Reducing Acrylamide Formation Potential by Targeting Free Asparagine Accumulation in Seeds.

Acrylamide is a probable carcinogen in humans and is formed when reducing sugars react with free asparagine (Asn) during thermal processing of food. Although breeding for low reducing sugars worked well in potatoes, it is less successful in cereals. However, reducing free Asn in cereals has great potential for reducing acrylamide formation, despite the role that Asn plays in nitrogen transport and amino acid biosynthesis. In this perspective, we summarize the efforts aimed at reducing free Asn in cereal grains and discuss the potentials and challenges associated with targeting this essential amino acid, especially in a seed-specific manner.

Mediators of change in psychosocial interventions for cancer patients: a systematic review.

Careful reviews and meta-analyses have made valuable contributions to understanding the efficacy of psychosocial interventions for cancer patients. An important next step is to determine the mediators that explain the influence of efficacious interventions on outcomes. This systematic review summarizes tests of mediating variables from twenty-two projects conducted from 1989-2010. Although all authors provided some type of rationale for considering particular mediating relationships, the investigations varied widely with respect to the extent to which formal theoretical constructs were tested, the type and goals of the interventions studied, and the broad types of outcomes and potential mediators examined. Although there was some evidence supporting selected mediating relationships, with positive findings often found when mediating variables represented behaviors targeted by an intervention, the findings were mixed. Expanding the focus of research to include mechanisms in psychosocial oncology intervention research is necessary for providing a unified picture of how mediating relationships may be operating in this field.

Published versus unpublished dissertations in psycho-oncology intervention research.

OBJECTIVE: There are conflicting views regarding whether gray literature, including unpublished doctoral dissertations, should be included in systematic reviews and meta-analyses. Although publication status frequently is used as a proxy for study quality, some research suggests that dissertations are often of superior quality to published studies. METHODS: We examined 107 projects involving doctoral dissertations (42 published, 65 unpublished) that studied psychosocial interventions for cancer patients. RESULTS: Published dissertations were more likely to be supported by research funding but were not more likely than unpublished dissertations to examine specific types of interventions. Across several indices of methodological quality there were minimal differences. Dissertations with significant findings tended to be more likely to be published than those without significant findings. CONCLUSIONS: Unpublished dissertations focusing on psychosocial interventions for cancer patients are not necessarily of vastly inferior quality to those that eventually are published. Because doctoral dissertations are easy to access relative to other forms of gray literature, are free from some types of bias, and are reported thoroughly, they merit inclusion in comprehensive literature reviews.

Pre-intervention distress moderates the efficacy of psychosocial treatment for cancer patients: a meta-analysis.

This meta-analysis examined whether effects of psychosocial interventions on psychological distress in cancer patients are conditional upon pre-intervention distress levels. Published articles and unpublished dissertations between 1980 and 2005 were searched for interventions reporting the Hospital Anxiety and Depression Scale (HADS) or the Spielberger State-Trait Anxiety Inventory (STAI). Multilevel mixed-effects modeling was used to meta-analyze effect-sizes separately for the HADS (27 trials, 2,424 patients) and STAI (34 trials, 2,029 patients). Pre-intervention distress significantly moderated intervention effects, explaining up to 50% of the between-study effect-size variance: effects on anxiety and depression were generally negligible when pre-intervention distress was low and pronounced when it was high. These results could not be explained by differences in intervention type, setting, dose, and whether intervention was targeted at distressed patients. Psychosocial interventions may be most beneficial for cancer patients with elevated distress. Future research should identify which treatment components are most effective for these patients to facilitate optimal treatment tailoring and cost-effective health care.

What psychological and physical changes predict patients' attainment of personally meaningful goals six months following a CBT based pain management intervention?

PURPOSE: To examine the influence of demographic measures, and changes in physical ability, pain, self-efficacy and emotional distress on Goal Attainment Scaling (GAS) scores, after a 15-day CBT based pain management programme. METHOD: Chronic pain patients (N = 257) were referred; 225 (88%) completed the programme and were invited for follow up six months later. One hundred and sixty-two (63%), (mean age 47.7, 71% female) completed the reassessment procedures. GAS scores (which were also repeated at the end the programme), an 11-point Pain Numerical Rating Scale, Pain Self-Efficacy Questionnaire, Hospital Anxiety and Depression Scale, distance walked in 5 mins, number of sit/stand repetitions in 1 min and number of stairs climbed in 1 min were measured on the first day and six months following the programme. RESULTS: At six months post discharge, changes in goal attainment, physical measures, pain intensity, depression and self-efficacy were observed. Hierarchical regression showed change in GAS was predicted by improvement in walking tolerance and self-efficacy. CONCLUSIONS: The achievement of personally important goals was most significantly associated with change in walking ability and self-efficacy, while controlling for the influence of change in pain. Implications for Rehabilitation Chronic pain can reduce psychological and physical functioning, leading to a reduction in meaningful activities. Achievement of personally important activities as measured by Goal Attainment Scaling can be a more sensitive measure of programme outcome than that captured by many other standard measures. Self-efficacy is an important predictor of attainment of patient preferred goals following a CBT based pain management programme, and could be emphasized during treatment along with improved walking ability, to enhance patients' goal achievement.

The effect of electromagnetic shielding on phantom limb pain: A placebo-controlled double-blind crossover trial.

BACKGROUND: Environmental electromagnetic fields influence biological systems. Evidence suggests these have a role in the experience of phantom limb pain in patients with amputations. OBJECTIVES: This article followed a previous study to investigate the effect of electromagnetic field shielding with a specially designed prosthetic liner. STUDY DESIGN: Randomised placebo-controlled double-blind crossover trial. METHODS: Twenty suitable participants with transtibial amputations, phantom pain at least 1 year with no other treatable cause or pathology were requested to record daily pain, well-being, activity and hours of prosthetic use on pre-printed diary sheets. These were issued for three 2-week periods (baseline, electromagnetic shielding (verum) and visually identical placebo liners - randomly allocated). RESULTS: Thirty-three per cent of the recruited participants were unable to complete the trial. The resulting N was therefore smaller than was necessary for adequate power. The remaining data showed that maximum pain and well-being were improved from baseline under verum but not placebo. More participants improved on all variables with verum than placebo. CONCLUSION: Electromagnetic field shielding produced beneficial effects in those participants who could tolerate the liner. It is suggested that this might be due to protection of vulnerable nerve endings from nociceptive effects of environmental electromagnetic fields. CLINICAL RELEVANCE: Electromagnetic field shielding with a suitable limb/prosthesis interface can be considered a useful technique to improve pain and well-being in patients with phantom limb pain.

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.

Effects of a supervised, outpatient exercise and physiotherapy programme in children with cystic fibrosis.

Previous work suggests benefit from outpatient exercise and physiotherapy in children with cystic fibrosis (CF), namely improved exercise capacity and lung function measures, as well reduced intravenous (IV) antibiotic needs. Our study aim was to investigate the effect of a year-long supervised outpatient exercise and physiotherapy programme in children with CF. Subjects with CF aged ≥10 years who had received ≥4 courses of IV antibiotics in 2009 were enrolled and seen fortnightly for supervised exercise and physiotherapy throughout 2010. In addition, they were expected to exercise three times weekly, and if unwell complete additional physiotherapy sessions extra to usual chest physiotherapy. Assessments of exercise capacity using the Modified Shuttle Test (MST) and quality of life (QOL; CFQ-UK) were recorded at baseline and after 1 year. Regular spirometry was performed before and throughout the study. Data were collected on IV antibiotic days. 12 subjects (6 female) were enrolled with mean (95% CI) age of 13.3 (11.8-14.6) years at study entry. A significant reduction in IV antibiotic days from 60 (56-64) days in 2009 to 50 (44-56) in 2010 (P = 0.02) was noted, along with improved MST distance (m) [735 (603-867) vs. 943 (725-1,161), P = 0.04] and level attained [9.4 (8.4-10.5) vs. 11.1 (9.6-12.6), P = 0.04]. Significant improvements in CFQ-UK scores for physical [59 (47-72) vs. 83 (74-92), P = 0.001], emotional [63 (55-72) vs. 84 (74-93), P < 0.001], treatment [41 (30-51) vs. 61 (48-73), P = 0.002], and respiratory [54 (42-66) vs. 76 (70-82), P = 0.002] domains were noted. The mean (95% CI) rate of change of FEV(1) was -4 (-18, +10)% in 2009, but was +6 (-2, +13)% in 2010, although this did not reach statistical significance. Supervised, outpatient exercise and physiotherapy are associated with improvements in QOL and exercise tolerance, a reduction in IV antibiotic days, and a trend towards reducing lung function decline in children with CF. The cost of IV antibiotics was reduced by £66,384 ($104,000) in 2010 when compared with 2009. Such cost-benefit may have implications for workforce planning and service provision.

Why are Optimists Optimistic?

This study examined what is brought to mind when responding to the items comprising a measure of dispositional optimism. Participants (N = 113) completed the Life Orientation Test and the COPE, a measure of coping style, and described why they responded the way they did to the items assessing optimism. Participants' explanations comprised eight types of reasoning: (1) faith in a higher power; (2) belief in fate or a just world; (3) personal fortune; (4) belief in the role of one's own ability; (5) reliance on idioms; (6) beliefs about the usefulness of thinking optimistically; (7) matter-of-fact statements; and (8) a feeling, intuition, or hope. These types were also related to coping styles. Responses to positively-worded items were explained with respect to external forces and responses to negatively-worded items were explained with respect to internal forces. Understanding how people explain their optimism may be the first step in fostering this outlook.

Open innovation for phenotypic drug discovery: The PD2 assay panel.

Phenotypic lead generation strategies seek to identify compounds that modulate complex, physiologically relevant systems, an approach that is complementary to traditional, target-directed strategies. Unlike gene-specific assays, phenotypic assays interrogate multiple molecular targets and signaling pathways in a target "agnostic" fashion, which may reveal novel functions for well-studied proteins and discover new pathways of therapeutic value. Significantly, existing compound libraries may not have sufficient chemical diversity to fully leverage a phenotypic strategy. To address this issue, Eli Lilly and Company launched the Phenotypic Drug Discovery Initiative (PD(2)), a model of open innovation whereby external research groups can submit compounds for testing in a panel of Lilly phenotypic assays. This communication describes the statistical validation, operations, and initial screening results from the first PD(2) assay panel. Analysis of PD(2) submissions indicates that chemical diversity from open source collaborations complements internal sources. Screening results for the first 4691 compounds submitted to PD(2) have confirmed hit rates from 1.6% to 10%, with the majority of active compounds exhibiting acceptable potency and selectivity. Phenotypic lead generation strategies, in conjunction with novel chemical diversity obtained via open-source initiatives such as PD(2), may provide a means to identify compounds that modulate biology by novel mechanisms and expand the innovation potential of drug discovery.

Characteristics and methodological quality of 25 years of research investigating psychosocial interventions for cancer patients.

The considerable amount of research examining psychosocial interventions for cancer patients makes it important to examine its scope and methodological quality. This comprehensive overview characterizes the field with as few exclusions as possible. A systematic search strategy identified 673 reports comprising 488 unique projects conducted over a 25 year time span. Although the literature on this topic has grown over time, the research was predominantly conducted in the United States (57.0%), largely with breast cancer patients (included in 70.5% of the studies). The intervention approach used most frequently was cognitive behavioral (32.4%), the treatment goal was often improving quality of life generally (69.5%), and the professionals delivering the interventions were typically nurses (29.1%) or psychologists (22.7%). Overall, there was some discrepancy between the types of interventions studied and the types of supportive services available to and sought by cancer patients. Strengths of this research include using randomized designs (62.9%), testing for baseline group equivalence (84.5%), and monitoring treatment, which rose significantly from being used in 48.1-64.4% of projects over time. However, deficiencies in such areas as examining treatment mechanisms and the adequacy of reporting of methodology, essential for useful syntheses of research on these interventions, remain to be addressed. Methodological challenges related to the complexity of this applied research, such as participants seeking treatment outside of research, contamination, and reactions to randomization, also were apparent. Future research could benefit from closer interactions between academic and voluntary sectors and expanding the diversity of participants.

Lessons to be learned from 25 years of research investigating psychosocial interventions for cancer patients.

Conducting rigorous psychosocial intervention research with cancer patients has many challenges including encouraging them to join studies, asking them to engage in interventions or be part of control conditions, and to provide data over follow-up assessments. Here, we highlight valuable insights regarding such challenges provided by investigators studying psychosocial interventions for cancer patients. Handling these skillfully has important implications for the internal and external validity of this research and the ethical treatment of participants. Challenges noted in research reports included in a systematic review of 25 years of research (comprising 488 unique projects) investigating interventions designed to enhance cancer patients' quality of life were compiled. Among the difficulties mentioned was the fact that patients may not feel the need for psychosocial interventions and thus may not be interested in joining an intervention study. Patients who do feel the need for such interventions may be deterred from joining trials by the prospect of being randomized to a nonpreferred group; if they do join a trial, participants may be disappointed, drop out, or seek compensatory additional assistance when they are assigned to a control group. Apart from randomization, other aspects of research may be off-putting to participants or potential participants, such as the language of consent forms or the intrusiveness of questions being asked. Potential remedies, such as research awareness interventions, monetary incentives, partnering with cancer support organizations, and using designs that take preferences into account merit consideration and further research inquiry.

Measuring the sensations of urge and bladder filling during cystometry in urge incontinence and the effects of neuromodulation.

AIMS: As urge and urgency contribute greatly to a patient's symptoms, it follows that sensory evaluation combined with noninvasive neuromodulation during urodynamics may provide new criteria for improving patient selection for an implantable stimulator. The purpose of this research was to develop and validate an objective measure of bladder sensations during filling cystometry and then to apply this technique to evaluate the effects of neuromodulation on the sensations of urge measured in this way. METHODS: In study 1 a new patient-activated keypad device was tested during urodynamics to measure bladder sensations according to a 0-4 scale and validated by using a technique adapted from a standard psychophysical sensory threshold testing method. In study 2 the effects of pudendal afferent nerve stimulation on measured sensations of urge were assessed during cystometry with patients as their own controls. Forty-three patients diagnosed with idiopathic detrusor instability were studied; 10 participated in study 1 and 35 in study 2. RESULTS: The new device gave reliable and repeatable measures of sensations with statistically significant differences in bladder volume at each of the urge levels tested (Wilcoxon matched pairs test). Neuromodulation suppressed urinary urge in 89% of the 35 patients. This effect was associated with a statistically significant increase in bladder volume at all urge levels. CONCLUSIONS: A new patient operated key-pad device provided a reliably objective measure of sensations of urge during urodynamics without the need for prompting. Neuromodulation using noninvasive pudendal afferent stimulation suppressed these sensations whilst increasing bladder volume.