Anthracycline-free tumor elimination in mice leads to functional and molecular cardiac recovery from cancer-induced alterations in contrast to long-lasting doxorubicin treatment effects

Stefan Pietzsch; Katharina Wohlan; James T. Thackeray; Maren Heimerl; Sven Schuchardt; Michaela Scherr; Melanie Ricke-Hoch; Denise Hilfiker-Kleiner

doi:10.1007/s00395-021-00902-7

Anthracycline-free tumor elimination in mice leads to functional and molecular cardiac recovery from cancer-induced alterations in contrast to long-lasting doxorubicin treatment effects

Basic Research in Cardiology ◽

10.1007/s00395-021-00902-7 ◽

2021 ◽

Vol 116 (1) ◽

Cited By ~ 1

Author(s):

Stefan Pietzsch ◽

Katharina Wohlan ◽

James T. Thackeray ◽

Maren Heimerl ◽

Sven Schuchardt ◽

...

Keyword(s):

Circadian Clock ◽

Clock Genes ◽

Gene Expression Pattern ◽

Suicide Gene ◽

Cardiac Response ◽

Additional Stress ◽

Repair System ◽

Long Term Effects ◽

Recovery Potential

AbstractSystemic effects of advanced cancer impact on the heart leading to cardiac atrophy and functional impairment. Using a murine melanoma cancer model (B16F10 melanoma cells stably transduced with a Ganciclovir (GCV)-inducible suicide gene), the present study analysed the recovery potential of cancer-induced cardiomyopathy with or without use of doxorubicin (Dox). After Dox-free tumor elimination and recovery for 70 ± 5 days, cancer-induced morphologic, functional, metabolic and molecular changes were largely reversible in mice previously bearing tumors. Moreover, grip strength and cardiac response to angiotensin II-induced high blood pressure were comparable with healthy control mice. In turn, addition of Dox (12 mg/kg BW) to melanoma-bearing mice reduced survival in the acute phase compared to GCV-alone induced recovery, while long-term effects on cardiac morphologic and functional recovery were similar. However, Dox treatment was associated with permanent changes in the cardiac gene expression pattern, especially the circadian rhythm pathway associated with the DNA damage repair system. Thus, the heart can recover from cancer-induced damage after chemotherapy-free tumor elimination. In contrast, treatment with the cardiotoxic drug Dox induces, besides well-known adverse acute effects, long-term subclinical changes in the heart, especially of circadian clock genes. Since the circadian clock is known to impact on cardiac repair mechanisms, these changes may render the heart more sensitive to additional stress during lifetime, which, at least in part, could contribute to late cardiac toxicity.

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Loss of Circadian Protection in Adults Exposed to Neonatal Hyperoxia

10.1101/2020.07.10.197277 ◽

2020 ◽

Author(s):

Yasmine Issah ◽

Amruta Naik ◽

Soon Y Tang ◽

Kaitlyn Forrest ◽

Thomas G Brooke ◽

...

Keyword(s):

Circadian Clock ◽

Early Life ◽

Influenza A ◽

Negative Impact ◽

Influenza Infection ◽

Time Of Day ◽

Long Term Effects ◽

Neonatal Hyperoxia ◽

Early Life Exposures

AbstractAdverse early life exposures having a lasting negative impact on health. For examples, neonatal hyperoxia which is a risk factor for chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) confers susceptibility to respiratory infections like Influenza A (IAV) later in life. Given our previous findings that the circadian clock exerts a protective effect on injury from IAV, we asked if the long-term impact of neonatal hyperoxia includes disruption of circadian rhythms. We show here that neonatal hyperoxia abolishes the circadian clock mediated time of day protection from IAV, not through the regulation of viral burden, but through host tolerance pathways. We further discovered that that this dysregulation is mediated through the intrinsic clock in the lung, rather than through central or immune system clocks. Loss of circadian protein, Bmal1, in AT2 cells of the lung recapitulates the increased mortality, loss of temporal gating and other key features of hyperoxia-exposed animals. Taken together, our data suggest a novel role for the circadian clock in AT2 clock in mediating long-term effects of early life exposures to the lungs.Brief SummaryNeonatal hyperoxia abrogates the circadian protection from Influenza infection in recovered adults.

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Sleep–wake-driven and circadian contributions to daily rhythms in gene expression and chromatin accessibility in the murine cortex

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1910590116 ◽

2019 ◽

Vol 116 (51) ◽

pp. 25773-25783 ◽

Cited By ~ 13

Author(s):

Charlotte N. Hor ◽

Jake Yeung ◽

Maxime Jan ◽

Yann Emmenegger ◽

Jeffrey Hubbard ◽

...

Keyword(s):

Gene Expression ◽

Mrna Expression ◽

Serum Response Factor ◽

Clock Genes ◽

Chromatin Accessibility ◽

Long Term Effects ◽

Homeostatic Process ◽

Gene Expression Dynamics ◽

Damped Oscillation

The timing and duration of sleep results from the interaction between a homeostatic sleep–wake-driven process and a periodic circadian process, and involves changes in gene regulation and expression. Unraveling the contributions of both processes and their interaction to transcriptional and epigenomic regulatory dynamics requires sampling over time under conditions of unperturbed and perturbed sleep. We profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a 3-d period, including a 6-h sleep deprivation (SD) on day 2. We used mathematical modeling to integrate time series of mRNA expression data with sleep–wake history, which established that a large proportion of rhythmic genes are governed by the homeostatic process with varying degrees of interaction with the circadian process, sometimes working in opposition. Remarkably, SD caused long-term effects on gene-expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a damped oscillation of most core clock genes, includingArntl/Bmal1, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Dynamics in distal regions, rather than promoters, correlated with mRNA expression, implying that changes in expression result from constitutively accessible promoters under the influence of enhancers or repressors. Serum response factor (SRF) was predicted as a transcriptional regulator driving immediate response, suggesting that SRF activity mirrors the build-up and release of sleep pressure. Our results demonstrate that a single, short SD has long-term aftereffects at the genomic regulatory level and highlights the importance of the sleep–wake distribution to diurnal rhythmicity and circadian processes.

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Simple and complex interactions between sleep-wake driven and circadian processes shape daily genome regulatory dynamics in the mouse

10.1101/677807 ◽

2019 ◽

Author(s):

Charlotte N. Hor ◽

Jake Yeung ◽

Maxime Jan ◽

Yann Emmenegger ◽

Jeffrey Hubbard ◽

...

Keyword(s):

Gene Expression ◽

Sleep Deprivation ◽

Mrna Expression ◽

Clock Genes ◽

Poor Quality ◽

Chromatin Accessibility ◽

Time Of Day ◽

Long Term Effects ◽

Regulatory Dynamics

AbstractThe timing and duration of sleep results from the interaction between a sleep-wake driven, or homeostatic, process (S) and a circadian process (C), and involves changes in gene expression and genomic regulation. Unraveling the respective contributions of S and C, and their interaction, to transcriptional and epigenomic regulatory dynamics requires sampling over time under unperturbed conditions and conditions of perturbed sleep. Here, we profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a three-day period, including a 6-hour sleep deprivation (SD) on day two. Mathematical modeling established that a large proportion of rhythmic genes are actually governed by Process S with varying degrees of interaction with Process C, sometimes working in opposition. Remarkably, SD causes long-term effects on gene expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a dampening of the oscillation of most core clock genes, including Bmal1, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Distal regions, rather than promoters, display dynamics corresponding to gene transcription, implying that changes in mRNA expression result from constantly accessible promoters under the influence of distal enhancers or repressors. Srf was predicted as a transcriptional regulator driving immediate response, suggesting that Srf activity mirrors the build-up and release of sleep pressure. Our results demonstrate that a single, short SD has long-term aftereffects at the genomic regulatory level. Such effects might accumulate with repeated sleep restrictions, thereby contributing to their adverse health effects.Significance statementWhen and how long we sleep is determined by the time-of-day and how long we have been awake, which are tracked molecularly by a circadian and a sleep-wake driven process, respectively. We measured the long-term consequences of a short-term sleep deprivation (SD) on gene expression and regulation in the mouse brain, and used mathematical models to determine the relative contributions of the circadian and sleep-wake driven processes. We find that many genes, including most of the genes that constitute the molecular circadian clock, are perturbed by SD long after the mice ceased showing behavioral signs of sleep loss. Our results have implications for human health, given the high prevalence of insufficient and poor quality sleep in our contemporary society.

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Bicycling-related concussions leading to postconcussion syndrome in adults

BMJ Open Sport & Exercise Medicine ◽

10.1136/bmjsem-2020-000746 ◽

2020 ◽

Vol 6 (1) ◽

pp. e000746

Author(s):

Connor Moore ◽

Paria Baharikhoob ◽

Mozhgan Khodadadi ◽

Charles H Tator

Keyword(s):

Motor Vehicle ◽

Retrospective Chart Review ◽

Long Term Effects ◽

Postconcussion Syndrome ◽

Patient Demographics ◽

Persistent Symptoms ◽

Recovery Potential ◽

The Mean

BackgroundConcussions among adult bicyclists are common, but little is known about the long-term effects of the consequences of these concussions such as postconcussion syndrome (PCS) including its occurrence, clinical features and recovery potential. Indeed, our study is the first to examine PCS due to bicycling in any age group.ObjectivesWe examined patient demographics, concussion mechanisms and persistent symptoms as factors leading to PCS in adults and the potential for recovery.MethodsWe conducted a retrospective chart review of 28 patients age 18 or older who sustained a concussion while bicycling and were referred to the Canadian Concussion Centre for management of PCS.ResultsEighteen patients (64.3%) fell from their bicycles due to loss of control, attempts to avoid a crash or collision with an object. Eight patients (28.6%) were struck by a motor vehicle, and two patients (7.1%) were injured by collision with another bicycle. The mean duration of PCS was 23.7 months and at the time of the last follow-up, 23 (82.1%) patients had failed to recover completely. Patients with one or more previous concussions had a significantly longer duration of PCS (p=0.042). Bicycling concussions resulted in a greater mean duration of PCS (23.7 months) than a comparison group of patients with PCS due to collision sports (16.1 months) (p=0.07).ConclusionAdults who sustain bicycling-related concussions and develop PCS often have long-lasting symptoms; greater attention should be given to prevention strategies such as improved bicycling infrastructure and safer bicycling practices to reduce concussions in adult bicyclists.

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Long-term effect of systemic RNA interference on circadian clock genes in hemimetabolous insects

Journal of Insect Physiology ◽

10.1016/j.jinsphys.2013.02.009 ◽

2013 ◽

Vol 59 (4) ◽

pp. 494-499 ◽

Cited By ~ 12

Author(s):

Outa Uryu ◽

Yuichi Kamae ◽

Kenji Tomioka ◽

Taishi Yoshii

Keyword(s):

Rna Interference ◽

Circadian Clock ◽

Clock Genes ◽

Term Effect ◽

Long Term Effect ◽

Circadian Clock Genes ◽

Systemic Rna

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The Effect of Chronic Morphine or Methadone Exposure and Withdrawal on Clock Gene Expression in the Rat Suprachiasmatic Nucleus and AA-NAT Activity in the Pineal Gland

Physiological Research ◽

10.33549/physiolres.933183 ◽

2016 ◽

pp. 517-525 ◽

Cited By ~ 6

Author(s):

D. PAČESOVÁ ◽

J. NOVOTNÝ ◽

Z. BENDOVÁ

Keyword(s):

Pineal Gland ◽

Suprachiasmatic Nucleus ◽

Clock Genes ◽

Brain Structures ◽

Long Term Effects ◽

Chronic Morphine ◽

Clock Gene Expression ◽

Induced Changes ◽

Opiate Administration

The circadian rhythms of many behavioral and physiological functions are regulated by the major circadian pacemaker in the suprachiasmatic nucleus. Long-term opiate addiction and drug withdrawal may affect circadian rhythmicity of various hormones or the sleep/activity pattern of many experimental subjects; however, limited research has been done on the long-term effects of sustained opiate administration on the intrinsic rhythmicity in the suprachiasmatic nucleus and pineal gland. Here we compared the effects of repeated daily treatment of rats with morphine or methadone and subsequent naloxone-precipitated withdrawal on the expression of the Per1, Per2, and Avp mRNAs in the suprachiasmatic nucleus and on arylalkylamine N-acetyltransferase activity in the pineal gland. We revealed that 10-day administration and withdrawal of both these drugs failed to affect clock genes and Avp expression in the SCN. Our results indicate that opioid-induced changes in behavioral and physiological rhythms originate in brain structures downstream of the suprachiasmatic nucleus regulatory output pathway. Furthermore, we observed that acute withdrawal from methadone markedly extended the period of high night AA-NAT activity in the pineal gland. This suggests that withdrawal from methadone, a widely used drug for the treatment of opioid dependence, may have stronger impact on melatonin synthesis than withdrawal from morphine.

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Ovarian Dysfunction in Fetally Irradiated Beagles

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100080717 ◽

1977 ◽

Vol 35 ◽

pp. 658-659

Author(s):

T. M. Seed ◽

M. H. Sanderson ◽

D. L. Gutzeit ◽

T. E. Fritz ◽

D. V. Tolle ◽

...

Keyword(s):

Gamma Rays ◽

Low Dose ◽

Long Term Effects ◽

Ovarian Dysfunction ◽

Dose Rates ◽

Highly Sensitive ◽

Microscopic Evaluation ◽

Ovarian Pathology ◽

Normal Offspring

The developing mammalian fetus is thought to be highly sensitive to ionizing radiation. However, dose, dose-rate relationships are not well established, especially the long term effects of protracted, low-dose exposure. A previous report (1) has indicated that bred beagle bitches exposed to daily doses of 5 to 35 R 60Co gamma rays throughout gestation can produce viable, seemingly normal offspring. Puppies irradiated in utero are distinguishable from controls only by their smaller size, dental abnormalities, and, in adulthood, by their inability to bear young.We report here our preliminary microscopic evaluation of ovarian pathology in young pups continuously irradiated throughout gestation at daily (22 h/day) dose rates of either 0.4, 1.0, 2.5, or 5.0 R/day of gamma rays from an attenuated 60Co source. Pups from non-irradiated bitches served as controls. Experimental animals were evaluated clinically and hematologically (control + 5.0 R/day pups) at regular intervals.

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Ultrastructural investigations of MDL 19,660-induced effects on the canine platelet and megakaryocyte

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100159412 ◽

1990 ◽

Vol 48 (3) ◽

pp. 374-375

Author(s):

D.E. Loudy ◽

J. Sprinkle-Cavallo ◽

J.T. Yarrington ◽

F.Y. Thompson ◽

J.P. Gibson

Keyword(s):

Antidepressant Drug ◽

Beagle Dogs ◽

Long Term Effects ◽

Short Term ◽

Platelet Counts ◽

Toxicological Studies ◽

Induced Aggregation ◽

Internal Architecture

Previous short term toxicological studies of one to two weeks duration have demonstrated that MDL 19,660 (5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3Hl, 2,4-triazole-3-thione), an antidepressant drug, causes a dose-related thrombocytopenia in dogs. Platelet counts started to decline after two days of dosing with 30 mg/kg/day and continued to decrease to their lowest levels by 5-7 days. The loss in platelets was primarily of the small discoid subpopulation. In vitro studies have also indicated that MDL 19,660: does not spontaneously aggregate canine platelets and has moderate antiaggregating properties by inhibiting ADP-induced aggregation. The objectives of the present investigation of MDL 19,660 were to evaluate ultrastructurally long term effects on platelet internal architecture and changes in subpopulations of platelets and megakaryocytes.Nine male and nine female beagle dogs were divided equally into three groups and were administered orally 0, 15, or 30 mg/kg/day of MDL 19,660 for three months. Compared to a control platelet range of 353,000- 452,000/μl, a doserelated thrombocytopenia reached a maximum severity of an average of 135,000/μl for the 15 mg/kg/day dogs after two weeks and 81,000/μl for the 30 mg/kg/day dogs after one week.

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