Insomnia is two to three times more prevalent in cancer survivors than in the general population, where it is estimated to be 10% to 20%. Cognitive-behavioral therapy for insomnia (CBT-I) is the ...recommended treatment for chronic insomnia, but meeting survivor needs remains a challenge. Internet-delivered CBT-I (iCBT-I) has been shown efficacious in otherwise healthy adults. We tested the efficacy of iCBT-I in breast cancer survivors with clinically significant sleep disturbance.
Women from a national sample of Danish breast cancer survivors who experienced clinically significant sleep disturbance were randomly allocated to iCBT-I or waitlist control (55:45). The fully automated iCBT-I program consisted of six cores. Online measures of insomnia severity, sleep quality, and fatigue were collected at baseline, postintervention (nine weeks), and follow-up (15 weeks). Online sleep diaries were completed over two-week periods pre- and postintervention. Intention-to-treat analyses (time × group interactions) were conducted with mixed linear models and corrected for multiple outcomes. All statistical tests were two-sided.
A total of 255 women were randomly allocated to iCBT-I (n = 133) or waitlist control (n = 122). Statistically significant (P ≤ .02) time × group interactions were found for all sleep-related outcomes from pre- to postintervention. Effect sizes (Cohen's d) ranged from 0.33 (95% confidence interval CI = 0.06 to 0.61) for wake after sleep onset to 1.17 (95% CI = 0.87 to 1.47) for insomnia severity. Improvements were maintained for outcomes measured at follow-up (d = 0.66-1.10).
iCBT-I appears to be effective in breast cancer survivors, with additional benefit in terms of reduced fatigue. This low-cost treatment could be incorporated in cancer rehabilitation programs.
The microarray technique is an important tool in gene expression analysis to study the activities of thousands of genes measured by their transcript levels under disease or laboratory controlled ...experimental conditions. Recent studies have suggested a genetic component in the variations of gene expression thus indicating the important role of genetic control over gene activities. In this study, we analyze and report the twin correlation on gene expression in whole blood samples of six female Danish twin pairs aged from 81 to 85 years. We studied the expression phenotype by treating the measured gene expression as a quantitative trait and introducing analytical approaches including the traditional twin methods in population genetics and the multivariate statistical methods. Using this combinatory approach, we were able to estimate and compare the twin correlation on the expression phenotype while accounting for systematic influence in microarray experiments. Analyses on our twin data detected a significant correlation on the expression levels of the actively regulated genes in both monozygotic and dizygotic twins, which is more pronounced in monozygotic twins. Gene ontology analysis has shown that these actively regulated genes are predominantly involved in defense and immune responses against antigenic stimulus. In conclusion, the correlation patterns revealed in our twin data provide evidence of the existence of a heritable mechanism in gene expression regulation persistently functioning even in aged subjects.
Laboratory assays are needed for early stage non-small lung cancer (NSCLC) that can link molecular and clinical heterogeneity to predict relapse after surgical resection. We technically validated two ...miRNA assays for prediction of relapse in NSCLC. Total RNA from seventy-five formalin-fixed and paraffin-embedded (FFPE) specimens was extracted, labeled and hybridized to Affymetrix miRNA arrays using different RNA input amounts, ATP-mix dilutions, array lots and RNA extraction- and labeling methods in a total of 166 hybridizations. Two combinations of RNA extraction- and labeling methods (assays I and II) were applied to a cohort of 68 early stage NSCLC patients.
RNA input amount and RNA extraction- and labeling methods affected signal intensity and the number of detected probes and probe sets, and caused large variation, whereas different ATP-mix dilutions and array lots did not. Leave-one-out accuracies for prediction of relapse were 63% and 73% for the two assays. Prognosticator calls ("no recurrence" or "recurrence") were consistent, independent on RNA amount, ATP-mix dilution, array lots and RNA extraction method. The calls were not robust to changes in labeling method.
In this study, we demonstrate that some analytical conditions such as RNA extraction- and labeling methods are important for the variation in assay performance whereas others are not. Thus, careful optimization that address all analytical steps and variables can improve the accuracy of prediction and facilitate the introduction of microRNA arrays in the clinic for prediction of relapse in stage I non-small cell lung cancer (NSCLC).
Sleep disturbances are common in women treated for breast cancer. We have previously shown that internet-delivered cognitive-behavioral therapy for insomnia (e-CBT-I) is an efficacious, low-cost ...treatment approach. Furthermore, research has shown that e-CBT-I can result in sustained improvements at 12 months post-treatment. However, given the complexity and long duration of post-treatment symptomatology in breast cancer patients, as well as the recommended use of antihormonal therapy for up to 10 years, it is relevant to investigate long-term (>12 months) changes in sleep following e-CBT-I in this population. In the present study, we report data from a 3-year long-term follow-up assessment after e-CBT-I.
Women treated for breast cancer with sleep disturbances (Pittsburg Sleep Quality Index PSQI global score >5) who had previously been enrolled in a randomized-controlled trial investigating the efficacy of e-CBT-I (n = 255), were invited to participate in a 3-year follow-up study. All women in the initial control group had also been granted access to e-CBT-I. Assessment included self-reported sleep quality (PSQI), insomnia severity (Insomnia Severity Index, ISI), cancer-related fatigue and symptoms of depression. Within-group changes in these outcomes from baseline to the 3-year long-term follow-up assessment were analyzed.
A total of 131 women (51%) participated in the 3-year follow-up study of which 77 (59%) were from the initial intervention group and 54 (41%) from the initial control group. For the pooled sample, within-group improvements from baseline to the 3-year follow-up assessment corresponding to large effect sizes were observed in sleep quality (Cohen's d = 1.0 95% CI 0.78, 1.21) and insomnia severity (Cohen's d = 1.36 CI 95% 1.12, 1.59). Similar changes were observed in cancer-related fatigue (Cohen's d = 0.48 CI 95% 0.30, 0.66) and symptoms of depression (Cohen's d = 0.80 CI 95%. 0.60, 0.99). The proportion of patients with scores above established cut-offs on the PSQI and the ISI were 56.1% and 29.8%, respectively. Within the initial intervention group, 15.6% evidenced relapse at the 3-year assessment.
Overall, these results indicate that long-term sleep quality and insomnia severity following the use of e-CBT-in women treated for breast cancer is significantly lower than the pre-treatment levels. However, a substantial proportion of participants still evidence sleep disturbances.
•Three years after internet-based CBT-I, sleep quality and insomnia severity were significantly lower than pre-treatment levels.•Women on hormone therapy evidenced smaller improvements compared to those who did not.•A substantial proportion of women continued to evidence sleep disturbances at the long-term follow-up assessment.
TNF-related apoptosis inducing ligand (TRAIL) is a promising anticancer agent because of its ability to selectively induce apoptosis in cancer cells but not in most normal cells. However, some cancer ...cells are resistant to TRAIL cytotoxicity thereby limiting its therapeutic efficacy. Using genome-wide mRNA expression profiles from the NCI60 panel and their differential sensitivities to TRAIL-induced apoptosis, we have identified 71 genes whose expression levels are systemically higher in TRAIL-sensitive cell lines than resistant lines. The elevated expression of the 71 genes was able to accurately predict TRAIL sensitivity in the NCI60 training set and two test sets consisting of a total of 95 human cancer cell lines. Interestingly, the 71-gene signature is dominated by two functionally related gene families-interferon (IFN)-induced genes and the MHC genes. Consistent with this result, treatment with IFN-γ augmented TRAIL-induced apoptosis. The 71-gene signature could be evaluated clinically for predicting tumor response to TRAIL-related therapies.
Highland populations of several Drosophila species in Argentina were active early in the afternoon in the field as opposed to populations from a much warmer lowland site, where flies were mainly ...active in the early evening prior to sunset. For one of these species, Drosophila buzzatii, we tested for a genetic component of activity differences by carrying out crosses within and between populations and measuring oviposition activity of the progeny in the laboratory. We found that activity in the highland population exceeded that in the lowland one during the midafternoon, whereas activity in the lowland population exceeded that in the highland one prior to the beginning of the dark period. Oviposition activity for the period corresponding to the field observations was regressed on the proportion of the genome derived from the highland population. This variable significantly predicted oviposition activity between 1400 and 1600 and between 2000 and 2200 h. Activity of both reciprocal crosses was intermediate and not significantly different from each other, suggesting that nuclear genetic, rather than cytoplasmic factors contribute to differences in oviposition activity between the populations. Two morphological, one genetic, and one stress resistance trait were also scored to examine whether temperature differences between environments were associated with other differences between populations. Wing length of wild‐caught and laboratory‐reared flies from the highland population significantly exceeded that in the lowland. Thorax length of laboratory‐reared flies from the highland population also significantly exceeded that from the lowland. Chromosomal inversion frequencies differed significantly between the two populations with a fivefold reduction in the frequency of arrangement 2st in the highland as compared to the lowland population. This arrangement is known for its negative dose effect on size, and thus, the highland population has experienced a genetic change, perhaps as a result of adaptation to the colder environment, where body size and the frequency of arrangement 2st have changed in concert. Finally, a heat knockdown test revealed that the lowland population was significantly more resistant to high temperature than the highland one. In conclusion, we suggest that temperature has been an important selective agent causing adaptive differentiation between these two populations. We also suggest that the activity rhythms of the two populations have diverged as a consequence of behavioral evolution, that is, through avoidance of stressful temperatures as a mean of thermal adaptation.
MicroRNAs (miRNA) are a group of short noncoding RNAs that regulate gene expression at the posttranscriptional level. It has been shown that microRNAs are independent predictors of outcome in ...patients with diffuse large B-cell lymphoma (DLBCL) treated with the drug combination R-CHOP. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of doxorubicine, cyclophosphamide, vincristine and etoposide as well as the baseline microRNA expression of the 60 cell lines, a microRNA based response predictor to CHOP was developed. The response predictor consisting of 20 microRNAs was blindly validated in a cohort of 116 de novo DLBCL patients treated with R-CHOP or R-CHOEP as first line treatment. The predicted sensitivity based on diagnostic FFPE samples matched the clinical response, with decreasing sensitivity in poor responders (P = 0.03). When the International Prognostic Index (IPI) was included in the prediction analysis, the separation between responders and non-responders improved (P = 0.001). Thirteen patients developed relapse, and five patients predicted sensitive to their second and third line treatment survived a median 1194 days, while eight patients predicted not sensitive to their second and third line treatment survived a median 187 days (90% CI: 485 days versus 227 days). Among the latter group it was predicted that four would have been sensitive to another second line treatment than the one they received. The predictions were almost the same when diagnostic biopsies were used as when relapse biopsies were used. These preliminary findings warrant testing in a larger cohort of relapse patients to confirm whether the miRNA based predictor can select the optimal second line treatment and increase survival.
In this review, we present clinical studies on mindfulness-based therapy (MBT) with a focus on mediating mechanisms for its health promoting effects. These constitute awareness, self-compassion, ...regulation of dysfunctional patterns of thoughts and emotions, neural network and cellular processes. Among cellular processes are inflammation, oxidative stress, mitochondrial dysfunction and telomere shortening, which all contribute to the molecular pathophysiology of several of today's lifestyle diseases. Finally, we address applications, where strong evidence exists for the clinical impact of MBT.
Highland populations of several Drosophila species in Argentina were active early in the afternoon in the field as opposed to populations from a much warmer lowland site, where flies were mainly ...active in the early evening prior to sunset. For one of these species, Drosophila buzzatii, we tested for a genetic component of activity differences by carrying out crosses within and between populations and measuring oviposition activity of the progeny in the laboratory. We found that activity in the highland population exceeded that in the lowland one during the midafternoon, whereas activity in the lowland population exceeded that in the highland one prior to the beginning of the dark period. Oviposition activity for the period corresponding to the field observations was regressed on the proportion of the genome derived from the highland population. This variable significantly predicted oviposition activity between 1400 and 1600 and between 2000 and 2200 h. Activity of both reciprocal crosses was intermediate and not significantly different from each other, suggesting that nuclear genetic, rather than cytoplasmic factors contribute to differences in oviposition activity between the populations. Two morphological, one genetic, and one stress resistance trait were also scored to examine whether temperature differences between environments were associated with other differences between populations. Wing length of wild-caught and laboratory-reared flies from the highland population significantly exceeded that in the lowland. Thorax length of laboratory-reared flies from the highland population also significantly exceeded that from the lowland. Chromosomal inversion frequencies differed significantly between the two populations with a fivefold reduction in the frequency of arrangement 2st in the highland as compared to the lowland population. This arrangement is known for its negative dose effect on size, and thus, the highland population has experienced a genetic change, perhaps as a result of adaptation to the colder environment, where body size and the frequency of arrangement 2st have changed in concert. Finally, a heat knockdown test revealed that the lowland population was significantly more resistant to high temperature than the highland one. In conclusion, we suggest that temperature has been an important selective agent causing adaptive differentiation between these two populations. We also suggest that the activity rhythms of the two populations have diverged as a consequence of behavioral evolution, that is, through avoidance of stressful temperatures as a mean of thermal adaptation. Corresponding Editor: L. Stevens
Multiple Myeloma (MM) is a lethal hematological malignancy with an incidence of 40–60 per 1.000.000 per year. Over the last decade, the most significant therapeutic improvement has been the ...introduction of high-dose Melphalan therapy in combination with autologous stem cell support. This strategy has led to an increase in survival from a median of approximately 3 years till now >6 years also in Denmark (unpublished data from Nordic Myeloma Study Group, NMSG #7/98). Despite this important increase in survival, substantial variability still persists among patients in response to high-dose Melphalan. Clinical and genetic heterogeneity is a characteristic feature of MM, and new methodological approaches, such as global gene expression profiling (GEP), are valuable tools in order to link clinical endpoints, such as response to treatment and survival, with the molecular and genetic heterogeneity of the disease (Shaughnessy, J. et al., Blood 98, 217–223, 2001). Here we present a bioinformatic analysis of the clinical impact of a novel chemo sensitivity index based on GEP of 1) a panel of sixty cell lines (NCI60) that subsequently have been exposed to a range of anti-cancer agents, including Melphalan, and, 2) a retrospective validation of our method from lung, brain and lymphoma patients. Figure 1, presents a retrospective leave-one-out cross-validation of the prediction whether a patient will respond to the treatment given. Lung- and brain cancer patients were treated with Cisplatin, and the predicted sensitivity or resistance to this drug was used to group patients (hazard ratio 2.9, 95% CI 0.7–11). Lymphoma patients were treated with Vincristine and Adriamycine, and the patients were grouped according to their predicted sensitivity or resistance to these drugs. Patient and raw DNA chip data were obtained from: Beer et al, Nature Medicine 8(8):816–824; Pomeroy et al, Nature 415(6870):436–442; Shipp et al, Nature Medicine 8(1):68–74. For each patient, the method may also allow for a quantitative prediction of drug sensitivity towards a range of drugs including Melphalan. Figure 2 shows the drug sensitivity profile for two selected Multiple Myeloma patients (patient #2 and #9 from Agnelli L et al. Haematologica. 2007 Jan; 92(1):56–65). We are currently collecting chip data from a cohort of 70 newly diagnosed biobanked bone marrow samples from MM patients treated with high-dose Melphalan in NMSG trial #9/99 in order to further confirm these results in MM. These data are subsequently being validated using an independent population of bone marrow samples from MM patients also treated with high-dose Melphalan. We demonstrate that GEP can provide new information concerning resistance towards Melphalan and a range of anti-cancer drugs, separately or in combination (multi drug regimen), which may be clinically useful, and serve as a guide for the future development of individualized treatment strategies.
Display omitted
PDF
