Novel antibody-antibiotic conjugate using KRM-1657 as payload eliminates intracellular MRSA in vitro and in vivo.

Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S.aureus within host cells may cause long-term colonization and clinical failure. Current treatments have poor efficacy in clearing intracellular bacteria. Antibody-antibiotic conjugates (AACs) is a novel strategy for eliminating intracellular bacteria. Herein, we use KRM-1657 as payload of AAC for the first time, and we conjugate it with anti S. aureus antibody via a dipeptide linker (Valine-Alanine) to obtain a novel AAC (ASAK-22). The ASAK-22 exhibits good in vitro pharmacokinetic properties and inhibitory activity against intracellular MRSA, with 100 µg/mL of ASAK-22 capable of eliminating intracellular MRSA to the detection limit. Furthermore, the in vivo results demonstrate that a single administration of ASAK-22 significantly reduces the bacterial burden in the bacteremia model, which is superior to the vancomycin treatment.

Azobenzene-Based Linker Strategy for Selective Activation of Antibody-Drug Conjugates.

Existing antibody-drug conjugate (ADC) linkers, whether cleavable or non-cleavable, are designed to release highly toxic payloads or payload derivatives upon internalisation of the ADCs into cells. However, clinical studies have shown that only <1 % of the dosed ADCs accumulate in tumour cells. The remaining >99 % of ADCs are nonspecifically distributed in healthy tissue cells, thus inevitably leading to off-target toxicity. Herein, we describe an intelligent tumour-specific linker strategy to address these limitations. A tumour-specific linker is constructed by introducing a hypoxia-activated azobenzene group as a toxicity controller. We show that this azobenzene-based linker is non-cleavable in healthy tissues (O2 >10 %), and the corresponding payload derivative, cysteine-appended azobenzene-linker-monomethyl auristatin E (MMAE), can serve as a safe prodrug to mask the toxicity of MMAE (switched off). Upon exposure to the hypoxic tumour microenvironment (O2<1 %), this linker is cleaved to release MMAE and fully restores the high cytotoxicity of the ADC (switched on). Notably, the azobenzene linker-containing ADC exhibits satisfactory antitumour efficacy in vivo and a larger therapeutic window compared with ADCs containing traditional cleavable or non-cleavable linkers. Thus, our azobenzene-based linker sheds new light on the development of next-generation ADC linkers.

Design, synthesis and biological activity evaluation of a series of bardoxolone methyl prodrugs.

Bardoxolone methyl (CDDO-Me) has exhibited positive therapeutic effects in clinical trials for diabetic nephropathy (DN), but serious safety risks in the heart exist because of the potential off-target response resulting from the highly active part of CDDO-Me. Herein, we reported a novel strategy to prepare Cathepsin B (CTSB) cleavable and improved water-soluble prodrugs of CDDO-Me. CTSB linkers connection to the highly active α-cyano-α, ß-unsaturated ketone (CUK) part of CDDO-Me with the incorporation of polyethylene glycol (PEG) moieties, provided a series of prodrugs of CDDO-Me without CUK part exposure. Theoretically, these prodrugs shielding CUK part can be stably circulated and finally cleaved by CTSB in lysosomes to release CDDO-Me. In this paper, preliminary curative effects and safety of all prodrugs were determined. Wherein, prodrug 20 displayed relatively better activities than other prodrugs in inhibiting the release of NO from RAW264.7 cells, activating Keap1-Nrf2-ARE signaling pathway and inhibiting NF-κB signaling pathway, which were comparable to CDDO-Me. More importantly, prodrug 20 showed relatively lower human ether-a-go-go-related gene (hERG) inhibitory activity compared with CDDO-Me, which demonstrated prodrug 20 might be safer than CDDO-Me. In conclusion, the novel strategy of shielding CUK part with CTSB linkers provided a new idea for solving the limitations of CDDO-Me in clinical application.

Development of a nitroreductase-dependent theranostic payload for antibody-drug conjugate.

Antibody-drug conjugates are gradually revolutionizing anticancer therapy. Payload is one of the most crucial components of ADC for high antitumor activity. However, there is no direct and real-time monitoring method for the intracellular release mechanism of the payload. Herein, we developed a theranostic payload that possessed dual functions of therapy and imaging. This payload consisted of the classic payload MMAE and the novel nitro-coumarin probe reported for the first time, which has the dual characteristics of electron transfer ability and the on-off fluorescence property. In this paper, the theranostic property of the novel payload has been preliminarily demonstrated. The fluorescence intensity of the payload in target cells greatly increased approximately 9 times in 120 min through the high content analysis, and the intracellular distribution of the payload could be directly monitored by a confocal microscope. In in vitro cytotoxicity assays, the payload showed broad-spectrum and high antitumor activity (0.09 nM to 1.2 nM), which was equivalent to the MMAE (0.06 nM to 1.1 nM). Moreover, the ADC loaded with L-233 maintained the theranositc property. In conclusion, our work developed a theranostic payload for the first time and provides a new direct and real-time monitoring method for intracellular studies of ADC payloads.

Reductions in sleep quality and circadian activity rhythmicity predict longitudinal changes in objective and subjective cognitive functioning in women treated for breast cancer.

PURPOSE: To examine long-term cognitive effects of chemotherapy and identify predictors among women with breast cancer (WBC). PATIENTS AND METHODS: Sixty-nine WBC scheduled to receive chemotherapy, and 64 matched-controls with no cancer, participated. Objective and subjective cognition, total sleep time, nap time, circadian activity rhythms (CAR), sleep quality, fatigue, and depression were measured pre-chemotherapy (Baseline), end of cycle 4 (Cycle-4), and one-year post-chemotherapy (1-Year). RESULTS: WBC showed no change in objective cognitive measures from Baseline to Cycle-4 but significantly improved from both time points to 1-Year. Matched-controls showed an increase in test performance at all time points. WBC had significantly higher self-reported cognitive dysfunction at Cycle-4 and 1-Year compared to baseline and compared to matched-controls. Worse neuropsychological functioning was predicted by less robust CARs (i.e., inconsistent 24 h pattern), worse sleep quality, longer naps, and worse cognitive complaints. Worse subjective cognition was predicted by lower sleep quality and higher fatigue and depressed mood. CONCLUSION: Objective testing showed increases in performance scores from pre- and post-chemotherapy to one year later in WBC, but matched-controls showed an increase in test performance from baseline to Cycle-4 and from Cycle-4 to 1-Year, likely due to a practice effect. The fact that WBC showed no practice effects may reflect a form of learning deficit. Compared with the matched-controls, WBC reported significant worsened cognitive function. In WBC, worse objective and subjective cognitive functioning were predicted by worse sleep and sleep-related behaviors (naps and CAR). Interventions that target sleep, circadian rhythms, and fatigue may benefit cognitive function in WBC.

How formal caregiver's BPSD knowledge influences positive aspects of caregiving: the mediating role of attitude and the moderating role of self-efficacy.

BACKGROUND: The current study investigated the relationship between behavioural and psychological symptoms of dementia (BPSD) knowledge and positive aspects of caregiving (PAC), in addition, how caregiving attitude and self-efficacy mediate or moderate this relationship. METHODS: Two hundred twenty-nine formal caregivers (51males and 178females) who has worked in nursing homes for more than a month were recruited.With a cross-sectional, face-to-face survey, structural questionnaires were implemented to evaluate formal caregiver's BPSD knowledge, attitude, self-efficacy and PAC.A 13-item self-developed questionnaire was used to assess caregiver's BPSD knowledge about disease characteristics, care and risks, and treatment needs. Dementia attitude, self-efficacy and positive aspects of caregiving were measured by dementia attitude scale, the General self-efficacy scale, and Chinese version of positive aspects of caregiving respectively. Model 5 in the PROCESS micro was employed in order to verify the mediating effect of attitude and the moderating effect of self-efficacy on the relationship between BPSD knowledge and PAC. RESULTS: The results showed that greater BPSD knowledge was associated with increased PAC, and this relationship was fully mediated by increased friendly attitude toward people with dementia. Moreover, direct effect was moderated by self-efficacy, and that only among those with high self-efficacy, the direct effect of BPSD knowledge was found on promoting PAC. CONCLUSIONS: By elucidating the knowledge-attitude-practice pathway in handling patient's BPSD, the current study extends existing literature and provides insights for developing psychoeducation programs among formal caregivers.

Development of bifunctional anti-PD-L1 antibody MMAE conjugate with cytotoxicity and immunostimulation.

In recent years, tumor immunotherapy, especially the combination of PD1/PD-L1 inhibitors and chemotherapy, has developed rapidly. However, the systemic side effects induced by chemotherapy remain a crucial problem that needs to be addressed. Antibody drug conjugates (ADCs) are exceptional target-specific prodrugs that greatly improve the therapeutic window of chemotherapy drugs. Therefore, designing PD-L1-targeting ADCs is an interesting research project. In this study, we confirmed for the first time that the commercial anti-PD-L1 antibody Atezolizumab has better endocytosis efficiencies than Avelumab, and was more suitable for ADC design. Then, the most popular cytotoxic payload MMAE was conjugated to Atezolizumab via a classical dipeptide (valine-alanine) linker to generate a bifunctional PD-L1 ADC (ADC 3). An in vitro cytotoxicity test indicated the potent tumor cell inhibitory activity of ADC 3, with EC50 values of 9.75 nM to 11.94 nM. In addition, a co-culture of PBMCs in vitro proved that ADC 3 retained the immune activation effect of the Atezolizumab antibody. Moreover, ADC 3 exhibited a higher tumor inhibition rate and tumor regression rate in humanized immune system mice. To the best of our knowledge, this is the most active PD-L1-ADC reported thus far, which may promote the development of immunotherapy and novel ADCs.

Relationship between circadian activity rhythms and fatigue in hospitalized children with CNS cancers receiving high-dose chemotherapy.

PURPOSE: Robust circadian rhythms are increasingly recognized as essential to good health. Adult cancer patients with dysregulated circadian activity rhythms (CAR) experience greater fatigue, lower responsiveness to chemotherapy, and shorter time to relapse. There is scant research describing circadian rhythms and associated outcomes in children with cancer. As part of a larger study examining whether a cognitive-behavioral intervention could preserve sleep in children and adolescents with central nervous system cancers hospitalized for high-dose chemotherapy (HDCT), this study aimed to compare CAR of these children to published values and to investigate the relationship between CAR and fatigue. METHODS: Participants aged 4-19 years wore an actigraph throughout their hospitalization (5 days). From activity counts recorded by actigraphy, six CAR variables were calculated: amplitude, 24-h autocorrelation (r24), dichotomy index (I < O), interdaily stability (IS), intradaily variability (IV), and acrophase. Parent-reported child fatigue and child/adolescent self-reported fatigue measures were collected daily. RESULTS: Thirty-three participants were included. Three CAR variables (amplitude, r24, and I < O) showed dysregulation compared to published values. Older age was significantly associated with later acrophase and greater dysregulation of all other CAR variables. Controlling for age, more dysregulated amplitude (p = 0.001), r24 (p = 0.003), IS (p = 0.017), and IV (p = 0.001) were associated with higher parent-reported fatigue; more dysregulated IV (p = 0.003) was associated with higher child-reported fatigue. CONCLUSIONS: Participants demonstrated dysregulated CAR during hospitalization for HDCT. Greater dysregulation was associated with greater fatigue. Research on circadian dysregulation and its relationship to health-related outcomes in children with cancer, and interventions to support circadian rhythmicity, is urgently needed.

Design, Synthesis, and In Vitro Evaluation of the Photoactivatable Prodrug of the PARP Inhibitor Talazoparib.

In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug's expected activity was lost after PPG protection. In BRCA1- and BRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.

A pilot randomized controlled trial to improve sleep and fatigue in children with central nervous system tumors hospitalized for high-dose chemotherapy.

OBJECTIVES: To determine whether a sleep intervention compared with standard of care (SOC) was successful in preserving nighttime sleep in children with central nervous system cancers hospitalized for high-dose chemotherapy (HDCT) and autologous stem cell rescue, and to explore associations between sleep and fatigue during treatment. METHODS: An unblinded, randomized, controlled, multicomponent intervention (NCT00666614) including evidence-based cognitive and behavioral strategies to improve sleep was implemented in 33 children (age 4-12 years) and adolescents (age 13-19 years) during hospitalization. Children wore an actigraph to measure sleep and wake, and reported fatigue scores daily. Parents concurrently kept a sleep diary and reported fatigue scores for their children. RESULTS: The mean age was 9.5 ± 3.9 years, 81.8% were white, and 60.6% were male. Sleep in all children was seriously disturbed throughout the study. Children in the intervention group maintained their longest nighttime sleep across the study, while it declined in children receiving SOC (P = 0.009 for interaction). There were few other differences in sleep between groups. Controlling for age and baseline fatigue, higher nighttime activity score, and lower percent sleep were significantly associated with higher next-day adolescent-reported fatigue (P < 0.05); longest sleep was significantly positively associated with next-day child-reported fatigue (P = 0.018). CONCLUSION: In this sample of children undergoing HDCT, a multicomponent sleep intervention modestly preserved nighttime sleep duration, although overall sleep was poor in both groups. Sleep is an integral component of health, and may influence outcomes of children receiving HDCT. Further investigation into methods of preserving sleep in children undergoing intensive cancer therapy is warranted.

Cognition, quality-of-life, and symptom clusters in breast cancer: Using Bayesian networks to elucidate complex relationships.

OBJECTIVE: Breast cancer patients frequently complain of cognitive dysfunction during chemotherapy. Patients also report experiencing a cluster of sleep problems, fatigue, and depressive symptoms during chemotherapy. We aimed to understand the complex dynamic interrelationships of depression, fatigue, and sleep to ultimately elucidate their role in cognitive performance and quality of life amongst breast cancer survivors undergoing chemotherapy treatment. METHODS: Our study sample comprised 74 newly diagnosed stage I to III breast cancer patients scheduled to receive chemotherapy. An objective neuropsychological test battery and self-reported fatigue, mood, sleep quality, and quality of life were collected at 3 time points: before the start of chemotherapy (baseline: BL), at the end of cycle 4 chemotherapy (C4), and 1 year after the start of chemotherapy (Y1). We applied novel Bayesian network methods to investigate the role of sleep/fatigue/mood on cognition and quality of life prior to, during, and after chemotherapy. RESULTS: The fitted network exhibited strong direct and indirect links between symptoms, cognitive performance, and quality of life. The only symptom directly linked to cognitive performance was C4 sleep quality; at C4, fatigue was directly linked to sleep and thus indirectly influenced cognitive performance. Mood strongly influenced concurrent quality of life at C4 and Y1. Regression estimates indicated that worse sleep quality, fatigue, and mood were negatively associated with cognitive performance or quality of life. CONCLUSIONS: The Bayesian network identified local structure (eg, fatigue-mood-QoL or sleep-cognition) and possible intervention targets (eg, a sleep intervention to reduce cognitive complaints during chemotherapy).

Circadian dysfunction and fluctuations in gait initiation impairment in Parkinson's disease.

In people with Parkinson's disease (PD), anticipatory postural adjustments may be prolonged, reduced in amplitude, or absent, contributing to impaired gait initiation. In addition to motor symptoms, disturbance of the circadian rhythm (CR) is one of the common non-motor symptoms of PD. The purpose of this study was to investigate whether time of day modulates the magnitude of gait initiation impairment, and furthermore, if there is any relationship between CR dysfunction and impaired postural control in PD. Seven consecutive 24-h periods of wrist actigraphy (as a measure of CR), and then gait initiation studies (at two different times, 9:00 a.m. and 2:30 p.m., of the same day) were conducted in two cohorts of ten subjects each: people with PD, and age-matched control subjects. We found that in the PD group, the amplitude of medial/lateral center of pressure (CoP) excursions were significantly reduced in the afternoon as compared with the morning session across all trials (p < 0.05). Actigraphy results showed that CR amplitude was significantly decreased (p < 0.05) in the PD group, which suggests that the PD group suffered from CR disruption. More importantly, changes in medial/lateral CoP displacement were correlated with abnormal CR amplitude in the PD group. These findings provide novel evidence that diurnal fluctuations in treatment-resistant motor symptoms of PD, such as postural and gait initiation deficits, are associated with CR dysfunction. This study supports the idea that therapeutic correction of circadian misalignment should be considered in combination with pharmaceutical and rehabilitation treatments of motor symptoms in PD.

Smoking prevalence in urban and rural populations: findings from California between 2001 and 2012.

BACKGROUND: Tobacco smoking and related health problems are still major public health concerns in the United States despite the declining smoking prevalence. OBJECTIVES: This study explored differences in smoking prevalence between urban and rural areas potentially relevant to tobacco control efforts in California. METHODS: Public use adult smoking data from the California Health Interview Survey (CHIS) between 2001 and 2011-2012 were analyzed. A total of 282 931 adults were surveyed across the six CHIS cycles. A ZIP code-based geographic classification (Urban, Second-City, Suburban, and Town/Rural) was used to examine the association between smoking prevalence and area of residency. RESULTS: The overall smoking prevalence in California decreased from 17.0% in 2001 to 13.8% in 2011-2012. Within each CHIS cycle, the Town/Rural areas had the highest smoking prevalence, followed by Urban and Second-City areas, and Suburban areas had the lowest. Pooled data from all CHIS cycles showed a similar pattern, with rates in Urban, Second-City, Suburban and Town/Rural areas being 15.2%, 15.2%, 13.1% and 17.3%, respectively. Weighted multivariate logistic regression analysis indicated significantly higher odds of smoking in Urban, Second-City and Town/Rural areas compared to Suburban areas (all adjusted odds ratios > 1.10), although this trend varied by race/ethnicity, being present in non-Hispanic Whites and not present in Hispanics. CONCLUSIONS: Town/Rural and Urban populations of California are consistently at higher risk of smoking than Suburban populations. These results indicate a need for population-specific tobacco control approaches that address the lifestyle, behavior, and education of disparate populations within the same state or region.

Sleep, fatigue, depression, and circadian activity rhythms in women with breast cancer before and after treatment: a 1-year longitudinal study.

PURPOSE: Sleep disturbance, fatigue and depression are common complaints in patients with cancer, and often contribute to worse quality of life (QoL). Circadian activity rhythms (CARs) are often disrupted in cancer patients. These symptoms worsen during treatment, but less is known about their long-term trajectory. METHODS: Sixty-eight women with stage I-III breast cancer (BC) scheduled to receive ≥4 cycles of chemotherapy, and age-, ethnicity-, and education-matched normal, cancer-free controls (NC) participated. Sleep was measured with actigraphy (nocturnal total sleep time [nocturnal TST] and daytime total nap time [NAPTIME]) and with the Pittsburgh Sleep Quality Index (PSQI); fatigue with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF); depression with the Center of Epidemiological Studies-Depression (CES-D). CARs were derived from actigraphy. Several measures of QoL were administered. Data were collected at three time points: before (baseline), end of cycle 4 (cycle 4), and 1 year post-chemotherapy (1 year). RESULTS: Compared to NC, BC had longer NAPTIME, worse sleep quality, more fatigue, more depressive symptoms, more disrupted CARs, and worse QoL at baseline (all p values <0.05). At cycle 4, BC showed worse sleep, increased fatigue, more depressive symptoms, and more disrupted CARs compared to their own baseline levels and to NC (all p values <0.05). By 1 year, BC's fatigue, depressive symptoms, and QoL returned to baseline levels but were still worse than those of NC, while NAPTIME and CARs did not differ from NC's. CONCLUSION: Additional research is needed to determine if beginning treatment of these symptoms before the start of chemotherapy will minimize symptom severity over time.

Efficacy and safety of Xiaoyao Pill combined with Western medicine in the treatment of schizophrenia: A Meta-analysis and Systematic review.

BACKGROUND: The efficacy and safety of Xiaoyao Pill combined with Western medicine in the treatment of schizophrenia are still inconclusive. This meta-analysis summarized relevant studies to compare the efficacy and safety of Xiaoyao Pill combined with Western medicine and Western medicine alone in the treatment of schizophrenia, aiming to provide guidance for clinical treatment. METHODS: In this meta-analysis, we searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, CQVIP, and CBM databases from the establishment of the databases to August 2023. The study proposed to include studies that reported combination of Xiaoyao Pill with Western medicine and Western medicine alone in the treatment of schizophrenia, excluding published literature, unpublished literature, literature with incomplete or inadequate information, animal experiments, literature reviews and systematic studies. Data were analyzed using Review manager 5.3. RESULTS: About 9 studies (6 RCTs and 3 case-control studies) were included in this meta-analysis. The sample size ranged from 60 to 128, with a total of 779 patients, including 395 in the combined treatment group and 384 in the control group. Pooled results showed that the total effective rate of combined treatment group was significantly higher than that of Western medicine alone (OR = 4.21, 95% CI: 1.50-11.83, P = .006). Positive and Negative Syndrome Scale (PANSS) (-) (MD = -2.30, 95% CI: -3.72 ~ -0.89, P = .001) and PANSS (+) (MD = -2.60, 95% CI: -3.34 ~ -1.86, P < .00001) of combined treatment group were all significantly lower than that of Western medicine alone. Additionally, PRL levels of combined treatment group was significantly lower than that of Western medicine alone (MD = -28.78, 95% CI: -42.20 ~ -15.35, P < .0001). However, there was no significant difference in BPRS and total PANSS between combined treatment group and Western medicine alone group. Notably, pooled results showed that there was no significant difference in incidence of adverse events between combined treatment group and Western medicine alone group. CONCLUSION: The effective rate of Xiaoyao Pill combined with Western medicine in the treatment of schizophrenia is higher than that of Western medicine alone, which can effectively relieve the positive and negative symptoms of schizophrenia, and can significantly reduce the level of PRL. In the treatment of schizophrenia, clinicians can give priority to Xiaoyao Pill combined with Western medicine therapy.

Prevention of quality-of-life deterioration with light therapy is associated with changes in fatigue in women with breast cancer undergoing chemotherapy.

PURPOSE: During chemotherapy, women with breast cancer not only experience poor quality of life (QOL), they also have little exposure to bright light, which has been shown to be associated with depression, fatigue, and poor sleep in other chronic illnesses. This study examined whether increased light exposure would have a positive effect on QOL. METHODS: Thirty-nine women with stage I-III breast cancer scheduled to receive ≥ 4 cycles of chemotherapy were randomized to a bright white light (BWL, n = 23) or dim red light (DRL, n = 16) treatment group. Data were collected before (baseline) and during cycles 1 and 4 of chemotherapy. Light was administered via a light box (Litebook(®), Ltd.). QOL was assessed with the Functional Assessment of Cancer Therapy-Breast (FACT-B) and the Functional Outcomes of Sleep Questionnaire (FOSQ). RESULTS: Compared with baseline, the DRL group demonstrated significant decline in QOL during the treatment weeks of both cycles (all ps < 0.02), whereas the BWL group had no significant decline (all ps > 0.05). Mixed model analyses revealed that there was a group-by-time interaction for FOSQ at the treatment week of cycle 4, and this interaction was mediated by fatigue. CONCLUSION: The data suggest that increased exposure to bright light during chemotherapy may prevent the decline in QOL via preventing the increase in fatigue.

Decreased health-related quality of life in women with breast cancer is associated with poor sleep.

This study examined the longitudinal relation between health-related quality of life (HR-QOL) and subjective and objective sleep quality in 166 women with newly diagnosed Stage-1 through Stage-3 breast cancer, who were scheduled to receive ≥ 4 cycles of adjuvant/neoadjuvant chemotherapy. HR-QOL was assessed with the Medical Outcomes Study 36-item Short Form, Physical Component Scale (PCS), and Mental Component Scale (MCS) scores; subjective sleep was assessed with the Pittsburgh Sleep Quality Index; and objective sleep was measured with actigraphy. Data were collected before starting chemotherapy and during the last week of Cycle 4 of chemotherapy. Patients reported poor HR-QOL and poor sleep quality before and during chemotherapy. Short sleep time and long naps were recorded at both time points. The MCS score was related to reports of poor sleep, but not to recorded sleep; worse PCS scores were associated with reports of poor sleep and less recorded naptime, suggesting sleep plays an important role in cancer patients' HR-QOL.

Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy.

Fatigue and sleep disturbances are two of the most common and distressing symptoms reported by cancer patients. Fatigue and sleep are also correlated with each other. While fatigue has been reported to be associated with some inflammatory markers, data about the relationship between cancer-related sleep disturbances and inflammatory markers are limited. This study examined the relationship between fatigue and sleep, measured both subjectively and objectively, and inflammatory markers in a sample of breast cancer patients before and during chemotherapy. Fifty-three women with newly diagnosed stage I-III breast cancer scheduled to receive at least four 3-week cycles of chemotherapy participated in this longitudinal study. Fatigue was assessed with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and objective sleep was measured with actigraphy. Three inflammatory markers were examined: Interleukin-6 (IL-6), Interleukin-1 receptor antagonist (IL-1RA) and C-reactive protein (CRP). Data were collected before (baseline) and during cycle 1 and cycle 4 of chemotherapy. Compared to baseline, more fatigue was reported, levels of IL-6 increased and IL-1RA decreased during chemotherapy. Reports of sleep quality remained poor. Mixed model analyses examining changes from baseline to each treatment time point revealed overall positive relationships between changes in total MFSI-SF scores and IL-6, between changes in total PSQI scores and IL-6 and IL-1RA, and between total wake time at night and CRP (all p's<0.05). These relationships suggest that cancer-related fatigue and sleep disturbances may share common underlying biochemical mechanisms.

Light treatment prevents fatigue in women undergoing chemotherapy for breast cancer.

PURPOSE: Fatigue is one of the most disturbing complaints of cancer patients and is often the reason for discontinuing treatment. This randomized controlled study tested the hypothesis that increased morning bright light, compared to dim light, would result in less fatigue in women with breast cancer undergoing chemotherapy. METHODS: Thirty-nine women newly diagnosed with stage I-III breast cancer were randomized to either bright white light (BWL) or dim red light (DRL) treatment and were instructed to use the light box for 30 min every morning throughout the first four cycles of chemotherapy. The Multidimensional Fatigue Symptom Inventory was administered prior to the start of chemotherapy (baseline), during the chemotherapy treatment week of cycle 1 (C1TW), the last week (recovery week) of cycle 1 (C1RW), the chemotherapy treatment week of cycle 4 (C4TW), and the last week (recovery week) of cycle 4 (C4RW). RESULTS: The DRL group reported increased fatigue at C1TW (p = 0.003) and C4TW (p < 0.001) compared to baseline, while there was no significant change from baseline in the BWL group. A secondary analysis showed that the increases in fatigue levels in the DRL group were not mediated through nor associated with changes in sleep or in circadian rhythms as measured with wrist actigraphy. CONCLUSIONS: The results of this study suggest that morning bright light treatment may prevent overall fatigue from worsening during chemotherapy. Although our hypothesis that overall fatigue would improve with bright light treatment was not supported, the lack of deterioration in total fatigue scores suggests that bright morning light may be a useful intervention during chemotherapy for breast cancer.

Bright light therapy protects women from circadian rhythm desynchronization during chemotherapy for breast cancer.

Circadian rhythms (CRs) are commonly disrupted in women undergoing chemotherapy for breast cancer (BC). Bright light improves and strengthens CRs in other populations. This randomized controlled study examined the effect of morning administration of bright light therapy on CRs in women undergoing chemotherapy for BC. It was hypothesized that women receiving bright light therapy would exhibit more robust rhythms than women exposed to dim light. Thirty-nine women newly diagnosed with BC and scheduled for chemotherapy were randomized into 2 groups: bright white light (BWL) or dim red light (DRL). Women were instructed to use the light box every morning for 30 min during their first 4 cycles of chemotherapy. Wrist actigraphy was recorded at 5 time points: prior to chemotherapy (baseline), Cycle-1 treatment week (C1TW), Cycle-1 recovery week (C1RW), Cycle-4 treatment week (C4TW), and Cycle-4 recovery week (C4RW). There was a Group × Time interaction at C4TW compared to baseline such that the DRL group showed significant deterioration in the mean of the activity rhythm (mesor) and amplitude, whereas the BWL group exhibited a significant increase in both mesor and amplitude. The DRL group also exhibited significant deterioration in overall rhythm robustness at C1TW, C4TW, and C4RW. Women in the BWL group also showed significant decreases in overall rhythm robustness at C1TW and C4TW, but returned to baseline levels at both recovery weeks. The results suggest that morning administration of bright light may protect women from experiencing CR deterioration during chemotherapy.