust under sensitivity analyses, but we could not be certain that mortality was identically defined in both databases.

Conclusions

We found a complex pattern of similarities and differences between databases. Overall treatment effect estimates were not statistically different, adding to a growing body of evidence that different UK PCDs produce comparable effect estimates. However, individually the two studies lead to different conclusions regarding the safety of β-blockers and some subgroup effects differed significantly. Single studies using even internally well-validated databases do not guarantee generalisable results, especially for subgroups, and confirmatory studies using at least one other independent data source are strongly recommended.
010 OP: MAKING CHRONIC PAIN MATTER—HOW CAN QUALITATIVE RESEARCH SHAPE THE CONVERSATION?
Authors: Gonzalez-Polledo E , Cornish F , Tarr J
Published: April 2015

This paper reflects on our experience of designing, running and evaluating participatory qualitative research methods to better understand pain communication. It emerges from Communicating Chronic Pain: Interdisciplinary methods for non-verbal data, a research project funded by the National Centre for Research Methods, which aimed to bridge the gap between experiencing and communicating about pain. Focusing on non-verbal forms of communication instead of personal illness narratives, this project explored pain communication in non-clinical contexts, analysing non-verbal forms of pain expression across multiple social media platforms and by using arts methods as experimental and participatory methodologies to explore pain communication.

Involving a mixed group of people living with different forms of chronic pain, clinicians and pain researchers, we set up a series of four workshops which were designed as a context in which participants could collectively explore dimensions of pain communication beyond individual pain narratives. Each of these workshops was collaboratively led by two arts practitioners and attended by our team of three researchers as full participants. Workshops were structured around a process of making or working with objects (drawings, photographs, soundscapes and spaces). We analysed both the content of participants' communication about pain, and the processes enabling that communication. Regarding content, the methods yielded evocative and relational versions of pain that encompassed tensions (such as immediate/chronic; owned/disowned; internal/external), rather than repeating traditional linguistic distinctions. Regarding process, we argue that the combination of practical arts methods and inclusive, anti-hierarchical social relations fostered a context which allowed for ambiguity and multiple meanings, in ways that are not traditionally enabled in the context of clinical communication.

In this paper we ask

Did this type of experimental/participatory workshops succeed at reframing pain in ways that could improve clinical communication? What practices worked best in terms of participant engagement? Could this format be taken forward as a form of collaborative, open-ended, participatory research practice?
003 PP: USING FOCUS GROUPS IN NATURALLY OCCURRING SETTINGSa
Authors: Brown S
Published: April 2015

One of the strengths of focus groups is the insight they provide into participant interaction, which differs depending on whether participants are strangers or acquaintances. In this paper I reflect on experiences of conducting focus groups amongst acquaintances in naturally occurring settings, where participants were known to each other and participation was less about being recruited, and more about being there when the focus group took place. I draw on data from field notes as well as from the groups themselves. I describe challenges and benefits of using naturally occurring groups, and reflect on the way the findings from these groups illuminated aspects of the study concerning relationships. I conclude by suggesting that using focus groups in naturally occurring settings alongside other qualitative data collection affords insights into the research topic that would not otherwise be available.

aBrown S. Using focus groups in naturally occurring settings.Qualitative Research Journal2015;15:86–97.
004 PP: THE RESEARCHER IN RESIDENCE MODEL: GETTING EMBEDDED IN THE WELC INTEGRATED CARE PROGRAMME
Authors: Eyre L
Published: April 2015

The Researcher in Residence model is a methodological innovation being developed by UCLPartners and Improvement Science London to help bring academic and practitioner communities more closely together to improve outcomes for patients and value for the health system. The model places the researcher as a key member of the delivery team rather than an external observer of change, and gives them a stake in the success, or otherwise, of the initiative. The expertise which the Researcher in Residence brings to the programme in which they are embedded is communicated to and negotiated with, rather than imposed on, the practitioners in the delivery team and other stakeholders.

The model is being applied in the Waltham Forest, East London and City (WELC) Integrated Care pioneer programme. The programme commissioned an embedded and process oriented local evaluation, which focuses less on whether the programme ‘works’ and more on how to use established research evidence to optimise the effectiveness of the implementation team. The WELC care collaborative has brought together commissioners, providers and local authorities covering the area served by Barts Health NHS Trust. The partners have come together to build a model of integrated care that looks at the whole person—their physical health, mental health and social care needs.

The overall aim of the WELC Integrated Care programme evaluation is to explore the processes by which integrated care is being implemented across WELC in order to enhance and improve the effectiveness of delivery of the programme objectives. The project has a strongly participative approach, underpinned by a critical realist ontology, an interpretive epistemology, and a Critical Discourse Analysis methodology.
008 PP: BEYOND EFFECTIVENESS: CONDUCTING QUALITATIVE RESEARCH ALONGSIDE A CLUSTER RANDOMISED CONTROLLED TRIAL OF HIV TESTING IN GENERAL PRACTICE
Authors: McMullen H , Griffiths C , Greenhalgh T
Published: April 2015

I worked as a trial manager of a cluster randomized controlled trial of rapid HIV testing in primary care settings over a 2.5 year period. This left me with a number of questions that were unanswered by the trial design. I have since undertaken a PhD applying qualitative methodology to explore trial phenomena, including process evaluation, case study and qualitative interviews. We applied the Diffusion of Innovations in Healthcare Settingsamodel to process data from the trial to explore high and low performing practices. This provided a rich picture of the intervention implementation process, as intended; however this data also prompted the need to revisit some of the assumptions upon which the trial was based. The trial assumed rapid testing would detect undiagnosed HIV however the exploration of patient data revealed this was not always the case. For example, already knowing their status, one patient used the rapid test to manage a number of factors related to their identity and personal circumstances, demonstrating the way testing and treatment creates meaning for patients. It also echoes what Annemarie Mol suggests in the Logic of Care, that we pay attention not only to what technologies are supposed to do, but what they happen to do.bThis example, among other unexpected findings, highlights the need for a greater theorisation of the data and the unravelling of trial assumptions. We explore the experience of conducting qualitative analysis alongside a cluster randomised controlled trial related to a stigmatised illness and discuss the challenges and insights gained in the process.

aGreenhalgh T, Robert G, McFarlane F,et al. Diffusion of innovations in service organizations: systematic review and recommendations.Milbank Quarterly2004;82:581–629.

bMol A.The logic of care: health and the problem of patient choice. London, United Kingdom: Routledge, 2008.
011 PP: FOOD-RELATED INTERVENTIONS IN DEMENTIA: A QUALITATIVE STUDY OF CAREGIVERS' PERSPECTIVES
Authors: Papachristou I , Hickey G , Illife S
Published: April 2015

As dementia progresses, caregivers increasingly have to manage the decline of food-related abilities with little intervention. The provision of food coping skills and knowledge can lessen the burden on caregivers. However, there is little research on caregivers' perspectives on food-related interventions. This paper reports on a qualitative study to investigate informal caregivers' experiences of, and views on, food —related interventions in dementia. Twenty informal caregivers were interviewed and the transcripts from these interviews were analysed using both inductive and deductive thematic analysis. Three categories emerged. ‘Direct food-related interventions’, covers written material, training and lunch clubs ‘Indirect non-food related interventions’ covers respite services and domestic help at home. Finally ‘No interventions’ covers those who did not feel they needed any form of intervention due to confidence in managing food-related processes or having no change in dementia progression and food responsibility. Most caregivers will need different levels of education and support at different stages of dementia. It is necessary therefore to undertake ongoing individual assessment of food education and support needs. This study is the first to explore dementia and food-related social support and education needs and availability from the perspective of caregivers. A further, longitudinal study could investigate further the extent to which food-related interventional needs change over time. As dementia increases, caregivers seek more education and social support, therefore the timing of receiving this intervention is important to prepare caregivers in advance and to prevent negative outcomes occurring later.
015 PP: A LONE VOICE: REFLECTIONS ON PRESENTING QUALITATIVE RESEARCH AT A SURGEON'S CONFERENCE
Authors: Trusson D
Published: April 2015

In this paper I describe how I used my dual position of service user and sociologist to present my research findings at an international conference for surgeons. As a former breast cancer patient I was invited to participate in a study of women's experiences of having breast reconstruction using their own body tissue. Questions included rating my happiness and confidence on a scale of 1–10 which challenged me as a qualitative researcher. The study also revealed parallels with my own research with 24 women who had been treated for early stage breast cancer, where similar issues had emerged organically through their narratives. When I discussed this with the breast care team I was encouraged to submit an abstract to the conference where the results of the quantitative study were going to be presented.

The subsequent paper, entitled ‘Autologous Breast Reconstruction from the Patient's Perspective: A Qualitative Study,’ was presented at the 5thInternational Meeting of Oncoplastic and Reconstructive Breast Surgery in Nottingham in September 2013.

My reflections on my experience of presenting to an audience, who were unaccustomed to qualitative research, include the challenges of facing my own intimidation by health professionals as a patient. I will discuss the positive feedback that I received which will hopefully encourage other qualitative health researchers to reach beyond the usual audiences in order to disseminate their research findings.
Darwin’s legacy II: why biology is not physics, or why it has taken a century to see the dependence of genes on the environment
Authors: Singh Rama S.
Published: April 2015

Genes and environment make the organism. Darwin stood firm in his denial of any direct role of environment in the modification of heredity. His theory of evolution heralded two debates: one about the importance and adequacy of natural selection as the main mechanism of evolution, and the other about the role of genes versus environment in the modification of phenotype and evolution. Here, I provide an overview of the second debate and show that the reasons for the gene versus environment battle were twofold: first, there was confusion about the role of environment in modifying the inheritance of a trait versus the evolution of that trait, and second, there was misunderstanding about the meaning of environment and its interaction with genes in the production of phenotypes. It took nearly a century to see that environment does not directly affect the inheritance of a phenotype (i.e., its heredity), but it is nevertheless the primary mover of phenotypic evolution. Effects of genes and environment are not separate but interdependent. One cannot separate the effect of genes from that of environment, or nature from nurture. To answer the question posed in the title, it is partly because the 20th century has been a century of unending progress in genetics. But also because unlike physics, biology is not colorblind; progress in biology has often been delayed beyond the Kuhnian paradigm change due to built-in interest in negating the influence of environment. Those who are against evolution, of course, cannot be expected to understand the role of environment in evolution. Those for it, many biologists included, believing in the supremacy of genes empowers them by giving adaptation a solely gene-directed (self-driven) “teleological” interpretation.
The binding energies of an off-center hydrogenic donor impurity in a GaAs/GaAlAs nanowire superlattice: Comparison between spherical and cylindrical wells
Authors: Safarpour Gh. , Novzari M. , Izadi M. A. , Niknam E. , Dialameh M.
Published: April 2015

In this paper, the effect of an off-center donor impurity on electronic structure of nanowire superlattices (NWSLs) is numerically studied using finite difference (FD) approximation. Energy levels and binding energies of ground and first excited states (1s and 2p) are computed for two different NWSL with circular cross-section which involved an array of spherical or cylindrical quantum dots (QDs) along their axis which are called Sph and Cyl NWSLs, respectively. The numerical results show that oscillatory behaviors appear in electronic energy levels and binding energies as impurity shifts away from the center of QDs. Maximum values of ground state binding energies occur when impurity is located at the center of QDs and these values shift towards higher energies as number of unit cells of NWSL decreases. An opposite behavior is observed for first excited state as impurity shifts away from the center of QDs. Also, as the QDs' volumes increase binding energies (i) decrease, (ii) increase, (iii) decrease, reach minimum values and then increase, or (iv) increase, reach maximum values and then decrease; which strongly depend on the type of NWSL, position of impurity and number of unit cells involved in NWSLs. Additionally, it is found that binding energies of Sph NWSL are larger than those of Cyl NWSL.
The σ-Derivations of ℂ[x±1,y±1]
Authors: Song Guang'ai , Wu Yuezhu , Xin Bin
Published: April 2015

In the present paper, the σ-derivations of ℂ[x±1,y±1] are determined, and their applications are considered.
Cortical drive of low-frequency oscillations in the human nucleus accumbens during action selection
Authors: Stenner Max-Philipp , Litvak Vladimir , Rutledge Robb B. , Zaehle Tino , Schmitt Friedhelm C. , Voges Jürgen , Heinze Hans-Jochen , Dolan Raymond J.
Published: April 2015

The nucleus accumbens is thought to contribute to action selection by integrating behaviorally relevant information from multiple regions, including prefrontal cortex. Studies in rodents suggest that information flow to the nucleus accumbens may be regulated via task-dependent oscillatory coupling between regions. During instrumental behavior, local field potentials (LFP) in the rat nucleus accumbens and prefrontal cortex are coupled at delta frequencies (Gruber AJ, Hussain RJ, O'Donnell P. PLoS One 4: e5062, 2009), possibly mediating suppression of afferent input from other areas and thereby supporting cortical control (Calhoon GG, O'Donnell P. Neuron 78: 181–190, 2013). In this report, we demonstrate low-frequency cortico-accumbens coupling in humans, both at rest and during a decision-making task. We recorded LFP from the nucleus accumbens in six epilepsy patients who underwent implantation of deep brain stimulation electrodes. All patients showed significant coherence and phase-synchronization between LFP and surface EEG at delta and low theta frequencies. Although the direction of this coupling as indexed by Granger causality varied between subjects in the resting-state data, all patients showed a cortical drive of the nucleus accumbens during action selection in a decision-making task. In three patients this was accompanied by a significant coherence increase over baseline. Our results suggest that low-frequency cortico-accumbens coupling represents a highly conserved regulatory mechanism for action selection.
Examining Provincial HPV Vaccination Schemes in Canada: Should We Standardise the Grade of Vaccination or the Number of Doses?
Authors: Rogers Carley , Smith Robert J.
Published: April 2015

Human papillomavirus (HPV) infection is the most common sexually transmitted infection, which is linked to several cancers and genital warts. Depending on the Canadian province, the quadrivalent vaccine is given to girls in grades 4 through 10 with either a two- or three-dose schedule. We use a mathematical model to address the following research questions: (1) Does the grade at which the girls are vaccinated significantly affect the outcome of the program? (2) What coverage rate must the provinces reach in order to reduce the impact of HPV on the Canadian population? (3) What are the implications of vaccinating with two versus three doses? The model suggests the grade of vaccination and the number of doses do not make a significant difference to the outcome of the public vaccination program. The most significant factor is the coverage rate of children and adults. We recommend that provinces vaccinate as early as possible to avoid vaccine failure due to previous infection. We also recommend that the main focus of the program should be on obtaining a large enough coverage rate for children and/or adults in order to achieve the desired outcome with either two or three doses of the vaccine.
Feasibility and Safety of Continuous and Chronic Bilateral Deep Brain Stimulation of the Medial Forebrain Bundle in the Naïve Sprague-Dawley Rat
Authors: Furlanetti Luciano L. , Döbrössy Máté D. , Aranda Iñigo A. , Coenen Volker A.
Published: April 2015

Objective. Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (MFB) has provided rapid and dramatic reduction of depressive symptoms in a clinical trial. Early intracranial self-stimulation experiments of the MFB suggested detrimental side effects on the animals’ health; therefore, the current study looked at the viability of chronic and continuous MFB-DBS in rodents, with particular attention given to welfare issues and identification of stimulated pathways.Methods. Sprague-Dawley female rats were submitted to stereotactic microelectrode implantation into the MFB. Chronic continuous DBS was applied for 3–6 weeks. Welfare monitoring and behavior changes were assessed. Postmortem histological analysis ofc-fosprotein expression was carried out.Results. MFB-DBS resulted in mild and temporary weight loss in the animals, which was regained even with continuing stimulation. MFB-DBS led to increased and long-lastingc-fosexpression in target regions of the mesolimbic/mesocortical system.Conclusions. Bilateral continuous chronic MFB-DBS is feasible, safe, and without impact on the rodent’s health. MFB-DBS results in temporary increase in exploration, which could explain the initial weight loss, and does not produce any apparent behavioral abnormalities. This platform represents a powerful tool for further preclinical investigation of the MFB stimulation in the treatment of depression.
Dealing with Stigma: Experiences of Persons Affected by Disabilities and Leprosy
Authors: Lusli Mimi , Zweekhorst Marjolein B. M. , Miranda-Galarza Beatriz , Peters Ruth M. H. , Cummings Sarah , Seda Francisia S. S. E. , Bunders Joske F. G. , Irwanto
Published: April 2015

Persons affected by leprosy or by disabilities face forms of stigma that have an impact on their lives. This study seeks to establish whether their experiences of stigma are similar, with a view to enabling the two groups of people to learn from each other. Accounts of experiences of the impact of stigma were obtained using in-depth interviews and focus group discussion with people affected by leprosy and by disabilities not related to leprosy. The analysis shows that there are a lot of similarities in impact of stigma in terms of emotions, thoughts, behaviour, and relationships between the two groups. The main difference is that those affected by leprosy tended to frame their situation in medical terms, while those living with disabilities described their situation from a more social perspective. In conclusion, the similarities offer opportunities for interventions and the positive attitudes and behaviours can be modelled in the sense that both groups can learn and benefit. Research that tackles different aspects of stigmatization faced by both groups could lead to inclusive initiatives that help individuals to come to terms with the stigma and to advocate against exclusion and discrimination.
Congenital Cholesteatoma Localized to the Mastoid Cavity and Presenting as a Mastoid Abscess
Authors: Tabook Salim M. Sloma , Abdel Tawab Hazem M. , Gopal Naveen Kumar
Published: April 2015

Introduction. Congenital cholesteatoma is a pearly white mass that rarely originates from the mastoid process.Case Report. A 21-year-old male patient presented to our department with severe right mastoid pain and postauricular fluctuant swelling for 23 days. There was no preceding history of ear complaints and examination showed a normal right ear drum. Emergency exploration of the mastoid process was done on the same day and revealed localized cholesteatoma limited only to the mastoid cavity.Conclusion. Despite a rarity, the mastoid process should be always put in mind as a site of origin for congenital cholesteatoma.
Conservative Management in Congenital Bilateral Upper Eyelid Eversion
Authors: Dohvoma Viola Andin , Nchifor Alice , Ngwanou Aronette Nana , Attha Elisabeth , Ngounou Faustin , Bella Assumpta Lucienne , Ebana Mvogo Côme
Published: April 2015

Aim. To report the case of congenital bilateral upper eyelid eversion with severe chemosis that was successfully managed conservatively.Report. The patient was a six-hour-old male neonate with bilateral congenital upper eyelid eversion and severe chemosis, following uneventful delivery. Conservative management consisted of the application of antibiotic ointment and padding the exposed conjunctiva with 5% hypertonic saline-soaked gauze. The eyelids reverted spontaneously on day 3 and the condition was completely resolved by the third week.Conclusion. Congenital upper lid eversion is usually a benign condition which responds well to conservative treatment. Creating awareness amongst healthcare professionals is essential.
Diabetes and Its Link with Cancer: Providing the Fuel and Spark to Launch an Aggressive Growth Regime
Authors: Joshi Sanket , Liu Menghan , Turner Nigel
Published: April 2015

Diabetes is a disease involving metabolic derangements in multiple organs. While the spectrum of diabetic complications has been known for years, recent evidence suggests that diabetes could also contribute to the initiation and propagation of certain cancers. The mechanism(s) underlying this relationship are not completely resolved but likely involve changes in hormone and nutrient levels, as well as activation of inflammatory and stress-related pathways. Interestingly, some of the drugs used clinically to treat diabetes also appear to have antitumour effects, further highlighting the interaction between these two conditions. In this contribution we review recent literature on this emerging relationship and explore the potential mechanisms that may promote cancer in diabetic patients.
Low Frequency Electromagnetic Field Conditioning Protects against I/R Injury and Contractile Dysfunction in the Isolated Rat Heart
Authors: Bialy Dariusz , Wawrzynska Magdalena , Bil-Lula Iwona , Krzywonos-Zawadzka Anna , Wozniak Mieczyslaw , Cadete Virgilio J. J. , Sawicki Grzegorz
Published: April 2015

Low frequency electromagnetic field (LF-EMF) decreases the formation of reactive oxygen species, which are key mediators of ischemia/reperfusion (I/R) injury. Therefore, we hypothesized that the LF-EMF protects contractility of hearts subjected to I/R injury. Isolated rat hearts were subjected to 20 min of global no-flow ischemia, followed by 30 min reperfusion, in the presence or absence of LF-EMF. Coronary flow, heart rate, left ventricular developed pressure (LVDP), and rate pressure product (RPP) were determined for evaluation of heart mechanical function. The activity of cardiac matrix metalloproteinase-2 (MMP-2) and the contents of coronary effluent troponin I (TnI) and interleukin-6 (IL-6) were measured as markers of heart injury. LF-EMF prevented decreased RPP in I/R hearts, while having no effect on coronary flow. In addition, hearts subjected to I/R exhibited significantly increased LVDP when subjected to LF-EMF. Although TnI and IL-6 levels were increased in I/R hearts, their levels returned to baseline aerobic levels in I/R hearts subjected to LF-EMF. The reduced activity of MMP-2 in I/R hearts was reversed in hearts subjected to LF-EMF. The data presented here indicate that acute exposure to LF-EMF protects mechanical function of I/R hearts and reduces I/R injury.
{2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic Acid Methyl Ester Inhibited Hepatocellular Carcinoma Growth in Bel-7402 Cells and Its Resistant Variants by Activation of NOX4 and SIRT3
Authors: Li Ye , Wang Wenjing , Xu Xiaoxue , Sun Shiyue , Xu Xiaoyu , Qu Xian-jun
Published: April 2015

{2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester (MIAM) is a novel indole compound, which possessed high efficacy against many cancers xenografted in mice without obvious toxicity. In this study, we aimed to investigate the effects of MIAM on human hepatocellular carcinoma (HCC) Bel-7402 cells and its resistant variants Bel-7402/5FU. MIAM inhibited the growth of HCC more potent in Bel-7402/5FU cells than its parent cells. MIAM increased cellular reactive oxygen species (ROS) levels, induced cell apoptosis, and arrested cell cycle in G0/G1phase. MIAM might exert its action on Bel-7402/5FU cells through activation of NADPH oxidase 4 (NOX4)/p22, Sirtuin3 (SIRT3)/SOD2, and SIRT3/p53/p21pathways. MIAM might inhibit HCC growth through the modulation of SIRT3. When SIRT3 was silenced, the inhibitory effect of MIAM on Bel-7402/5FU was lowered, showing the characteristic of resistance against MIAM, whereas Bel-7402/5FU cells with high expression of SIRT3 by SIRT3 adenovirus infection demonstrated the high sensitivity to MIAM. These results suggested that MIAM might exert its action against Bel-7402/5FU growth through upregulation of SIRT3. We suggested that MIAM might be a promising candidate compound which could develop as a potent anticancer agent targeting NOX4 and SIRT3 activation.
Optimal Resource Allocation for Energy-Efficient OFDMA Networks
Authors: Wu Fan , Mao Yuming , Huang Xiaoyan , Leng Supeng
Published: April 2015

This paper focuses on radio resource allocation in OFDMA networks for maximizing the energy efficiency subject to the data rate requirements of users. We propose the energy-efficient water-filling structure to obtain the closed-form optimal energy-efficient power allocation for a given subcarrier assignment. Moreover, we establish a new sufficient condition for the optimal energy-efficient subcarrier assignment. Based on the theoretical analysis, we develop a joint energy-efficient resource allocation (JERA) algorithm to maximize the energy efficiency. Simulation results show that the JERA algorithm can yield optimal solution with significantly low computational complexity.
IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology
Authors: Croce Michela , Rigo Valentina , Ferrini Silvano
Published: April 2015

Interleukin- (IL-) 21 is a pleiotropic cytokine that regulates the activity of both innate and specific immunity. Indeed, it costimulates T and natural killer (NK) cell proliferation and function and regulates B cell survival and differentiation and the function of dendritic cells. In addition, IL-21 exerts divergent effects on different lymphoid cell leukemia and lymphomas, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the neoplastic lymphoid cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanism involving the activation of NK and T or B cell responses. Moreover, IL-21’s antitumor activity can be potentiated by its combination with other immune-enhancing molecules, monoclonal antibodies recognizing tumor antigens, chemotherapy, or molecular targeted agents. Clinical phase I-II studies of IL-21 in cancer patients showed immune stimulatory properties, acceptable toxicity profile, and antitumor effects in a fraction of patients. In view of its tolerability, IL-21 is also suitable for combinational therapeutic regimens with other agents. This review will summarize the biological functions of IL-21, and address its role in lymphoid malignancies and preclinical and clinical studies of cancer immunotherapy.
The Sarcomeric M-Region: A Molecular Command Center for Diverse Cellular Processes
Authors: Hu Li-Yen R. , Ackermann Maegen A. , Kontrogianni-Konstantopoulos Aikaterini
Published: April 2015

The sarcomeric M-region anchors thick filaments and withstands the mechanical stress of contractions by deformation, thus enabling distribution of physiological forces along the length of thick filaments. While the role of the M-region in supporting myofibrillar structure and contractility is well established, its role in mediating additional cellular processes has only recently started to emerge. As such, M-region is the hub of key protein players contributing to cytoskeletal remodeling, signal transduction, mechanosensing, metabolism, and proteasomal degradation. Mutations in genes encoding M-region related proteins lead to development of severe and lethal cardiac and skeletal myopathies affecting mankind. Herein, we describe the main cellular processes taking place at the M-region, other than thick filament assembly, and discuss human myopathies associated with mutant or truncated M-region proteins.
Impact of Metabolic Heterogeneity on Tumor Growth, Invasion, and Treatment Outcomes
Authors: Robertson-Tessi Mark , Gillies Robert J. , Gatenby Robert A. , Anderson Alexander R.A.
Published: April 2015

Histopathologic knowledge that extensive heterogeneity exists between and within tumors has been confirmed and deepened recently by molecular studies. However, the impact of tumor heterogeneity on prognosis and treatment remains as poorly understood as ever. Using a hybrid multiscale mathematical model of tumor growth in vascularized tissue, we investigated the selection pressures exerted by spatial and temporal variations in tumor microenvironment and the resulting phenotypic adaptations. A key component of this model is normal and tumor metabolism and its interaction with microenvironmental factors. The metabolic phenotype of tumor cells is plastic, and microenvironmental selection leads to increased tumor glycolysis and decreased pH. Once this phenotype emerges, the tumor dramatically changes its behavior due to acid-mediated invasion, an effect that depends on both variations in the tumor cell phenotypes and their spatial distribution within the tumor. In early stages of growth, tumors are stratified, with the most aggressive cells developing within the interior of the tumor. These cells then grow to the edge of the tumor and invade into the normal tissue using acidosis. Simulations suggest that diffusible cytotoxic treatments, such as chemotherapy, may increase the metabolic aggressiveness of a tumor due to drug-mediated selection. Chemotherapy removes the metabolic stratification of the tumor and allows more aggressive cells to grow toward blood vessels and normal tissue. Antiangiogenic therapy also selects for aggressive phenotypes due to degradation of the tumor microenvironment, ultimately resulting in a more invasive tumor. In contrast, pH buffer therapy slows down the development of aggressive tumors, but only if administered when the tumor is still stratified. Overall, findings from this model highlight the risks of cytotoxic and antiangiogenic treatments in the context of tumor heterogeneity resulting from a selection for more aggressive behaviors. Cancer Res; 75(8); 1567–79. ©2015 AACR.
Ibrutinib Exerts Potent Antifibrotic and Antitumor Activities in Mouse Models of Pancreatic Adenocarcinoma
Authors: Massó-Vallés Daniel , Jauset Toni , Serrano Erika , Sodir Nicole M. , Pedersen Kim , Affara Nesrine I. , Whitfield Jonathan R. , Beaulieu Marie-Eve , Evan Gerard I. , Elias Laurence , Arribas Joaquín , Soucek Laura
Published: April 2015

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal fibroinflammatory reaction that is a major obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells as key components of the PDAC microenvironment, and such infiltration correlates with poor patient outcome. Indeed, it has been hypothesized that stromal ablation is critical to improve clinical response in patients with PDAC. Ibrutinib is a clinically approved Bruton's tyrosine kinase inhibitor that inhibits mast cells and tumor progression in a mouse model of β-cell tumorigenesis. Here, we show that ibrutinib is highly effective at limiting the growth of PDAC in both transgenic mouse and patient-derived xenograft models of the disease. In these various experimental settings, ibrutinib effectively diminished fibrosis, extended survival, and improved the response to clinical standard-of-care therapy. Our results offer a preclinical rationale to immediately evaluate the clinical efficacy of ibrutinib in patients with PDAC. Cancer Res; 75(8); 1675–81. ©2015 AACR.
Germline Mutations in theCDKN2BTumor Suppressor Gene Predispose to Renal Cell Carcinoma
Authors: Jafri Mariam , Wake Naomi C. , Ascher David B. , Pires Douglas E.V. , Gentle Dean , Morris Mark R. , Rattenberry Eleanor , Simpson Michael A. , Trembath Richard C. , Weber Astrid , Woodward Emma R. , Donaldson Alan , Blundell Tom L. , Latif Farida , Maher Eamonn R.
Published: April 2015

Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC.

Significance: Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease. Cancer Discov; 5(7); 723–9. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 681
Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia
Authors: Mooij Christiaan F. , Parajes Silvia , Pijnenburg-Kleizen Karijn J. , Arlt Wiebke , Krone Nils , Claahsen-van der Grinten Hedi L.
Published: April 2015

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to accumulation of steroid precursors and adrenal androgens. These steroids may have a biological effect on the steroid receptor with clinical consequences on diagnostics and treatment in CAH patients. Therefore, we analysed the effect of accumulated steroids [17-hydroxyprogesterone (17OHP), progesterone, androstenedione and testosterone] on aldosterone-mediated transactivation of the human mineralocorticoid receptor (hMR). Methods: A transactivation assay using transiently transfected COS7 cells was employed. Cells were co-transfected with hMR-cDNA, MMTV-luciferase and renilla-luciferase expression vectors. Transfected cells were incubated with six different steroid concentrations in addition to aldosterone (10-10M). Luciferase and renilla activities were measured to quantify hMR transactivation. Results: Linear regression analysis showed statistically significant linear inhibition of transactivation of the hMR by 10-10M aldosterone in the presence of increasing 17OHP [F(1,5) = 11.34, p = 0.019] and progesterone [F(1,5) = 11.08, p = 0.021] concentrations. In contrast, neither androstenedione nor testosterone affected hMR transactivation by aldosterone at a concentration of 10-10M. Conclusion: Our study shows for the first time that neither androstenedione nor testosterone has a biological effect on aldosterone-mediated transactivation of the hMR. 17OHP and progesterone have an anti-mineralocorticoid effect in vitro that may clinically lead to an increased requirement of mineralocorticoids in poorly controlled CAH patients.
Acupuncture Efficacy on Ischemic Stroke Recovery
Authors: Zhang Shihong , Wu Bo , Liu Ming , Li Ning , Zeng Xianrong , Liu Hua , Yang Qingcheng , Han Zhao , Rao Ping , Wang Dong
Published: April 2015

Background and Purpose—

Acupuncture is a frequently used complementary treatment for ischemic stroke in China but the evidence available from previous randomized trials is inconclusive. The objective of this study was to assess the efficacy and safety of acupuncture in a more robustly designed larger scale trial.

Methods—

This is a multicenter, single-blinded, randomized controlled trial. Eight hundred sixty-two hospitalized patients with limb paralysis between 3 to 10 days after ischemic stroke onset were allocated acupuncture plus standard care or standard care alone. The acupuncture was applied 5 times per week for 3 to 4 weeks. The primary outcomes were defined as follows: (1) death/disability according to Barthel index and (2) death/institutional care at 6 months.

Results—

There was a tendency of fewer patients being dead or dependent in acupuncture group (80/385, 20.7%) than in control group (102/396, 25.8%) at 6 months (odds ratio, 0.75; 95% confidence interval, 0.54–1.05). The benefit was noted in subgroup receiving ≥10 sessions of acupuncture (odds ratio, 0.68; 95% confidence interval, 0.47–0.98). There was no statistical difference in death or institutional care between the 2 groups (odds ratio, 1.06; 95% confidence interval, 0.63–1.79). Severe adverse events occurred in 7.6% and 8.3% of patients in the 2 groups, respectively.

Conclusions—

Acupuncture seemed to be safe in the subacute phase of ischemic stroke. If the potential benefits observed are confirmed in future larger study, the health gain from wider use of the treatment could be substantial.

Clinical Trial Registration—

URL:
http://www.chictr.org/en/
. Unique identifier: ChiCTR-TRC-11001353.
Hypoxic Viable Tissue in Human Chronic Cerebral Ischemia Because of Unilateral Major Cerebral Artery Steno-Occlusive Disease
Authors: Saura Hiroaki , Ogasawara Kuniaki , Beppu Takaaki , Yoshida Koji , Kobayashi Masakazu , Yoshida Kenji , Terasaki Kazunori , Takai Yoshihiro , Ogawa Akira
Published: April 2015

Background and Purpose—

Positron emission tomography (PET) with radiolabeled 2-nitroimidazoles directly detects hypoxic but viable tissue present in an acute ischemic area in the human brain. This study using PET with 1-(2-
18
F-fluoro-1-[hydroxymethyl]ethoxy) methyl-2-nitroimidazole (
18
F-FRP170) aimed to determine whether tissue with an abnormally elevated uptake of
18
F-FRP170 exists in human chronic cerebral ischemia because of unilateral atherosclerotic major cerebral artery steno-occlusive disease.

Methods—

18
F-FRP170 PET was performed, and cerebral blood flow and metabolism were assessed using
15
O-gas PET in 20 healthy subjects and 52 patients. A region of interest (ROI) was automatically placed in 3 segments of the middle cerebral artery territory in both cerebral hemispheres with a 3-dimensional stereotaxic ROI template using SPM2, and each PET value was determined in each ROI. The ratio of values in the affected versus contralateral hemispheres was calculated for the
18
F-FRP170 PET image.

Results—

A significant correlation was observed between oxygen extraction fraction and
18
F-FRP170 ratios (
ρ
=0.509;
P
<0.0001) in a total of 156 ROIs in 52 patients. The specificity and positive-predictive value for a combination of an elevated oxygen extraction fraction and a moderately reduced cerebral oxygen metabolism for detection of an abnormally elevated
18
F-FRP170 ratio (19 ROIs: 12%) were significantly greater than those for the individual categories (elevated oxygen extraction fraction, moderately reduced cerebral oxygen metabolism, or reduced cerebral blood flow).

Conclusions—

Tissues with abnormally elevated uptake of
18
F-FRP170 exist in human chronic cerebral ischemia characterized by a combination of misery perfusion and moderately reduced oxygen metabolism because of unilateral atherosclerotic major cerebral artery steno-occlusive disease.
The Thrips formosanus group from Asia and Australia with a new species of the genus Thrips (Thysanoptera: Thripidae) from India
Authors: TYAGI KAOMUD , KUMAR VIKAS
Published: April 2015

A new species-group in the genus Thrips is designated as Thrips formosanus group from Asia and Australia. This includes the following six species: T. floreus Kurosawa from Japan, T. formosanus Priesner from Taiwan, T. obscuripes Priesner and T. rostratus Priesner from Java, T. tanicus Bhatti from India and T. hoddlei Mound and Masumoto from Australia. One new species, Thrips moundi sp. n., is described in this group from specimens collected on grasses in Himachal Pradesh State of India. A key to the seven species of Thrips formosanus group is also provided. Partial sequence data for the gene mitochondrial cytochrome c oxidase (mtCOI) from the holotype and paratype of this new species is provided.
Two new species of the genus Platambus Thomson, 1859 from China (Coleoptera: Dytiscidae, Agabinae)
Authors: HENDRICH LARS , PRZEWOŹNY MAREK
Published: April 2015

One new species of the genus Platambus Thomson, 1859 from Ganzi Tibetan Autonomous Prefecture, Sichuan Province (P. brancuccii sp. n.) and one from Chengdu, Sichuan Province (P. korgei sp. n.) are described. They belong to the Platambus semenowi-group sensu Nilsson (2000). Important species characters (median lobes and colour patterns) of the two new species are figured, and notes on their distribution are given. Altogether seven species of the semenowi-group are now known from higher mountain regions in Central Asia, northern India, Nepal, Bhutan, Pakistan and China. Six of them are illustrated with habitus photos and a modified key to all species of the semenowi-group is presented.
Evaluation of Submonthly Precipitation Forecast Skill from Global Ensemble Prediction Systems
Authors: Li Shuhua , Robertson Andrew W.
Published: April 2015

The prediction skill of precipitation at submonthly time scales during the boreal summer season is investigated based on hindcasts from three global ensemble prediction systems (EPSs). The results, analyzed for lead times up to 4 weeks, indicate encouraging correlation skill over some regions, particularly over the Maritime Continent and the equatorial Pacific and Atlantic Oceans. The hindcasts from all three models correspond to high prediction skill over the first week compared to the following three weeks. The ECMWF forecast system tends to yield higher prediction skill than the other two systems, in terms of both correlation and mean squared skill score. However, all three systems are found to exhibit large conditional biases in the tropics, highlighted using the mean squared skill score.

The sources of submonthly predictability are examined in the ECMWF hindcasts over the Maritime Continent in three typical years of contrasting ENSO phase, with a focus on the combined impact of the intraseasonal MJO and interannual ENSO. Rainfall variations over Borneo in the ENSO-neutral year are found to correspond well with the dominant MJO phase. The contribution of ENSO becomes substantial in the two ENSO years, but the MJO impact can become dominant when the MJO occurs in phases 2–3 during El Niño or in phases 5–6 during the La Niña year. These results support the concept that “windows of opportunity” of high forecast skill exist as a function of ENSO and the MJO in certain locations and seasons, which may lead to subseasonal-to-seasonal forecasts of substantial societal value in the future.