Summary This review examined the efficacy of cognitive behavior therapy for insomnia (CBT-I) in people diagnosed with cancer. Studies were identified through November 2014 using multiple databases, ...clinical trial records, and bibliography searches. Inclusion was limited to randomized controlled trials of CBT-I conducted in individuals with a cancer diagnosis who had clinically relevant insomnia. The primary outcome variable was sleep efficiency (SE) as measured by sleep diary. Eight studies including data from 752 cancer survivors met inclusion criteria. CBT-I resulted in a 15.5% improvement in SE relative to control conditions (6.1%) from pre- to post-intervention, with a medium effect size (ES: d = 0.53). Overall, sleep latency was reduced by 22 min with an ES of d = 0.43, compared to a reduction of 8 min in the control conditions. Wake after sleep onset was reduced by 30 min with an ES of d = 0.41, compared to 13 min in the control conditions. Large effect sizes were observed for self-reported insomnia severity ( d = 0.77) for those patients who received CBT-I, representing a clinically relevant eight point reduction. Effects were durable up to 6 mo. The quality of the evidence supports a strong recommendation for the use of CBT-I among cancer survivors.
Liver‐derived small extracellular vesicles (sEVs), prepared from small sets of banked serum samples using a novel two‐step protocol, were deployed as liquid biopsy to study the induction of ...cytochromes P450 (CYP3A4, CYP3A5, and CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (nonpregnant (T0), first, second, and third (T3) trimester women; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold‐increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg × 7 days (3.5, 95% CI = 2.5–4.5, N = 4, P = 0.029) and 600 mg × 14 days (3.7, 95% CI = 2.1–6.0, N = 5, P = 0.018) consistent with the mean oral midazolam area under the plasma concentration time curve (AUC) ratio in the same subjects (0.28, 95% CI = 0.22–0.34, P < 0.0001; and 0.17, 95% CI = 0.13–0.22, P < 0.0001). Compared with CYP3A4, liver sEV CYP3A5 protein (subjects genotyped CYP3A5*1/*3) was weakly induced (≤ 1.5‐fold). It was also possible to measure liver sEV‐catalyzed dextromethorphan (DEX) O‐demethylation to dextrorphan (DXO), correlated with sEV CYP2D6 expression (r = 0.917, P = 0.0001; N = 10) and 3‐hour plasma DXO‐to‐DEX concentration ratio (r = 0.843, P = 0.002, N = 10), and show that CYP2D6 was not induced by RIF. Nonparametric analysis of liver sEV revealed significantly higher CYP3A4 (3.2‐fold, P = 0.003) and CYP2D6 (3.7‐fold, P = 0.03) protein expression in T3 vs. T0 women. In contrast, expression of both OATPs in liver sEV was unaltered by RIF administration and pregnancy.
To address the most appropriate endogenous biomarker for drug–drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor ...(rifampicin, 150, 300, and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin, and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate‐3‐glucuronide, glycochenodeoxycholate‐3‐sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose‐dependent change in area under the plasma concentration‐time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC0‐24h between the endogenous compounds and the probe drugs, and by nonlinear regression analysis (AUCR−1 vs. rifampicin plasma Cmax (maximum total concentration in plasma)) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B‐mediated drug–drug interaction risk assessment approaches based on agency guidelines in early clinical trials.
The role of coastal nutrient sources in the persistence of Karenia brevis red tides in coastal waters of Florida is a contentious issue that warrants investigation into the regulation of nutrient ...responses in this dinoflagellate. In other phytoplankton studied, nutrient status is reflected by the expression levels of N- and P-responsive gene transcripts. In dinoflagellates, however, many processes are regulated post-transcriptionally. All nuclear encoded gene transcripts studied to date possess a 5' trans-spliced leader (SL) sequence suggestive, based on the trypanosome model, of post-transcriptional regulation. The current study therefore sought to determine if the transcriptome of K. brevis is responsive to nitrogen and phosphorus and is informative of nutrient status.
Microarray analysis of N-depleted K. brevis cultures revealed an increase in the expression of transcripts involved in N-assimilation (nitrate and ammonium transporters, glutamine synthetases) relative to nutrient replete cells. In contrast, a transcriptional signal of P-starvation was not apparent despite evidence of P-starvation based on their rapid growth response to P-addition. To study transcriptome responses to nutrient addition, the limiting nutrient was added to depleted cells and changes in global gene expression were assessed over the first 48 hours following nutrient addition. Both N- and P-addition resulted in significant changes in approximately 4% of genes on the microarray, using a significance cutoff of 1.7-fold and p ≤ 10-4. By far, the earliest responding genes were dominated in both nutrient treatments by pentatricopeptide repeat (PPR) proteins, which increased in expression up to 3-fold by 1 h following nutrient addition. PPR proteins are nuclear encoded proteins involved in chloroplast and mitochondria RNA processing. Correspondingly, other functions enriched in response to both nutrients were photosystem and ribosomal genes.
Microarray analysis provided transcriptomic evidence for N- but not P-limitation in K. brevis. Transcriptomic responses to the addition of either N or P suggest a concerted program leading to the reactivation of chloroplast functions. Even the earliest responding PPR protein transcripts possess a 5' SL sequence that suggests post-transcriptional control. Given the current state of knowledge of dinoflagellate gene regulation, it is currently unclear how these rapid changes in such transcript levels are achieved.
Individuals with cancer are disproportionately affected by sleep disturbance and insomnia relative to the general population. These problems can be a consequence of the psychological, behavioral, and ...physical effects of a cancer diagnosis and treatment. Insomnia often persists for years and, when combined with already high levels of cancer-related distress, may place cancer survivors at a higher risk of future physical and mental health problems and poorer quality of life. The recommended first-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBT-I), a non-pharmacological treatment that incorporates cognitive and behavior-change techniques and targets dysfunctional attitudes, beliefs, and habits involving sleep. This article presents a comprehensive review of the literature examining the efficacy of CBT-I on sleep and psychological outcomes in cancer patients and survivors. The search revealed 12 studies (four uncontrolled, eight controlled) that evaluated the effects of CBT-I in cancer patients or survivors. Results suggest that CBT-I is associated with statistically and clinically significant improvements in subjective sleep outcomes in patients with cancer. CBT-I may also improve mood, fatigue, and overall quality of life, and can be successfully delivered through a variety of treatment modalities, making it possible to reach a broader range of patients who may not have access to more traditional programs. Future research in this area should focus on the translation of evidence into clinical practice in order to increase awareness and access to effective insomnia treatment in cancer care.
Endogenous biomarkers are emerging to advance clinical drug‐drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) ...inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2‐K‐mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2‐K. In addition to the previously reported endogenous biomarker candidates (creatinine and N1‐methylnicotinamide (1‐NMN)), N1‐methyladenosine (m1A) was included as novel biomarkers. 1‐NMN and m1A presented as superior MATE1/2‐K biomarkers since changes in their renal clearance (CLr) along with pyrimethamine dose were well‐correlated with metformin CLr changes. The CLr of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CLr changes. Nonlinear regression analysis (CLr vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (Ki) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo Ki value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro Ki for MATE1 (1‐NMN) and MATE2‐K (1‐NMN and m1A). It is concluded that 1‐NMN and m1A CLr can be leveraged as quantitative MATE1/2‐K biomarkers for DDI risk assessment in healthy volunteers.
Purpose
Cancer-related fatigue (CRF) is a common and distressing symptom that can persist after cancer treatment has concluded. Bright light therapy has shown preliminary efficacy in reducing CRF, ...but its impact on other psychosocial factors is unclear. The purpose was to examine the impact of a 1-month light therapy intervention on fatigue, mood, and quality of life in cancer survivors with fatigue.
Methods
This 4-week blinded randomized controlled trial recruited cancer survivors who met diagnostic criteria for CRF. Participants were randomly assigned to receive a light therapy device that produced either bright white light (BWL; intervention) or dim red light (DRL; active control). Participants were instructed to use the device daily for 30 min upon waking for 28 days. The primary outcome, fatigue, was assessed weekly. Secondary outcomes assessed pre- and post-intervention included mood, depressive symptoms, and quality of life.
Results
A total of 81 participants were randomly assigned to receive BWL (
n
= 42) or DRL (
n
= 39). Analyses revealed a group-by-time interaction for fatigue (
p
= .034), wherein the BWL condition reported a 17% greater reduction in fatigue than those in the DRL condition (between group
d
= .30). There were also significant improvements over time for both groups on measures of mood, depressive symptoms, and quality of life (
p
’s < .01).
Conclusions
BWL was associated with greater improvements in fatigue and both groups displayed improvements on secondary psychosocial outcomes.
Implications for cancer survivors
These findings, along with previous reports of light therapy for CRF, support the use of this intervention to improve fatigue in cancer survivors.
Mass spectrometry-based stable isotope labeling provides the advantages of multiplexing capability and accurate quantification but requires tailored bioinformatics tools for data analysis. Despite ...the rapid advancements in analytical methodology, it is often challenging to analyze stable isotope labeling-based metabolomics data, particularly for isobaric labeling using MS/MS reporter ions for quantification. We report Metandem, a novel online software tool for isobaric labeling-based metabolomics, freely available at http://metandem.com/web/. Metandem provides a comprehensive data analysis pipeline integrating feature extraction, metabolite quantification, metabolite identification, batch processing of multiple data files, online parameter optimization for custom datasets, data normalization, and statistical analysis. Systematic evaluation of the Metandem tool was demonstrated on UPLC-MS/MS, nanoLC-MS/MS, CE-MS/MS and MALDI-MS platforms, via duplex, 4-plex, 10-plex, and 12-plex isobaric labeling experiments and the application to various biological samples.
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•A novel online software tool, Metandem, was developed for isobaric labeling-based metabolomics.•Metandem provides highly accurate metabolite quantification on the MS/MS level.•Online parameter optimization, identification, and statistics can be conducted simultaneously.•Metandem was evaluated by various MS platforms and multiplex isobaric labeling experiments.
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