Prospective surveillance of breast cancer-related lymphoedema in the first-year post-surgery: feasibility and comparison of screening measures.

PURPOSE: To examine the feasibility of a breast cancer-related lymphoedema (BCRL) screening programme. Additionally, to investigate the efficacy of bioimpedance analysis (BIA) compared to circumferential measurements (CM) in detecting BCRL. METHODS: This was a 12-month prospective feasibility study. Participants were recruited from two diagnostic breast clinics and consented to be screened for BCRL. Pre-surgical assessments were conducted, and participants were followed up at quarterly intervals. BIA and CM measurements were conducted at all time points. An L-Dex score of >10 or a 10-U increase from baseline or a ≥5 % increase in proximal, distal or total percentage volume difference (PVD) from baseline was indicative of BCRL. Information was collected on subjective symptoms, potential risk factors, demographics and medical data. Feasibility was based on uptake and retention. RESULTS: One hundred twenty-six participants were recruited with an attrition rate of 16.2 %. Participants' mean age was 59 years with the majority having stage I (63.9 %), infiltrating ductal carcinoma (87.4 %). 31.6 % were identified as having BCRL, 90.3 % detected by CM and 35.5 % by BIA (p = ≤0.0001). We found no significant correlation between BIA and CM. Participants identified as having BCRL had a higher BMI, a recent injury to their 'at-risk' arm and more lymph nodes excised (p = <0.05). These findings were not evident across all time points. A large percentage of participants had transient BCRL when assessed by a lymphoedema physiotherapist. CONCLUSIONS: BCRL screening is acceptable and valued by breast cancer survivors. Work needs to continue to establish the most effective screening tool and the natural behaviour of BCRL within the first-year post-surgery.

Cancer survivors' exercise barriers, facilitators and preferences in the context of fatigue, quality of life and physical activity participation: a questionnaire-survey.

OBJECTIVE: To investigate the exercise barriers, facilitators and preferences of a mixed sample of cancer survivors as well as fatigue levels, quality of life (QoL) and the frequency and intensity of exercise that cancer survivors typically engage in. METHODS: An anonymous, postal questionnaire-survey with a convenience sample of 975 cancer survivors was used. Standardised measures were used to establish fatigue (Multidimensional Fatigue Symptom Inventory-Short Form), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30), exercise frequency and intensity (Leisure Score Index). RESULTS: A 52.3% response rate (n = 456) was achieved. A total of 76.0% were female, with stage I (18.3%) or stage II (21.0%) breast cancer (64.4%), and 62.3% were ≥ 3 years post treatment. A total of 73.5% reported fatigue with 57.2% experiencing fatigue on a daily basis. A total of 68.1% had never been given any advice on how to manage fatigue. A total of 9.4% reported to engage in strenuous physical activity, 43.5% in moderate physical activity and 65.5% in mild physical activity. Respondents experienced difficulties with emotional, cognitive and social functioning and the symptoms of fatigue, insomnia and pain. Barriers that interfered with exercise 'often/very often' were mainly related to respondents' health and environmental factors. A total of 50.2% were interested in exercise and 52.5% felt able to exercise. Exercise facilitators, preferences and motivators provide some insight into cancer survivors' needs in terms of becoming more physically active. CONCLUSIONS: Although cancer survivors continue to experience fatigue and QoL issues long after treatment completion, over half are willing and feel able to participate in exercise. Exercise barriers were mainly health related or environmental issues, however, the main barriers reported were those that had the potential to be alleviated by exercise.

A focus group study exploring gynecological cancer survivors' experiences and perceptions of participating in a RCT testing the efficacy of a home-based physical activity intervention.

PURPOSE: This study aims to explore gynecological cancer survivors' perceptions and experiences following participation in a randomised controlled trial (RCT) testing the efficacy of a home-based physical activity behavioral change intervention (Donnelly et al., Gynecol Oncol 122:618-624, 2011). METHODS: All participants completing a two-armed parallel RCT were invited to participate in the study (31/33) (Donnelly et al., Gynecol Oncol 122:618-624, 2011). Sixteen participants took part (16/31; physical activity (PA) group n = 9, contact control (CC) group n = 7). Four qualitative group interviews were conducted (focus group size 3-5). A structured interview guide was followed by an independent moderator. Groups were audio recorded, transcribed verbatim, and analyzed using the framework approach (Ritchie and Spencer 2001), a five-stage qualitative method of analysis. RESULTS: One of the most unanimously perceived benefits of taking part in the programme regarded participants' psychological well-being. Additional benefits included improved physical fitness and functioning. Important programme features included the weekly telephone calls from a physiotherapist, the patient-professional relationship, and goal setting. Participants' own motivation and programme timing were also identified as important factors. Suggestions for improvements include: opportunities for social interaction with other gynecological cancer survivors and greater exercise choice. CONCLUSION: Findings suggest that women diagnosed with gynecological cancer perceive participation in physical activity as important and participation provides benefits in terms of psychological well-being and improved physical functioning. Support for continuation of many of the current features of the home-based programme was provided. Findings provide insight and rationale for the selection of components for future home-based physical activity interventions. Findings also support further research into the development of multidimensional interventions for the gynecological cancer population.

A randomised controlled trial testing the feasibility and efficacy of a physical activity behavioural change intervention in managing fatigue with gynaecological cancer survivors.

OBJECTIVE: To determine the feasibility and efficacy of a physical activity behavioural change intervention in managing cancer-related fatigue among gynaecological cancer survivors during and post anti-cancer treatments. METHODS: A two arm, single blind, randomised controlled trial was conducted within the Northern Ireland regional Cancer Centre. Thirty three sedentary gynaecological cancer survivors (stage I-III; ≤3 years post diagnosis), experiencing cancer-related fatigue (mild-severe) took part. Participants were randomly assigned to a behavioural change, moderate intensity physical activity intervention (n=16) or a Contact Control group (n=17). The primary outcome was fatigue (Multidimensional Fatigue Symptom Inventory-Short Form and Functional Assessment in Chronic Illness Therapy-Fatigue subscale). Secondary outcomes included quality of life, physical functioning, positive and negative affect, depression, body composition, sleep dysfunction and self-reported physical activity. Feasibility was assessed based on the recruitment rate, programme and physical activity adherence and participants' programme evaluation, including optional focus groups (n=16). RESULTS: Twenty five percent of eligible women took part (33/134). Participants were 8.7 (SD=9.1) months post diagnosis, with a mean age of 53 (SD=10.3) years. The majority of the sample had a diagnosis of ovarian (n=12) or endometrial cancer (n=11). Significant differences favouring the intervention group were observed for fatigue at 12 weeks and 6 months follow-up (12 week: mean difference=-11.06; 95% confidence interval (CI)=-21.89 to -0.23; effect size (d)=0.13; p=0.046; 6 month: mean difference=-19.48; 95% CI=-19.67 to -19.15; effect size (d)=0.20; p=0.01). A mean of 10 calls (SD=1.2 calls) were delivered to the Physical Activity Group, and 10 (SD=1.6 calls) to the CC group. The intervention was positively perceived based on exit questionnaire and focus group findings. CONCLUSIONS: A physical activity behavioural change intervention for gynaecological cancer survivors is feasible in terms of participants' programme adherence and evaluation, and the intervention demonstrates improvements in fatigue. However, confirmation in the form of a larger fully powered RCT is warranted.

Computational approaches for combinatorial library design and molecular diversity analysis.

New approaches for combinatorial library design and molecular diversity analysis have been developed by extending previous work from the fields of quantitative structure-activity relationship, computational chemistry, and chemical information. Recent work has begun to address design efficiency and validation of descriptors for combinatorial library design.

Quantitative structure-activity relationship of 5-(X-benzyl)-2,4-diaminopyrimidines inhibiting bovine liver dihydrofolate reductase.

The inhibitory effect for a set of 23 5-(X-benzyl)-2,4-diaminopyrimidines acting on bovine liver dihydrofolate reductase (DHFR) had led to the following quantitative structure-activity relationship (QSAR): log 1/C = 0.62pi3 + 0.33epsilon sigma + 4.99, where r = 0.931 and s = 0.146. C in this expression is the molar concentration of inhibitor producing 50% inhibition, pi3 is the hydrophobic parameter for substituents on the 3 position of the phenyl moiety, and epsilon sigma is the the sum of the Hammett sigma constants for the 3, 4, and 5 substituents of the phenyl ring.

Actinidin hydrolysis of substituted-phenyl hippurates: a quantitative structure-activity relationship and graphics comparison with hydrolysis by papain.

The hydrolysis of 29 phenyl hippurates (XPhOCOCH2NHC(=O)C6H5) by the cysteine protease actinidin has been studied and a quantitative structure-activity relationship (QSAR) has been formulated: log 1/Km = 0.74 sigma + 0.50 pi'3 + 0.24MR4 + 2.90. In this expression Km is the Michaelis constant, sigma is the Hammett constant, pi'3 is the hydrophobic parameter for the more hydrophobic of the two meta substituents, and MR4 is the molar refractivity of para substituents. The QSAR for actinidin is compared with a similar one obtained for another cysteine plant protease papain. A color stereo computer graphics model constructed from the X-ray crystallographic coordinates of actinidin is compared with those of our previously reported models for papain.

Comparison of the inhibition of Escherichia coli and Lactobacillus casei dihydrofolate reductase by 2,4-diamino-5-(substituted-benzyl)pyrimidines: quantitative structure-activity relationships, X-ray crystallography, and computer graphics in structure-activity analysis.

The inhibition constants (Kiapp) obtained from the action of 44 2,4-diamino-5-(substituted-benzyl)pyrimidines on dihydrofolate reductase (DHFR) from Escherichia coli and Lactobacillus casei bacteria are used to derive quantitative structure-activity relationships (QSAR). These equations bring out a number of differences in the DHFR which can be understood at the atomic level by studying color stereo computer graphics models constructed from the X-ray coordinates of the enzyme-inhibitor complexes. The combination of QSAR and X-ray crystallography interpreted via high-performance computer graphics offers a new level of sophistication to extend our understanding of enzyme-ligand interactions, which, when the crystallography is known, opens up a more scientific approach to drug development.

Quantitative structure-selectivity relationships. Comparison of the inhibition of Escherichia coli and bovine liver dihydrofolate reductase by 5-(substituted-benzyl)-2,4-diaminopyrimidines.

A quantitative structure-activity relationship (QSAR) has been formulated for the inhibition of purified E. coli dihydrofolate reductase by 23 5-(substituted benzyl)-2,4-diaminopyrimidines: log 1/C = 1.14MR'3,4,5 + 5.73; r = 0.887; s = 0.285. In this expression, MR'3,4,5 refers to the sum of MR values for X in the 3, 4 and 5 positions of the phenyl moiety. MR' signifies that the effective value of MR is limited to 0.79. Comparison of the QSAR for E. coli enzyme inhibition with that previously obtained for bovine enzyme offers the first general explanation for the great selectivity of the important antibacterial agent trimethoprim. Such QSSR promise to be of value in devising more selective drugs.

Measuring diversity: experimental design of combinatorial libraries for drug discovery.

Screening synthetic combinatorial libraries, such as mixtures of oligo(N-substituted)glycines, facilitates rapid drug lead discovery and optimization by vastly increasing the number of candidate molecules made and tested. Discovery efficiency and productivity can be further improved by using experimental design to maximize molecular diversity for a given library size or to bias the library with key features for a specific receptor. We describe new methods to quantify molecular diversity using descriptors that characterize lipophilicity, shape and branching, chemical functionality, and specific binding features. Experimental design methods select sets of side chains that are diverse in these properties, and "flower plots" allow the diversity to be graphically compared. We also quantify the overall diversity accessible to different families of combinatorial chemistry.

Computer graphics in drug design: molecular modeling of thyroid hormone-prealbumin interactions.

Computer graphics modeling of the thyroxine-prealbumin complex provides a detailed picture of the interactions between thyroxine and prealbumin. A wide variety of thyroid hormone analogue-prealbumin complexes were modeled by calculating the molecular surfaces of the analogues and the prealbumin hormone-binding site. Analogues with high binding affinity were observed to fill more of the hormone-binding site than low-affinity analogues. These surface models described many aspects of the hormone-protein interaction which were not obvious using simple wire models and led us to develop a model which accounts for thyroid hormone-prealbumin structure-activity relationships and ultimately to predict and measure the relative binding affinities of four previously untested thyroid hormone analogues to prealbumin.

Crystallography, quantitative structure-activity relationships, and molecular graphics in a comparative analysis of the inhibition of dihydrofolate reductase from chicken liver and Lactobacillus casei by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazine s.

The inhibition of dihydrofolate reductase from chicken liver and from Lactobacillus casei has been studied with 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines. It was found that for the chicken enzyme, inhibitor potency for 101 triazines was correlated by the following equation: log 1/Kiapp = 0.85 sigma tau' - 1.04 log (beta X 10 sigma tau' + 1) + 0.57 sigma + 6.36. The parameter tau' indicates that for certain substituents, tau = 0. In the case of the L. casei DHFR results, meta and para derivatives could not be included in the same equation. For 38 meta-substituted compounds, it was found that log 1/Kiapp = 0.38 tau'3-0.91 log (beta X 10 tau'3 + 1) + 0.71I + 4.60 and for 32 para-substituted phenyltriazines log 1/Kiapp = 0.44 tau'4-0.65 log (beta tau'4 + 1') - 0.90 upsilon + 0.69I + 4.67. In the L. casei equation, I is an indicator variable for substituents of the type CH2ZC6H4-Y and ZCH2C6H4-Y, where Z = O, NH, S, or Se. The parameter upsilon is Charton's steric parameter, which is similar to Taft's Es. The mathematical models obtained from correlation analysis are compared with stereo color graphics models.

Conformational analysis using distance geometry methods.

Distance geometry methods have been used extensively to build models of molecules of various sizes, including small molecules, peptides, and proteins. These methods are often overlooked as tools for conformational analysis, even though they often perform as well as other conformational sampling methods. We have implemented two new distance geometry approaches in the DGEOM95 package. In the first new method, the traditional embedding algorithm is replaced with a procedure that generates random 4D coordinates for each atom, followed by refinement of these coordinates into 3D using the distance geometry error function. The conformational sampling produced by this method is comparable to that obtained with partial metrization, and superior to that obtained with the original embedding procedure. In the second method, a molecular dynamics step is included in the refinement stage. Although this method can be applied to any embedding algorithm, substantial improvements in sampling are seen primarily with the original embedding algorithm.

Hospital cancer deaths: late diagnosis and missed opportunity.

OBJECTIVES: To establish factors that influence and contribute to the death of patients with cancer in acute hospitals in Northern Ireland. DESIGN: Retrospective clinical note review. SETTING: 16 acute hospitals, covering 5 Health and Social Care Trusts across Northern Ireland. PARTICIPANTS: 793 adult patients with cancer who died in an acute hospital between July and December 2007 identified through the Northern Ireland Cancer Registry. Information was available for 695 (88%). RESULTS: Thee main reasons for acute hospital deaths were uncovered. First, 26.3% of patients were diagnosed with cancer during their last hospital admission. These patients were significantly different from the rest of the sample in being older, not partnered, having more comorbidities and fewer hospital admissions in their last year of life (all p<0.001). Second, patients were very ill with 78.7% admitted as an emergency, requiring medical attention as a result of cancer-related (37.4%) and urgent physical symptoms (33.5%). Third, despite 38.3% of patients specifically requesting discharge to their usual residence, hospice or other hospital, this was not achieved. For 76.3%, this was owing to a deterioration in their medical condition. However for 12.4% there was a lack of a suitable bed, a care package was not in place for 4.9% and 3.0% lacked the required family support. In addition, preferred place of death was only recorded for 41% of patients. CONCLUSIONS: Late diagnosis of cancer is a problem which requires further research. Training should be in place to ensure that a patient's preferred place of death is discussed, recorded and made part of routine end of life care. To achieve this, all medical staff should know when a patient is dying. Further research is required to establish what enables patients with cancer to die at home.

CHUCKLES: a method for representing and searching peptide and peptoid sequences on both monomer and atomic levels.

Dual representation of peptide and non-peptide structures in a chemical database as atomic-level molecular graphs and sequence strings permits chemical substructure and similarity searches as well as sequence-based substring and regular expression searches. CHUCKLES interconverts monomer-based sequences with SMILES, which represent atomic-level molecular graphs. Forward-translation maps peptide or other sequences into SMILES. Back-translation extracts monomer sequences from SMILES. This approach permits a generalized representation of monomers allowing user specification of any monomer. CHUCKLES allows mixing of atoms with user-defined monomer names; that is, monomer representation is consistent with SMILES notation. In addition, oligomer branching and cyclization are handled.

Orientational sampling and rigid-body minimization in molecular docking.

The biological activities of proteins depend on specific molecular recognition and binding. Computational methods for predicting binding modes can facilitate the discovery and design of ligands and yield information on the factors governing complementarity. The DOCK suite of programs has been applied to several systems; here, the degree of orientational sampling required to reproduce and identify known binding modes, with and without rigid-body energy minimization, is investigated for four complexes. There is a tradeoff between sampling and minimization. The known binding modes can be identified with intensive sampling alone (10,000 to 20,000 orientations generated per system) or with moderate sampling combined with minimization. Optimization improves energies significantly, particularly when steric clashes are present, and brings many orientations closer to the experimentally observed position. Whether or not minimization is performed, however, sampling must be sufficient to find at least one structure in the vicinity of the presumed true binding mode. Hybrid approaches combining docking and minimization are promising and will become more viable with the use of faster algorithms and the judicious selection of fewer orientations for minimization.

Calculating three-dimensional molecular structure from atom-atom distance information: cyclosporin A.

In recent years methods for deriving spatial molecular structure from atom-atom distance information have gained in importance due to the emergence of two-dimensional nuclear magnetic resonance (n.m.r) techniques, which make it possible to obtain such distance information for polypeptides, small proteins, sugars, and DNA fragments in solution. Distance geometry (DG) and restrained molecular dynamics (MD) refinement are applied to a cyclic polypeptide, the immunosuppressive drug cyclosporin A, and the results are compared. Two different procedures, DG followed by restrained MD, and straightforward restrained MD starting from the X-ray structure, both lead to a unique conformation that satisfies the 58 experimentally determined distance constraints. The results nicely show the relative merits of DG and restrained MD techniques for determining spatial molecular structure from distance information.