National working group meeting on ALK diagnostics in lung cancer

The global landscape of molecular testing is rapidly changing, with the recent publication of the International Association for the Study of Lung Cancer (IASLC)/College of American Pathologists (CAP) guidelines and the ALK Atlas. The IASLC/CAP guidelines recommend that tumors from patients with non-small cell lung cancer (NSCLC) be tested for ALK rearrangements in addition to epidermal growth factor receptor (EGFR) mutations. The spur for this recommendation is the availability of novel therapies that target these rearrangements. This article is based on coverage of a Pfizer-sponsored National Working Group Meeting on ALK Diagnostics in Lung Cancer, held around the 15th World Lung Cancer Conference, in Sydney on October 31, 2013. It is based on the presentations given by the authors at the meeting and the discussion that ensued. The content for this article was discussed and agreed on by the authors.

Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma : results from the European Thoracic Oncology Platform Lungscape Project

PURPOSE: The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non-small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population. METHODS: Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment. RESULTS: Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the prevalence of FISH positivity of 2.2%. FISH specificity was 100%, and FISH sensitivity was 35.0% (95% CI, 24.7% to 46.5%), with a sensitivity value of 81.3% (95% CI, 63.6% to 92.8%) for IHC 2+/3+ patients. The hazard of death for FISH-positive patients was lower than for IHC-negative patients (P = .022). Multivariable models, adjusted for patient, tumor, and treatment characteristics, and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival (OS). CONCLUSION: In this large cohort of surgically resected lung adenocarcinomas, the prevalence of ALK positivity was 6.2% using IHC and at least 2.2% using FISH. A screening strategy based on IHC or H-score could be envisaged. ALK positivity (by either IHC or FISH) was related to better OS.

A Memetic Algorithm for the location-based continuously operating reference stations placement problem in Network Real-Time Kinematic

Network Real-Time Kinematic (NRTK) is a technology that can provide centimeter-level accuracy positioning services in real time, and it is enabled by a network of Continuously Operating Reference Stations (CORS). The location-oriented CORS placement problem is an important problem in the design of a NRTK as it will directly affect not only the installation and operational cost of the NRTK, but also the quality of positioning services provided by the NRTK. This paper presents a Memetic Algorithm (MA) for the location-oriented CORS placement problem, which hybridizes the powerful explorative search capacity of a genetic algorithm and the efficient and effective exploitative search capacity of a local optimization. Experimental results have shown that the MA has better performance than existing approaches. In this paper we also conduct an empirical study about the scalability of the MA, effectiveness of the hybridization technique and selection of crossover operator in the MA.

Examining the neural correlates of choice behavior in a gambling task using steady state topography

The present study investigated the behavioral and neuropsychological characteristics of decision-making behavior during a gambling task as well as how these characteristics may relate to the Somatic Marker Hypothesis and the Frequency of Gain model. The applicability to intertemporal choice was also discussed. Patterns of card selection during a computerized interpretation of the Iowa Gambling Task were assessed for 10 men and 10 women. Steady State Topography was employed to assess cortical processing throughout this task. Results supported the hypothesis that patterns of card selection were in line with both theories. As hypothesized, these 2 patterns of card selection were also associated with distinct patterns of cortical activity, suggesting that intertemporal choice may involve the recruitment of right dorsolateral prefrontal cortex for somatic labeling, left fusiform gyrus for object representations, and the left dorsolateral prefrontal cortex for an analysis of the associated frequency of gain or loss. It is suggested that processes contributing to intertemporal choice may include inhibition of negatively valenced options, guiding decisions away from those options, as well as computations favoring frequently rewarded options.

Facilitating lifestyle changes to manage menopausal symptoms in women with breast cancer: A randomized controlled pilot trial of The Pink Women’s Wellness Program

OBJECTIVE Women diagnosed as having breast cancer may experience difficulties with posttreatment effects such as menopausal symptoms. The aims of this pilot study were to (1) evaluate the impact of a multimodal lifestyle program on reducing menopausal symptoms in women with breast cancer and (2) examine the impact of the program on health-related quality of life (HRQoL) and adherence to lifestyle recommendations. METHODS Overall, 55 women aged 45 to 60 years with one moderate to severe menopausal symptom and a history of breast cancer were randomized into an intervention group (n = 26) or a control group (n = 29). Women in the intervention group received a lifestyle intervention (The Pink Women’s Wellness Program) that included clinical consultations and a tailored health education program. Measurements of menopausal symptoms (Greene Climacteric Scale), HRQoL (SF-12 and Functional Assessment of Cancer Therapy—Breast), and modifiable lifestyle factors (food intake, physical activity, smoking and alcohol use, and sleep disturbance) were taken at baseline and 12 weeks. RESULTS Women in the intervention group reported clinically significant reductions in many menopausal symptoms, specifically somatic symptoms (d = 0.52), vasomotor symptoms (d = 0.55), sexual dysfunction (d = .65), and overall menopausal symptoms (d = 0.54), at 12 weeks compared with the control group (d = 0.03, d = 0.24, d = 0.18, and d = 0.05, respectively). Women in the intervention group reported improvements in Functional Assessment of Cancer Therapy—Breast subscale scores, physical well-being and functional well-being, and Functional Assessment of Cancer Therapy—General total scores (intervention group: d = 0.54, d = 0.50, and d = 0.48, respectively; control group: d = 0.22, d = 0.11, and d = 0.05, respectively). CONCLUSIONS The Pink Women’s Wellness Program is effective in decreasing menopausal symptoms, thus improving HRQoL. This being a pilot study, further research is recommended to investigate the benefits of combining nonpharmacological interventions for women with breast cancer to reduce their treatment-related menopausal symptoms.

Quantitative characterization of kaolinite dispersibility in styrene–butadiene rubber composites by fractal dimension

A fractal method was introduced to quantitatively characterize the dispersibility of modified kaolinite (MK) and precipitated silica (PS) in styrene–butadiene rubber (SBR) matrix based on the lower magnification transmission electron microscopic images. The fractal dimension (FD) is greater, and the dispersion is worse. The fractal results showed that the dispersibility of MK in the latex blending sample is better than that in the mill blending samples. With the increase of kaolinite content, the FD increases from 1.713 to 1.800, and the dispersibility of kaolinite gradually decreases. There is a negative correlation between the dispersibility and loading content. With the decrease of MK and increase of PS, the FD significantly decreases from 1.735 to 1.496 and the dipersibility of kaolinite remarkably increases. The hybridization can improve the dispersibility of fillers in polymer matrix. The FD can be used to quantitatively characterize the aggregation and dispersion of kaolinite sheets in rubber matrix.

Disorganising principles: Corporeal fragmentation and the possibilities for repair

Dancers investigate ever-expanding relationships to embodiment through the variety of unique choreographic signatures that are continually erupting in professional practice. They live fragmented lineages that are interrupted and redirected as they traverse between various projects led by different choreographers or the same choreographer pursuing different creative goals. As contemporary dance continues to reconceive ways of moving, the dominant lineages of dance training are less useful as reference points through which dancers can recalibrate bodily activity and thus rebalance. In this chapter, I examine the impulse towards fragmentation in contemporary dance and explore how moments of agency for dancers might arise and be seized within the complexities of this environment. These issues are discussed in relation to my encounter with a bodywork therapy of Japanese origin, Amatsu, which I studied throughout 2012, and through the teaching principles of Gill Clarke as illuminated through the Minding Motion project, which explored Clarke’s pedagogy for Tanzplan, Germany 2010 (Diehl and Lampert, 2011). Moments from performance and bodywork practice are offered as examples throughout the chapter.

Employee reactions to behavioural control under conditions of stress: The moderating role of self-efficacy

Extensive research conducted in the occupational stress literature has failed to provide convincing support for the stress-buffering effects of work control on employee adjustment. Drawing on research conducted in the laboratory context, it was proposed that the stress-buffering effects of work control on employee adjustment would be more marked at high, rather than low, levels of self-efficacy. In a sample of 100 customer service representatives, a significant three-way interaction among role conflict, work control and self-efficacy (measured at Time 1) was observed on (low) depersonalization (measured at Time 2). Consistent with expectations, work control reduced the negative effects of work stress on this outcome measure only for employees who perceived high levels of self-efficacy at work. In addition, there was evidence to suggest that self-efficacy moderated the main effects of work control on job satisfaction and somatic health. These findings are discussed in terms of their theoretical contribution to the job strain model, and also in relation to workplace interventions designed to improve levels of employee adjustment.

Creative adaptations: Integrating Feldenkrais principles in contemporary dance technique to facilitate the transition into tertiary dance education

As conservatoire-style dance teaching has traditionally utilised a hierarchical approach through which the student must conform to the ideal requirements of the conventional technique, current discourse is beginning to question how dance training can develop technical acuity without stifling students' ability to engage creatively. In recent years, there has been growing interest in the field of somatics and its relationship to tertiary dance training due to the understanding that this approach supports creative autonomy by radically repositioning the student's relationship to embodied learning, skill acquisition, enquiry and performance. This research addresses an observable disjuncture between the skills of dancers graduating from tertiary training and Australian dance industry needs, which increasingly demand the co-creative input of the dancer in choreographic practice. Drawing from Action Research, this paper will discuss a project which introduces somatic learning approaches, primarily from Feldenkrais Method and Hanna Somatics, to first-year dance students in their transition into tertiary education. This paper acknowledges previous research undertaken, most specifically the Somdance Manual by the University of Western Sydney, while directing focus to the first-year student transition from private dance studio training into the pre-professional arena.

Letter Reply: Distribution of TNFA haplotypes in healthy Caucasians: Comment on the articles by Newton et al and Zeggini et al

We thank Ploski and colleagues for their interest in our study. The explanation for the difference in our findings is a typographic error in Table 2 of our article, whereby the alleles for marker TNF ⫺1031 were labeled incorrectly...

The enigma of IgE+ B-cell memory in human subjects

Our understanding of the origin and fate of the IgE-switched B cell has been markedly improved by studies in mouse models. The immediate precursor of the IgE-switched B cell is either a relatively naive nonswitched B cell or a mature IgG-switched B cell. These 2 routes are referred to as the direct and indirect pathways, respectively. IgE responses derived from each pathway differ significantly, largely reflecting the difference in time spent in a germinal center and thus time for clonal expansion, somatic hypermutation, affinity maturation, and acquisition of a memory phenotype. The clinical and therapeutic implications for IgE responses in human subjects are still a matter of debate, largely because the immunization procedures used in the animal models are significantly different from classical atopic sensitization to allergens from pollen and mites. On the basis of the limited information available, it seems likely that these atopic IgE responses are characterized by a relatively low IgG/IgE ratio, low B-cell memory, and modest affinity maturation, which fits well with the direct switching pathway. It is still unresolved how the IgE response evolves to cover a wide epitope repertoire involving many epitopes per allergen, as well as many different allergens from a single allergen source. © 2013 American Academy of Allergy, Asthma & Immunology.

Altered immunoglobulin E diversity and regulation of allergic inflammation in asthma

The clinical efficacy of anti-immunoglobulin E (IgE) therapy indicates a central role for IgE in perpetuation of allergic inflammatory diseases. Omalizumab is now uti- lized in treatment of a wide variety of allergic conditions including severe asthma, allergic rhinitis, atopic dermati- tis, food allergy and urticaria either alone or adjunct with other therapies such as steroid administration or allergen- specific immunotherapy [1, 2]. Current research activity is focused on the cellular and molecular mechanisms by which IgE influences the immunopathogenesis of allergic disease [3]. Increased knowledge of how IgE exerts its effects will underpin effective clinical use of anti-IgE treatment. In this issue Kerzel et al. [4] investigate the effects of altered antibo dy repertoire on the outcomes of an experimental model of allergic asthma.

VH gene usage in immunoglobulin E responses of seasonal rhinitis patients allergic to grass pollen is oligoclonal and antigen driven

Background: IgE is the pivotal-specific effector molecule of allergic reactions yet it remains unclear whether the elevated production of IgE in atopic individuals is due to superantigen activation of B cell populations, increased antibody class switching to IgE or oligoclonal allergen-driven IgE responses. Objectives: To increase our understanding of the mechanisms driving IgE responses in allergic disease we examined immunoglobulin variable regions of IgE heavy chain transcripts from three patients with seasonal rhinitis due to grass pollen allergy. Methods: Variable domain of heavy chain-epsilon constant domain 1 cDNAs were amplified from peripheral blood using a two-step semi-nested PCR, cloned and sequenced. Results: The VH gene family usage in subject A was broadly based, but there were two clusters of sequences using genes VH 3-9 and 3-11 with unusually low levels of somatic mutations, 0-3%. Subject B repeatedly used VH 1-69 and subject C repeatedly used VH 1-02, 1-46 and 5a genes. Most clones were highly mutated being only 86-95% homologous to their germline VH gene counterparts and somatic mutations were more abundant at the complementarity determining rather than framework regions. Multiple sequence alignment revealed both repeated use of particular VH genes as well as clonal relatedness among clusters of IgE transcripts. Conclusion: In contrast to previous studies we observed no preferred VH gene common to IgE transcripts of the three subjects allergic to grass pollen. Moreover, most of the VH gene characteristics of the IgE transcripts were consistent with oligoclonal antigen-driven IgE responses.

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Tumor-associated mutations inO6-methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality

MGMT is the primary vehicle for cellular removal of alkyl lesions from the O-6 position of guanine and the O-4 position of thymine. While key to the maintenance of genomic integrity, MGMT also removes damage induced by alkylating chemotherapies, inhibiting the efficacy of cancer treatment. Germline variants of human MGMT are well-characterized, but somatic variants found in tumors were, prior to this work, uncharacterized. We found that MGMT G132R, from a human esophageal tumor, and MGMT G156C, from a human colorectal cancer cell line, are unable to rescue methyltransferase-deficient Escherichia coli as well as wild type (WT) human MGMT after treatment with a methylating agent. Using pre-steady state kinetics, we biochemically characterized these variants as having a reduced rate constant. G132R binds DNA containing an O6-methylguanine lesion half as tightly as WT MGMT, while G156C has a 40-fold decrease in binding affinity for the same damaged DNA versus WT. Mammalian cells expressing either G132R or G156C are more sensitive to methylating agents than mammalian cells expressing WT MGMT. G132R is slightly resistant to O6-benzylguanine, an inhibitor of MGMT in clinical trials, while G156C is almost completely resistant to this inhibitor. The impared functionality of expressed variants G132R and G156C suggests that the presence of somatic variants of MGMT in a tumor could impact chemotherapeutic outcomes.