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.

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with Western medicine and Western medicine alone in the treatment of schizophrenia, excluding published literature, unpublished literature, literature with incomplete or inadequate information, animal experiments, literature reviews and systematic studies.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.

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.

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.

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.

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.

Cornuside ameliorates cognitive impairments in scopolamine induced AD mice: Involvement of neurotransmitter and oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis Sieb. et Zucc., traditional Chinese medicine, has been widely used in the treatment of dementia. Cornel iridoid glycosides of Cornus officinalis is therapeutic to Alzheimer's disease (AD), while its pharmacodynamic material basis is not clear. Cornuside, an iridoid glycoside extracted from of Cornus officinalis Sieb. et Zucc, might be a potential anti-AD candidate. AIM OF THE STUDY: Cornuside was evaluated for its effect on scopolamine induced AD mice, and its action mechanisms were explored. MATERIALS AND METHODS: ICR mice were administered with 1 mg/kg scopolamine intraperitoneally to induce amnesia. The therapeutic effect of cornuside of cognitive function was evaluated via series of behavioral tests, including Morris water maze test, step-through test and step-down test. In addition, specific enzyme reaction tests were used to detect the content of acetylcholine (ACh) and malondialdehyde (MDA), as well as the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), catalase (CAT), monoamine oxidase (MAO) in the brain. The levels of monoamine neurotransmitters were detected by high performance liquid chromatography-electrochemical detection (HPLC-ECD). RESULTS: Cornuside ameliorated the spatial memory impairment in Morris water maze test and cognitive disruption in step-through and step-down test. Furthermore, cornuside improved the level of ACh by reducing the activities of AChE and BuChE, and increasing the activity of ChAT in hippocampus. Cornuside also increased the levels of monoamine neurotransmitters by inhibiting MAO activity in hippocampus and cortex. In addition, cornuside attenuated MDA by enhancing the activities of SOD and CAT in hippocampus and cortex. CONCLUSION: Cornuside improved cognitive dysfunction induced by scopolamine in behavioral tests. The mechanisms of cornuside were further investigated from the aspects of neurotransmitters and oxidative stress. Cornuside could inhibit oxidative stress and neurotransmitter hydrolases, increase ACh and monoamine neurotransmitters, which finally contributed to its therapeutic effect on scopolamine induced amnesia.

Development of applicable thiol-linked antibody-drug conjugates with improved stability and therapeutic index.

Maleimides are typically applicable for coupling with reactive thiol moieties of antibodies in antibody-drug conjugates (ADCs) via the thiol-Michael click chemistry. Even so, the thiosuccinimide group produced in ADCs is unstable under physiological conditions, which is a unresolved issue in the ADC industry that can cause serious off-target toxicity. Committed to solving the stability defects of traditional thiosuccinimide-containing ADCs, we explored a series of linkers based on the ring-opening hydrolysates of thiosuccinimide. Meanwhile, a type of linkers based on maleamic methyl ester were used to conjugate the popular monomethyl auristatin E to an anti-HER2 antibody to generate the target ADCs, which enhances the stability and do not need to change the structure of the ideal stable metabolite of traditional ADCs. In vivo studies demonstrate that our preferred ADC mil40-12b not only has better efficacy than traditional ADCs but also exhibits better safety parameters in mice. For example, complete tumor regression can still be achieved even when the dose is halved (2.5 mg/kg), and the maximum tolerable dose is increased by 40 mg/kg. This strategy is expected to provide an applicable tool for the construction of thiol-linked ADCs with improved therapeutic index.

Preventing Sleep Disruption With Bright Light Therapy During Chemotherapy for Breast Cancer: A Phase II Randomized Controlled Trial.

Purpose: The goal of this study was to examine whether daily increased morning light exposure would maintain or improve sleep and the circadian pattern of relatively more activity in the day and less during the night in women undergoing chemotherapy for breast cancer. Patients and Methods: Participants were 39 women with newly diagnosed breast cancer, randomized to either 30-mins of daily morning bright white light (BWL) or dim red light (DRL). Sleep/wake was measured objectively for 72-h with wrist actigraphy and subjectively with the Pittsburgh Sleep Quality Index (PSQI) prior to and during chemotherapy cycles 1 and 4. The study was registered with the National Institutes of Health ClinicalTrials.gov (Clinical Trials number: NCT00478257). Results: Results from actigraphy suggested that compared to the DRL group, women in the BWL group had longer night-time sleep, fewer sleep disturbances during the night, and had fewer and shorter daytime naps at the end of cycle 4 of chemotherapy as well as exhibiting less activity at night and more activity during the day by the end of cycle 4. Results from PSQI indicated that components of sleep quality improved but daytime dysfunction deteriorated during cycle 4 treatment in the BWL group; meanwhile the DRL group used more sleep medications in the treatment weeks which might have led to the improved sleep quality during the recovery weeks of both cycles. Conclusion: These results suggest that bright white light therapy administered every morning on awakening may protect women undergoing chemotherapy for breast cancer from nighttime sleep and daytime wake disruption. Randomized clinical trials in larger samples are needed to confirm these findings.

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.

Synthesis and evaluation of highly releasable and structurally stable antibody-SN-38-conjugates.

Camptothecins, traditional chemotherapy drugs, have been clinically used in antibody-drug conjugates (ADCs), which refreshes the recognition that ADCs preferably incorporate highly potent payloads. However, SN-38, active metabolite of irinotecan from camptothecins, tended to be incorporated into ADCs with an unstable acid sensitive bond, not with the widely used Cathepsin B (CTSB) sensitive bond, which may pose the risk of off-target. Herein, we reported a novel strategy to construct highly releasable and structurally stable SN-38-conjugates, in which CTSB linkers directly connected to the 10-OH group through ether bond, not to the common 20-OH group of lactones of SN-38. In this paper, rapid release of SN-38 was skillfully demonstrated by utilizing the fluorescence properties of SN-38. The SN-38-ether-ADC displayed highly stable serum stability with the half-life over 10 days. Moreover, the drug-antibody-ratio (DAR) of ADC could be elevated to 7.1 through the introduction of polyethylene glycol (PEG) moieties without aggregation. The optimized ADC exhibited potent in vitro activities up to 5.5 nM, comparable to SN-38. Moreover, this ADC group significantly delayed tumor growth in vivo. In conclusion, the novel strategy has the potential to promote the development of SN38-ADCs and enrich the conjugation approaches for hydroxyl-bearing payloads.

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.

A bifunctional molecule-based strategy for the development of theranostic antibody-drug conjugate.

Antibody-drug conjugates (ADCs) are being developed worldwide with the potential to revolutionize current cancer treatment strategies. Developing novel theranostic ADCs with therapeutic utility and imaging capability is an attractive and challenging subject that promises advances in the field of personalized medicine. In this work, we propose a bifunctional molecule-based strategy for the development of theranostic ADCs. Methods: We developed a theranostic ADC consisting of the anti-Her2 antibody Mil40, monomethyl auristatin E (MMAE) as the active payload, and a 7-amino-3-hydroxyethyl-coumarin (7-AHC)-based dipeptide linker, which functions as a novel bifunctional fluorescence probe that allows self-elimination cleavage in the presence of cathepsin B for payload release and fluorophore activation. The on-off fluorescence properties and the antitumor effect in vitro and in vivo were investigated. Results: A 48-fold fluorescence enhancement was observed within 1 h when the 7-AHC-based linker was exposed to cathepsin B. Cleavage upon exposure to cathepsin B allows MMAE and fluorophore intracellular release and the monitoring of MMAE distribution using confocal microscopy. Additionally, the newly developed ADC retains the advantages of traditional p-aminobenzyloxycarbonyl-containing ADCs, such as good stability (t1/2 > 7 days) and high activity in vitro (IC50 = 0.09-3.74 nM). Importantly, the theranostic ADC exhibited the equivalent antitumor efficacy to the marketed ADC T-DM1 in the classic breast cancer model. Conclusion: We suggest that the present strategy can be universally applied in all p-aminobenzyloxycarbonyl-containing ADCs. Overall, theranostic ADCs may play a role in developing new theranostic systems and promoting personalized medicine research.

Antibody-drug conjugates: Recent advances in linker chemistry.

Antibody-drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The present review summarizes the advance of the chemical trigger, linker‒antibody attachment and linker‒payload attachment over the last 5 years, and describes the ADMET properties of ADCs. This work also helps clarify future developmental directions for the linkers.

Research progress on repositioning drugs and specific therapeutic drugs for SARS-CoV-2.

SARS-CoV-2 has been widely spread around the world and COVID-19 was declared a global pandemic by the WHO. Limited clinically effective antiviral drugs are available now. The development of anti-SARS-CoV-2 drugs has become an urgent work worldwide. At present, potential therapeutic targets and drugs for SARS-CoV-2 are continuously reported, and many repositioning drugs are undergoing extensive clinical research, including remdesivir and chloroquine. On the other hand, structures of many important viral target proteins and host target proteins, including that of RdRp and Mpro were constantly reported, which greatly promoted structure-based drug design. This paper summarizes the current research progress and challenges in the development of anti-SARS-CoV-2 drugs, and proposes novel short-term and long-term drug research strategies.

Circadian activity rhythms and fatigue of adolescent cancer survivors and healthy controls: a pilot study.

STUDY OBJECTIVES: The primary objective of this study was to compare circadian activity rhythms (CARs) of adolescents within 5 years of completing cancer treatment (survivors) with that of healthy adolescent controls. Secondary objectives were to explore differences in the relationship of CARs and fatigue between survivors and controls and between early survivors (<12 months posttreatment) and late survivors (≥12 months posttreatment). METHODS: Twenty-nine survivors and 30 controls, aged 13-18 years, participated in this prospective, descriptive pilot study. Adolescents and their parents completed a baseline measure of adolescents' fatigue. Adolescents wore a wrist actigraph continuously for 7 days and concurrently kept a sleep diary. Activity data recorded by actigraphy were fitted to an extended cosine model to calculate six CAR variables: acrophase, amplitude, midline estimating statistic of rhythm (MESOR), up-MESOR, down-MESOR, and F-statistic. Linear mixed models explored the relationship between CARs and fatigue. RESULTS: There were no group differences on CAR or fatigue measures. Among survivors, earlier down-MESOR was associated with greater parent-reported fatigue (P = .020), and earlier acrophase (P = .023) and up-MESOR (P = .025) were associated with greater adolescent-reported fatigue. Significant CAR-by-time posttreatment interaction effects were found on fatigue between early and late survivors. Among controls, greater parent-reported fatigue was associated with greater MESOR (P = .0495). CONCLUSIONS: Survivors within the first 5 years posttreatment were similar to controls in CARs and fatigue, suggesting robust recovery of circadian rhythms posttreatment. Different CAR characteristics were associated with fatigue in survivors and controls. Time posttreatment influenced the relationship between CARs and fatigue for survivors, with significant effects only for early survivors.

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety.

Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced "bystander effect" inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10-11 M), but also shows improved safety with lower bystander toxicity (IC50: 10-9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.

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.

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.

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.