scholarly journals 4067 Cancer-related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

2020 ◽  
Vol 4 (s1) ◽  
pp. 125-125
Author(s):  
Josephine K. Liwang ◽  
Li Rebekah Feng ◽  
Brian Wolff ◽  
Jeniece Regan ◽  
Sarah Alshawi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Synergistic Effect ◽  
Mitochondrial Dysfunction ◽  
Androgen Deprivation Therapy ◽  
Mitochondrial Function ◽  
Wheel Running ◽  
Combined Treatment ◽  
Coupling Efficiency ◽  
Androgen Deprivation ◽  
Wheel Running Activity

OBJECTIVES/GOALS: Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is the standard of care treatment for non-metastatic prostate cancer (NMPC). Despite the efficacy, treatment-related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. METHODS/STUDY POPULATION: Sixty-four participants with NMPC were enrolled. Fatigue was assessed using the Functional Assessment of Cancer Therapy–Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMCs) extracted from participants’ whole blood. An ADT/RT-induced fatigue mouse model was developed with fatigue measured as a reduction in voluntary wheel-running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the ADT/RT mouse brains using Western blot analysis of Glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). RESULTS/ANTICIPATED RESULTS: Fatigue in the ADT group was exacerbated during RT compared to the non-ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMCs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non-fatigued subjects, indicative of mitochondrial dysfunction. The ADT/RT mice demonstrated a synergistic effect of ADT and RT in decreasing VWRA. Brain tissues of ADT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (CNS). The synergistic effect of ADT/RT is behaviorally reproducible in a mouse model, and its mechanism may be related to bioenergetics in the CNS.

The effects of androgen deprivation therapy and radiation therapy on cancer-related fatigue.

2019 ◽  
Vol 37 (31_suppl) ◽  
pp. 10-10
Author(s):  
Leorey Saligan
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Wheel Running ◽  
Androgen Deprivation ◽  
Common Symptom ◽  
Cancer Related Fatigue ◽  
Running Activity ◽  
Fatigue Development ◽  
Wheel Running Activity ◽  
Significant Difference

10 Background: Fatigue is a common symptom characterized by incapacitating tiredness. Androgen deprivation therapy (ADT) in combination with radiotherapy (RT) is one of the standard treatments for prostate cancer. Fatigue often worsens during RT with concomitant ADT and it persists long after treatment completion. The purpose of this study is to examine the effects of combined ADT and RT on fatigue in prostate cancer men and in a fatigue mouse model. Methods: 64 participants were recruited and followed at baseline, midpoint, completion, and 1 year post-RT. Two cohorts of men: +ADT cotinued after RT (n=27), +ADT during RT only (n=20), and -ADT (n=17). Fatigue was measured using FACT-F. Male C57BI/6 mice (n=55) were randomly placed into 2 groups: +ADT and –ADT (control). Mice were further subdivided into +RT and –RT (sham) groups. Voluntary Wheel Running Activity (VWRA) data from all mice were recorded for 6 days post-irradiation and the total average of all 6 days was used for analysis. Results: Fatigue (n=64) worsened during RT ( p=.02 at midpoint, p=.04 at completion). ADT significantly affected fatigue development over time (F3,42 = 3.80, p=.02) with the most significant difference occurring at midpoint ( p<.001) and completion of RT ( p<0.001). VWRA significantly decreased in mice that received the combination of ADT and irradiation, compared to those that received only ADT + sham radiation ( p=.001) and no ADT + sham radiation ( p=.004). Transcription factor A, mitochondrial (TFAM) in brain cortical samples was significantly reduced in irradiated mice compared to control mice ( p=.014). Glucose transported type 4 (GLUT4) in brain cortices was significantly reduced in irradiated mice compared to non-irradiated mice ( p=.0057). GLUT4 was also significantly reduced in irradiated mice receiving ADT compared to control mice receiving sham RT ( p=.043). Conclusions: There is a significant combined effect of ADT and RT on fatigue in both humans and mice. Mitochondrial function/neuronal bioenergetic markers were altered in the cortices of irradiated mice that received concomitant ADT. These findings suggest that fatigue experienced by subjects who receive ADT + RT could be attributable to impaired cortical energy production.

scholarly journals Effect of Salvage Radiotherapy and Endocrine Therapy on Patients with Biochemical Recurrence After Prostate Cancer Operation— a Meta‑Analysis

2021 ◽  
Vol 15 (3) ◽  
pp. 155798832110248
Author(s):  
Yong Yuan ◽  
Qiang Zhang ◽  
Chaofan Xie ◽  
Tao Wu
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Endocrine Therapy ◽  
Androgen Deprivation Therapy ◽  
Biochemical Recurrence ◽  
Meta Analysis ◽  
Combined Treatment ◽  
Androgen Deprivation ◽  
Salvage Radiotherapy ◽  
End Point

Context: Several studies reported the application of androgen deprivation therapy and radiotherapy in patients with biochemical recurrence after prostate cancer operation. Objective: To perform a systematic review and meta-analysis evaluating of endocrine therapy and radiotherapy in patients with biochemical recurrence after prostate cancer surgery. The primary end point was biochemical progression-free survival (bPFS). Secondary end point was overall survival (OS). Methods: A systematic review of PubMed/Medline, Embase, and Cochrane databases to identify relevant studies published in English up to March 2020. Twelve studies were selected for inclusion. Results: There were 11 studies included in the present study. Including two randomized controlled trials and nine cohort studies. The meta-analysis shows a significant bPFS benefit from androgen deprivation therapy and radiotherapy in patients with biochemical recurrence after prostate cancer operation. (hazard ratio [HR]: 0.57; 95% confidence interval CI, 0.52–0.63; p < .001). For patients with GS < 7 and low-risk patients, combined treatment can have a benefit for BPFs (HR: 0.53; 95% CI, 0.37–0.76; HR: 0.58; 95% CI, 0.36–0.93). Androgen deprivation therapy and radiotherapy in patients with biochemical recurrence was associated with a slightly OS improvement (HR: 0.73; 95% CI, 0.57–0.93; p = 0.01). Conclusions: Compared with salvage radiotherapy alone, This meta-analysis shows a significant bPFS benefit from endocrine therapy combined with salvage radiotherapy in patients with biochemical recurrence after prostate cancer operation. And benefit more for high-risk groups. However, there was no significant benefit in group GS ≥ 8. It shows a slightly OS benefit from endocrine therapy combined with salvage radiotherapy in patients with biochemical recurrence.

scholarly journals Circadian regulation of sleep in a pre-clinical model of Dravet syndrome: dynamics of sleep stage and siesta re-entrainment

SLEEP ◽  
2019 ◽  
Vol 42 (12) ◽  
Author(s):  
Raymond E A Sanchez ◽  
Ivana L Bussi ◽  
Miriam Ben-Hamo ◽  
Carlos S Caldart ◽  
William A Catterall ◽  
...  
Keyword(s):  
Mouse Model ◽  
Wheel Running ◽  
Intractable Epilepsy ◽  
Dravet Syndrome ◽  
Sleep Stages ◽  
Circadian Regulation ◽  
Jet Lag ◽  
Sleep Regulation ◽  
Wheel Running Activity

Abstract Study Objectives Sleep disturbances are common co-morbidities of epileptic disorders. Dravet syndrome (DS) is an intractable epilepsy accompanied by disturbed sleep. While there is evidence that daily sleep timing is disrupted in DS, the difficulty of chronically recording polysomnographic sleep from patients has left our understanding of the effect of DS on circadian sleep regulation incomplete. We aim to characterize circadian sleep regulation in a mouse model of DS. Methods Here we exploit long-term electrocorticographic recordings of sleep in a mouse model of DS in which one copy of the Scn1a gene is deleted. This model both genocopies and phenocopies the disease in humans. We test the hypothesis that the deletion of Scn1a in DS mice is associated with impaired circadian regulation of sleep. Results We find that DS mice show impairments in circadian sleep regulation, including a fragmented rhythm of non-rapid eye movement (NREM) sleep and an elongated circadian period of sleep. Next, we characterize re-entrainment of sleep stages and siesta following jet lag in the mouse. Strikingly, we find that re-entrainment of sleep following jet lag is normal in DS mice, in contrast to previous demonstrations of slowed re-entrainment of wheel-running activity. Finally, we report that DS mice are more likely to have an absent or altered daily “siesta”. Conclusions Our findings support the hypothesis that the circadian regulation of sleep is altered in DS and highlight the value of long-term chronic polysomnographic recording in studying the role of the circadian clock on sleep/wake cycles in pre-clinical models of disease.

scholarly journals Androgen deprivation therapy has no effect on Pim-1 expression in a mouse model of prostate cancer

2017 ◽  
Vol 13 (6) ◽  
pp. 4364-4370 ◽  
Author(s):  
Jiang Wang ◽  
Gang Li ◽  
Bo Li ◽  
Hualin Song ◽  
Zhiqun Shang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mouse Model ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation

scholarly journals Real World Evaluation of Upfront Docetaxel in Metastatic Castrate Sensitive Prostate Cancer

2021 ◽  
Author(s):  
Jenny Isaksson ◽  
Henrik Green ◽  
Dimitrios Papantoniou ◽  
Linn Pettersson ◽  
Mats Andén ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Real World ◽  
Treatment Strategy ◽  
Statistical Significance ◽  
Combined Treatment ◽  
Dose Intensity ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
Study Cohort

Abstract Background: Recent randomised phase III trials demonstrate survival benefit for the addition of upfront docetaxel to androgen deprivation therapy (ADT) in metastatic castrate sensitive prostate cancer (mCSPC). Following its implementation in routine care, this combined treatment strategy needs further evaluation in a real world setting.Methods: A multicentre retrospective cohort study in the South East Health care region of Sweden was conducted. All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included. Primary endpoint was progression free survival (PFS) at 12 months and secondary endpoints were PFS at 24 months, overall survival (OS), treatment intensity, adverse events, and unplanned hospitalisations. Exploratory analyses on potentially prognostic parameters were performed.Results: 94 patients were eligible and formed the study cohort. PFS at 12 and 24 months were 75% (95% CI 66-84) and 58% (46-70). OS at 12 and 24 months were 93% (87-99) and 86% (76-96). 91% (n=86) initiated docetaxel according to the standard protocol of 75 mg/m2 every 3 weeks (6 cycles), whereas 9% (n=8) received a modified protocol of 50 mg/m2 every 2 weeks (9 cycles). The average overall dose intensity for those commencing standard treatment was 91%. Univariate cox regression analyses revealed that baseline PSA >180 vs <180 and presence vs absence of distant metastases were negative prognostic factors (HR 2.86, 95% CI 1.39-5.87, p =0.0041 and 3.36, 95% CI 1.03-10.96, p=0.045). Following multivariate analysis, the statistical significance remained for PSA (2.51, CI 1.21-5.19, p =0.013) but not for metastatic status (2.60, 95% CI 0.78-8.65, p=0.12). Febrile neutropenia was recorded in 21% (n=20) and 26% (n=24) had at least one episode of unplanned hospitalisation under and up to 30 days after the treatment course. Conclusions: The outcome and safety profile of upfront docetaxel in addition to androgen deprivation therapy in metastatic castrate sensitive prostate cancer appear similar in real world and randomised controlled populations. Further implementation of this treatment strategy is encouraged.

scholarly journals Co-Administration of Gagam-Sipjeondaebo-Tang and Ibuprofen Alleviates the Inflammatory Response in MPTP-Induced Parkinson’s Disease Mouse Model and RAW264.7 Macrophages

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 268
Author(s):  
Sodam Won ◽  
Jade Heejae Ko ◽  
Hayoung Jeon ◽  
Seong-Sik Park ◽  
Seung-Nam Kim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Synergistic Effect ◽  
Dopaminergic Neurons ◽  
Combined Treatment ◽  
Behavioral Deficits ◽  
Raw264.7 Macrophages ◽  
Mice Brain

Parkinson’s disease (PD), a common neurodegenerative disease, is characterized by degeneration of dopaminergic neurons with neuroinflammation. Gagam-Sipjeondaebo-Tang (GST), a traditional herbal formula made of twelve medicinal herbs, is known to be effective in PD, and the use of ibuprofen has been associated with a lower risk of PD. The aim of this study was to evaluate whether the combined administration of GST and ibuprofen affects the inflammatory response of Parkinson’s disease. MPTP-induced parkinsonian mouse models were treated with GST or ibuprofen using oral gavage once a day for 5 days. The effects of GST were examined by measuring the TH level and expression of CD68 in the mice brain in addition to behavioral tests. The anti-inflammatory effect of GST on the LPS-treated RAW264.7 murine macrophages was examined using the NO assay. Inflammatory cytokines were analyzed using quantitative-PCR and flow cytometry. In the results, GST significantly improved the loss of dopaminergic neurons and alleviated PD-induced behavioral deficits. GST also decreased macrophage activation in the MPTP-induced PD mouse model. Interestingly, co-administration of GST and ibuprofen showed a synergistic effect in improving the loss of dopaminergic neurons and decreasing the activation of macrophages. Moreover, the NO level decreased in LPS-stimulated macrophages with this combined treatment. GST reduced iNOS, COX-2, IL-1β, and IL-6 levels, and co-administration with ibuprofen showed a synergistic effect. Furthermore, pretreatment of GST reduced the expression levels of MCP-1 and IL-12 p70 in LPS-stimulated RAW264.7 cells. These results can possibly suggest a future therapeutic approach for PD patients.

scholarly journals Bile acid excess impairs thermogenic function in brown adipose tissue

2020 ◽  
Author(s):  
Weinan Zhou ◽  
Philip VanDuyne ◽  
Chi Zhang ◽  
Ryan Riessen ◽  
Maribel Barragan ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mouse Model ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
De Novo ◽  
Farnesoid X Receptor ◽  
List Type ◽  
Double Knockout ◽  
Brown Adipose

SUMMARYBile acids (BAs) not only facilitate fat digestion but also protect against obesity. Here, we show that a genetic mouse model for BA overload (Farnesoid X receptor; Small heterodimer double knockout (DKO)) exhibits mitochondrial dysfunction resulting in a thermogenic defect. By housing DKO mice at thermoneutrality, the poor mitochondrial function in brown fat protects them from diet-induced obesity. Compared to control, we find higher adipose BA levels with excess accumulation of taurocholic acid in the DKO mice. We report that the expression of genes responsible for BA de novo synthesis, conjugation and transporters and accumulation of BAs are present in both brown and white adipocytes. We determine that BA overload is sufficient to cause adipocyte mitochondrial dysfunction and induce the expression of cellular senescence genes in vitro. Taken together, we uncover that BA levels within the adipose tissue may modulate its overall function.HighlightsMouse model of BA overload exhibits adipose defects, which is partially restored by housing at thermoneutrality.BAs are present in detectable concentrations in both BAT and WAT.Adipocytes express genes responsible for de novo synthesis, conjugation and transport of BAs, and accumulate BAs.Pathological accumulation of BAs impairs mitochondrial function leading to thermogenic defect.

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