INTRODUCTION TO PATHOLOGICAL CLOCKS AND CLOCK PATHOLOGIES Flashcards
HEALTH CONSEQUENCES OF NIGHTSHIFTS?
- E.G. INCREASED RISK OF LUNG CANCER, OVARIAN CANCER, BREAST CANCER!!!!!
- INCREASED RISK OF METABOLIC SYNDROME, T2D (REGARDLESS OF OTHER LIFESTYLE ASPECTS, THE LONGER ONE ENGAGES INTO NIGHTSHIFT WORK, THE HIGHER THE RISKS)
DUE TO CIRCADIAN CLOCK DISRUPTION
NIGHTSHIFT WORK IS PROBABLY CARCINOGENIC TO HUMANS, FALLING INTO WHICH GROUP OF CARCINOGENS?
2A
CARCINOGENS CLASSIFICATION
Group 1: Carcinogenic to humans
Sufficient evidence in humans
Group 2A: Probably carcinogenic to humans
Evidence is limited in humans but sufficient in experimental animals
Group 2B: Possibly carcinogenic to humans
Evidence is limited in humans and is less than sufficient in experimental animals; or evidence is inadequate in humans but is sufficient in experimental animals
Group 3: Not classifiable as to its carcinogenicity to humans
Evidence is inadequate in humans and is inadequate or limited in animals
Group 4: Probably not carcinogenic to humans
WHICH HALLMARKS OF CANCER ARE ASSOCIATED WITH THE CLOCK/CIRCADIAN RYTHM?
- SUSTAINING PROLIFERATIVE SIGNALLING
- DEREGULATING CELLULAR EPIGENETICS
- RESISTING CELL DEATH
- GENOME INSTABILITY AND MUTATION
- ACTIVATING INVASION AND METASTASIS
- TUMOUR PROMOTING INFLAMMATION
DICHOTOMY INDEX?
dichotomy index (I < O) Relative amount of activity In-bed that is less than median activity Out-of-bed
HOW DOES CIRCADIAN DISRUPTION AFFECT CANCER PATIENTS?
- REDUCES SURVIVAL
- REDUCES HR-QOL
- MAKES THE CANCER GROW FASTER
CHRONIC JET LAG?
Proper circadian rhythms are an important feature of normal health enabling organisms to adapt to daily changes in their environment. Frequent transmeridian travel and rotating shift work are well-known disruptors of this internal timing system in humans . In some individuals, short-term misalignment between the endogenous circadian clock and the desired destination sleep/wake schedule can produce a temporary “jet lag” disorder, which is associated with symptoms of fatigue, gastrointestinal distress, reduced psychomotor coordination, and diminished cognition and mood. These symptoms generally dissipate as the circadian clock gradually entrains to the new destinations’ time. However, with sustained periods of circadian disruption, a host of adverse health outcomes and clinical pathologies can occur, including a higher incidence of cancer, diabetes, obesity, cardiovascular diseases, and early mortality.
Long-term, repeated disturbances of the internal circadian system has been documented to adversely impact the brain. For example, flight attendants who had experienced repeated jet lag with limited recovery period between flights were found to have reduced temporal lobe volume and exhibited spatial learning deficits when compared to a ground crew control group. Interestingly, these cognitive deficits were long lasting—extending for several years—and were associated with elevated levels of the stress hormone cortisol, a key component of the hypothalamic-pituitary-adrenal stress axis. In addition, chronic sleep disturbances have been associated with reduced cortical gray matter volume in several brain regions, including the prefrontal cortex and hippocampus. These findings underscore that structural and functional brain adaptations can be downstream effects associated with frequent episodes of circadian dysrhythmia and sleep loss.
Experimental conditions of jet lag can be simulated in rodents through either advancing or delaying the onset of when housing lights are turned off. Using this approach, there is clear evidence that repeated phase shifts of the light/dark (LD) cycle can produce disruptions to learning and memory processes in rats with phase advances typically inducing the greatest impairment. While the adverse effect of chronic circadian disruption on cognition in rodents and humans is clear, the impact of these changes on affective behaviors is less known. Nonetheless, there is a long history demonstrating that repeated periods of circadian misalignment can contribute to the etiology of mood and anxiety disorders. For instance, jet lag was found to be a significant precipitator of depressive symptoms in some individuals with a history of psychiatric illness. In rodents, disruption of the natural circadian rhythm by constant lighting increases anxiety-like and depressive-like behavior. Furthermore, mice with mutations of circadian clock genes show abnormal emotional behaviors. These findings suggest that the proper entrainment of circadian rhythms is necessary for normal functioning of neural circuits that control emotion and regulate stress reactivity.
Despite the increasing awareness of the health risks associated with chronic jet lag, the neurobiological factors that underlie the accompanied changes in mood and cognitive behavior remain poorly understood.
CHRONIC JET LAG EXPERIMENT
We found that rats exposed to frequent phase advances, which mirror conditions of chronic jet lag in humans, exhibited impairments in object recognition memory and showed signature symptoms of depression, including anhedonia, increased anxiety behavior, and higher levels of immobility in the forced swim test
MYC?
MYC (MYC Proto-Oncogene) is a Protein Coding gene.
MYC gene encodes a multifunctional, nuclear phosphoprotein that controls a variety of cellular functions, including cell cycle, cell growth, apoptosis, cellular metabolism and biosynthesis, adhesion, and mitochondrial biogenesis.
MYC binds the genome through sites termed E-boxes, which are identical to the binding sites of the heterodimeric CLOCK-BMAL1 master circadian transcription factor. Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-driven components of the circadian network in cancer cells. We report here that deregulated expression of MYC or N-MYC (a certain number of MYC) disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression and oscillation of BMAL1, and this could be rescued by knockdown of REV-ERB. REV-ERBα expression predicts poor clinical outcome for N-MYC-driven human neuroblastomas that have diminished BMAL1 expression, and re-expression of ectopic BMAL1 in neuroblastoma cell lines suppresses their clonogenicity. Further, ectopic MYC profoundly alters oscillation of glucose metabolism and perturbs glutaminolysis. Our results demonstrate an unsuspected link between oncogenic transformation and circadian and metabolic dysrhythmia, which we surmise to be advantageous for cancer.
- CANCER PATIENTS WITH HIGH MYC EXPRESSION HAVE THE LOWEST OVERALL SURVIVAL
HAVING A ‘GOOD’ CLOCK ALWAYS LEADS TO BETTER SURVIVAL IN CANCER PATIENTS, TRUE OR FALSE?
FALSE
IN SOME CASES, BAD CLOCK ASSOCIATED WITH BETTER PROGNOSIS, UNCLEAR WHY
SOCIAL JET LAG?
Social jetlag (SJL), the difference in sleep timing between work and free days is a consequence of the discrepancy between the individual’s circadian rhythm and the social clock. SJL is considered a chronic stress factor and has been linked to various health problems.
- teenagers are particularly susceptible
- SJL WENT DOWN SIGNIFICANTLY DURING LOCKDOWNS (a positive impact of the pandemic)
- LOWER SJL CAN CONTRIBUTE TO LONGER DISEASE FREE SURVIVAL IN CANCER PATIENTS
HOW DO CLOCK ADJUSTMENTS/DAYLIGHT SAVINGS TIMES AFFECT THE CIRCADIAN RYTHM/BIOLOGICAL CLOCK?
DST LEADS TO MISALIGNMENT OF THE BIOLOGICAL CLOCK AND THE TIME CLOCK, MOST EUROPEAN COUNTRIES END UP IN A TIME ZONE THAT DOESN’T ALIGN WITH THE NATURAL/SUN DICTATED TIME (CAN THROW OFF SLEEPING TIME)
DISRUPTION OF BIOLOGICAL CLOCK, CAUSES AND CONSEQUENCES
- CAN BE CAUSED ANYTIME BY SOCIETY (TRANS MERIDIAN TRAVEL, NIGHT SHIFTS, SOCIAL JETLAG…)
- CAN BE MEASURED AT THE ORGANISMAL AS WELL AS CELLULAR MOLECULAR LEVEL
- CAN LEAD TO DISEASE, BUT ALSO BE CAUSED/WORSENED BY DISEASES, LEADING TO PATIENTS ENTERING A VICIOUS CYCLE
- CAN BE A BIOMARKER FOR DISEASES
DICHTOMYY INDEX INDICATING CIRCADIAN DISRUPTION?
LESS THAN 97.5% (MEDIAN)
