How to ride the new wave of immune therapies | Prof Brendon Coventry and Jill O’Donnell-Tormey PhD Show the Way

Good news on cancer: There is a definite change in the wind! The face of oncology is changing. Both cancer patients and oncologists are undergoing a cancer metamorphosis. Treatments are moving – albeit slowly from a killing cancer focus to a focus on retraining the body’s own immune system to seek and destroy cancer cells.

Good news on cancer: There is a definite change in the wind! The face of oncology is changing. Both cancer patients and oncologists are undergoing a cancer metamorphosis. Treatments are moving – albeit slowly from a killing cancer focus to a focus on retraining the body’s own immune system to seek and destroy cancer cells.

Riding the wave of new immune therapies. Pic: ABC News
Riding the wave of new immune therapies. Pic: ABC News

Last week on Navigating the Cancer Maze internet radio Prof Brendon Coventry spoke about cancer vaccines and in particular about his success treating advanced melanoma.

He also spoke about the importance of measuring a patient’s immune cycle as a new approach to that value-adds to the “New Wave” of immunotherapy treatments against cancer.

Click here to listen to that interview if you missed it – (live streaming or download on itunes to listen later at no cost).

Questions from cancer patients clearly demonstrate a thirst for knowledge about immune therapies.

Therefore – today – I have replayed my interview from mid last year(2014) with Cancer Research Institute’s CEO Jill O’Donnell-Tormey PhD.  Click Jill’s name to be redirected to the interview on Voice America internet radio. In this interview Jill provided a clear picture of where immune therapies are headed and what they actually do and where you can find trials and treatments.

Jill talks about the new immunotherapy pharmaceuticals – an innovative class of drugs that block PD-1.  (Stands for programmed cell death protein 1). PD-1 inhibitors, activate the immune system to attack tumors and are therefore used to treat cancer.  These drugs have complex names such as nivolumab successfully used in non-small-cell lung cancer, melanoma, and renal-cell cancer; Pembrolizumab; intended for use in treating metastatic melanoma; to name but a few. Then there are CTLA-4 antibodies such as Ipilimumab; a fully human, monoclonal antibody that overcomes CTLA-4–mediated T-cell suppression to enhance the immune response against tumors.

Anti-PD-1 and Anti-PD-L1 Antibodies – Unlike CTLA-4 antibodies, the PD-1/PD-L1 antibodies aim to potentiate the antitumor T-cell response at a tumor-specific level, by impairing the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumor cells

Cancer patients as well as doctors and oncologists are having to learn a new language and a new way of thinking about cancer. The process is slow – but the most important people in cancer medicine –  patients; need to know the basics and what to ask of their oncologists because these new immune drugs, cancer vaccines and immune timing of treatments, appears to hold the key to curing cancers.

As I see it – the only caution right now is that patients may be rushing to overseas alternative clinics who promote the new elaborate cocktails of immune therapies. Skill and experience is required in using these new immune treatments- best to ask an expert.

Now – back to Prof Coventry and Martin Ashdown’s work for some additional information….
There are many studies that demonstrate that conclusions made by Prof Brendon Coventry and Martin Ashdown that propose that our immune system has a rhythm that can be measured especially when a patient has advancing cancer.

T lymphocytes (orange colour) assembling to kill cancer
T lymphocytes (orange colour) assembling to kill cancer

 It is known that Cytokines (cell signalling molecules that aid cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation, infection and trauma), are crucial mediators for shaping immune responses. Cytokines are important regulators of both the innate and adaptive immune response.

The following from the Journal of Immunology Research 2014 – states that Several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to “circadian rhythms.” Such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur. However, the mechanisms behind circadian immunity have not been fully understood. Recent studies reveal that the internal time keeping system “circadian clock” plays a key role in driving the daily rhythms evident in the immune system. Importantly, several studies unveil molecular mechanisms of how certain clock proteins (e.g., BMAL1 and CLOCK) temporally regulate expression of cytokines. Since cytokines are crucial mediators for shaping immune responses, this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines. Continue reading “Review Article
Temporal Regulation of Cytokines by the Circadian Clock” at:

Research such as the above; should encourage us to support the important work on immune synchronization and timing of cancer treatments recently pioneered by Prof Brendon Coventry (and Martin Ashdown) as featured on my internet radio show: Navigating the Cancer Maze 23 January 2015; please see interviews and links below.

Biological_clock_human_svgProfessor Coventry’s first interview listed on the Science show with Robin Williams was broadcast : Saturday 17 April 2010 !! At last there is an intervention that can positively impact outcomes of treatments and that is relatively non invasive (apart from a series of blood tests over a 2 week period).

The information graphed from results can tell you when your window of opportunity for optimum response from your cancer treatments will be. It is my hope that patients will take the time to read and understand the research on both the immune system and immune synchronization of cancer treatments and its exciting implications and begin to ask for their immune systems rhythm to be measured and evaluated.

Prof Brendon Coventry Adelaide, South Australia
Prof Brendon Coventry Adelaide, South Australia

Prof Brendon Coventry says immune system rhythm, may be a fundamental discovery. Implications are better health and reduced costs for the health system. A survey showed that tumours disappear completely in just 7% of patients when treated with chemotherapy. Did the time of administering chemotherapy have an effect? Daily blood measurements show fluctuation in inflammatory markers in the blood. A cycle emerged. It’s now thought the immune system is being regulated, being switched on and off against the tumour. The periodicity is roughly 7 days. This matters, as hitting the immune system with chemicals when it isn’t receptive might be ineffective.

For more information visit the following URLs

Melanoma Study:


Immune System pulsing – Timing of Treatment

Martin Ashdown Window of Opportunity1

Be a particicipant in the medicines and approaches that could save your life!

until next time…..

Why Innovative Oncology is an Effective Way to Tackle Cancer

Today on Navigating the Cancer Maze I speak with Prof Brendon Coventry about melanoma and in particular, vaccines against melanoma. But more than a melanoma treatment, Cancer Vaccines are showing up as not only as a part of innovative and integrated oncology approaches; but as likely treatments for other types of cancers that have failed conventional treatments such as radiation and chemotherapy protocols.

Today on Navigating the Cancer Maze I speak with Prof Brendon Coventry about melanoma and in particular, vaccines against melanoma. But more than a only a melanoma treatment, Cancer Vaccines are showing up as not only as a part of innovative and integrated oncology approaches; but as likely treatments for other types of cancers that have failed conventional treatments such as radiation and chemotherapy protocols. For example Jeffrey Deslandes, who after 4 recurrences of NH lymphoma – found his success with cancer vaccines. He is 9 years clear of the disease.

Prof Brendon Coventry with Grace Gawler
Prof Brendon Coventry with Grace Gawler

 The combination of Surgical Oncologist  in combination with a PhD in Immunology – is rare; but this is what Prof Coventry brings to the cancer “treatment table”. He has many years experience in cancer research, vaccine therapies and the role of the immune system in cancer control.

To Listen to audio of show – 4 sessions – select  each link below

Listen to Navigating the Cancer Maze-with Prof Brendon Coventry

Sessions one to four  with

Remember the show is for you and sponsored by our charity – The Grace Gawler Institute. It is free to air and free to listen live streaming within an hour of live broadcast. It is archived indefinitely on my Voice America Page. Crucial to the shows intention – to educate patients and families about the availability of  scientifically valid cancer treatments and safe and effective complementary medicine; we ask that you forward the ecard (available on the website) or URL to those you know who are trying to navigate the increasingly complex cancer maze.

Every week, some 160,000 people die of advanced cancer around the world, despite our best attempts at cancer treatment globally. Some $32 billion is being spent on oncology drugs and the USA National Cancer Institute/ NIH spends about $5.2 billion on cancer research, per annum. Sadly, cancer has remained a tremendously costly public health problem of major proportions for over 5 decades, and our progress has been puzzling slow towards solving this using standard methods.

On today’s show, Navigating the Cancer Maze, my guest Professor Brendon Coventry, an Adelaide-based oncology surgeon suggests there may be another way to approach the problem and shows that the immune system my hold the answer. With a special interest in Melanoma Surgery, he is a clinical researcher whose interests include anti-tumour immune response in human malignancies, tumour Immunology and cancer vaccine treatments.

His group’s research paper, published in 2014, entitled “Vaccinia Melanoma Cell Lysate Vaccine (VMCL) Trial for treatment of advanced Stage IV Melanoma with and without Chemotherapy”, captured the attention of medical and scientific community. Trial conclusions reported high complete response rates (where all cancer disappears) of 17%, with useful clinical responses occurring in nearly 80% of patients overall (slowing the disease), and over 15% of patients experiencing survivals past 5-years, with essentially no toxicity. The longest survivor now remains alive for over 14 years. These response rates and survivals are unusual for advanced melanoma. The researchers reason that the repetitive and prolonged delivery of the vaccine therapy might hold part of the clue, because this was a strikingly different approach to that used in other trials.

At this weeks Meeting of Minds in Brisbane Prof Coventry with Grace Gawler and Martin Ashdown
At this weeks Meeting of Minds in Brisbane (LtoR) Martin Ashdown with Grace Gawler and Prof Coventry

Prof Coventry with colleague Martin Ashdown, have now developed a remarkable understanding of how the human immune system continuously oscillates in a dynamic fashion. The timing of ‘when’ the therapy dose is precisely delivered in synchrony with each individual patient’s own immune system waveform or cycle might hold the very key to improving cancer treatment, thus leading to better survival.

Martin Ashdown says: …..”The concept of immune monitoring and accurately synchronizing therapy (immune synchronization), brings a new level of science to oncology. The published mouse experiments and human clinical trials, together with our knowledge of physiology tells us this is the way forward, particularly with the new cancer immunotherapies. This approach potentially has the triple benefit of increasing efficacy, lowering toxicity and substantially reducing the cost of treatment”

Professor Brendon Coventry is well crendentialled

Professor Brendon Coventry BMBS, PhD, FRACS, FACS, FRSM is an Associate Professor of Surgery at the University of Adelaide and Senior Consultant Surgeon (General, Breast-Endocrine, Surgical Oncology & Trauma Surgery) at the Royal Adelaide Hospital since 1993.

He holds a PhD in cancer immunology.

• Immediate Past Chairman, Surgical Oncology Section, Royal Australasian College of Surgeons;
• Research Director, Australian Melanoma Research Foundation & Board Member;
• Past Chairman, Melanoma and Skin Cancer Group, Clinical Oncological Society of Australia;
• Foundation Chairman, Multidisciplinary Melanoma Management Group, Royal Adelaide Hospital
• Senior Examiner, Australian Medical Council
• Board Member of Cancer Care Centre, Unley

• Royal Australasian College of Surgeons,
• American College of Surgeons
• Royal Society of Medicine.

• Over 85 journal publications; including New England Journal of Medicine, British Journal of Cancer, Journal of Clinical Oncology, Lancet Oncology; widely published topics including surgical treatment for melanoma and breast cancer, sentinel node surgery, sarcoma surgery, adjuvant radiation therapy, melanoma vaccine therapies,laparoscopic spleen surgery techniques, neuroscience, microscopic methods, high-sensitivity tissue immunochemistry, public health,
medical education, internet learning.
• NIH Principal Investigator: Multicenter Selective Lymphadenectomy Trial (MSLT-I) surgical sentinel node; C-Vax melanoma vaccine studies (x2).
• Editor-in-Chief, 7-Volume international textbook series “Surgery: Complications, Risks and Consequences” published by Springer; general adult, paediatric and cardio-vascular surgery.
Current Research:
• Surgical Complications, Safety and Quality improvement
• Vaccine Therapies for Advanced Melanoma, novel findings from repetitive dosing where 5-year survival and Complete Response rates have been significantly improved
• Timing of Therapies is novel collaborative work with Martin Ashdown concerning serial blood biomarker monitoring for advanced cancer patients for more accurate timing to improve therapy dose delivery and clinical efficacy further, which is gaining recognition


More on Vaccine successes – listen to Jeffrey Deslandes interviewed on Juice radio – Gold Coast yesterday 16 January 2015.

Sometimes we can’t make financial donations for a cause – but we can use the internet, emails social media and word of mouth to help bring about change. Patient demand through critical need will make a difference- but voices are required! Please spread the word about this interview and the show and make your contribution to change the paradigm of treating cancer for the benefit of humanity.

Until next time

Options, Choices and Treatments for Cancer Recovery| Navigating the Cancer Maze

New cancer treatments are always controversial; BUT – this method is not a treatment. It’s a smart approach. A Smart approach that utilizes all that we know so far about cancer. It works because ultimately; our innate immune system knows what to do.

Options, Choices and Treatments for Cancer Recovery: De mystifying the oscillating the immune cycle.

When my ex husband and I had the idea for starting support groups for cancer patients in the early 1980’s. cancer organizations, patients and doctors were initially not supportive. In fact they were skeptical. They could not see any possible therapeutic benefit could come from people attending a support group.  How wrong they were! Move forward Body rhythms diagram40 years! Yes this December marks my beginning working with cancer patients 40 years ago in a time when there was no support in the health system and no support groups. Now, the benefit of patients attending structured supports and the well being benefit is indisputable.

There are still many new areas to explore, which leads me to discussing the immune cycle. It would seem that during 2014 on Navigating the Cancer Maze – we uncovered and delivered some significant “missing” pieces of the cancer treatment puzzle. It is my hope that as 2014 comes to an end – that 2015 will truly usher in a new paradigm in cancer treatments. The foundation has been laid, extensive research already done, the concept has been introduced worldwide – the  immune cycle measurement is here – NOW!
Now it is up to cancer patients to prove Martin Ashdown and Brendon Coventry right….or wrong. I liked it when Martin Ashdown said – “We believe this is so, a breakthrough – but we are open to being proven wrong!” As in the early days of my first charitable  foundation – it was people power – patient power that made a difference to the success of the Cancer Support Group Movement. Once told there would likely be a measured benefit from attending a support group – the press broadcast the news and the patients came on board en masse!

New cancer treatments are always controversial; BUT – this method is not a treatment. It’s a smart approach. A Smart approach that utilizes all that we know so far about cancer. It works because ultimately; our innate immune system knows what to do. It is just in temporary overwhelm. So doesn’t it make perfect sense that to find the best time to work in synch within the cycle of each person’s immune system to add the best chemotherapy or monoclonal antibody or other targeted treatment. Isn’t this the personalized approach we have been searching for? We all thought it would come in a pill – not an approach and that’s a paradigm shift that some in the world of science and medicine are struggling with.

measuring immune cycleKnowing how one’s immune cycle oscillates holds a clue, “the missing link” that can direct doctors to seek the best time to treat patients in their personal window of opportunity. Then within the parameters of what we know they will have the best chance of a good response or complete response to treatment. (CR)

When cancer cells challenge us – they are also smart. They are a part of us created by our internal systems. You could define cancer as an internal systems error!  These cancer cells cleverly recruit our intelligent mechanisms using them for their own growth and survival. It seems a bit crazy that something that wants to survive – kills its host. But – that’s life! To listen to the latest Voice America related to this blog visit:

So – I believe as do Ashdown and Coventry – that if there is enough of the immune response left in a patient – that the cycle can still be measured and timed so administer the right treatment at the right time. It is simple enough – the only real cost being a series of blood tests. Then finding a doctor who will look at the science and research and say yes – they administer treatment during the 12 hour window of opportunity. The Grace Gawler Institute is keen to let you know and experience the immune cycle for yourself. Please Read more below or join the immune cycle registry at: also see our Next “Survivor Academy” Course!

Martin Ashdown and Brendon Coventry have built upon earlier excellent work in the study of chronobiology: Below are references given on Navigating the Cancer Maze today: I have provided abstract content as well as links.

Until next time……Grace

  • Annu Rev Pharmacol Toxicol. 2010;50:377-421. doi: 10.1146/annurev.pharmtox.48.113006.094626.
    Circadian timing in cancer treatments.
    Lévi F1, Okyar A, Dulong S, Innominato PF, Clairambault J.
    Author information
    The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.
    [PubMed – indexed for MEDLINE]

Ann Pharm Fr. 2008 Jun;66(3):175-84. doi: 10.1016/j.pharma.2008.05.003.
[The circadian-timing system: a determinant of drug activity and a target of anticancer treatments].
[Article in French]
Lévi F.
Author information
Cellular proliferation and drug detoxification are controlled over the 24h by the circadian-timing system, whose disruption can favor malignant processes. Thus, prolonged shift work appears to increase the risk of breast, colon or prostate cancer. Alterations in circadian physiology and/or molecular-clock genes accelerate cancer progression in experimental models and in cancer patients. In addition, anticancer treatments can also dampen or reinforce the circadian-timing system, as a function of dose and time of administration. The adjustment of anticancer-drug delivery to the circadian-timing system (chronotherapeutics) has allowed to reduce five-fold the incidence of severe adverse events as compared to constant rate infusion or wrongly-timed chronomodulated delivery in cancer patients. In experimental models, the best antitumor efficacy is usually obtained following treatment delivery near the least toxic time, a statement that also seems to apply to patients. Dedicated technologies include programmable in time pumps and rhythm monitors and are required for chronotherapeutics. Recent results have revealed that the optimal chronotherapeutic schedule could differ as a function of gender and circadian physiology. In conclusion, the circadian-timing system was shown to negatively control malignant proliferation via partly identified molecular mechanisms. The components of the circadian-timing system thus constitute new potential therapeutic targets in oncology. Mathematical models help toward a better understanding of the role of variability for the determination of the optimal chronotherapeutic schedule and constitute useful tools for the personalization of cancer chronotherapeutics.

Handb Exp Pharmacol. 2013;(217):261-88. doi: 10.1007/978-3-642-25950-0_11.
Cancer chronotherapeutics: experimental, theoretical, and clinical aspects.
Ortiz-Tudela E1, Mteyrek A, Ballesta A, Innominato PF, Lévi F.
Author information
The circadian timing system controls cell cycle, apoptosis, drug bioactivation, and transport and detoxification mechanisms in healthy tissues. As a consequence, the tolerability of cancer chemotherapy varies up to several folds as a function of circadian timing of drug administration in experimental models. Best antitumor efficacy of single-agent or combination chemotherapy usually corresponds to the delivery of anticancer drugs near their respective times of best tolerability. Mathematical models reveal that such coincidence between chronotolerance and chronoefficacy is best explained by differences in the circadian and cell cycle dynamics of host and cancer cells, especially with regard circadian entrainment and cell cycle variability. In the clinic, a large improvement in tolerability was shown in international randomized trials where cancer patients received the same sinusoidal chronotherapy schedule over 24h as compared to constant-rate infusion or wrongly timed chronotherapy. However, sex, genetic background, and lifestyle were found to influence optimal chronotherapy scheduling. These findings support systems biology approaches to cancer chronotherapeutics. They involve the systematic experimental mapping and modeling of chronopharmacology pathways in synchronized cell cultures and their adjustment to mouse models of both sexes and distinct genetic background, as recently shown for irinotecan. Model-based personalized circadian drug delivery aims at jointly improving tolerability and efficacy of anticancer drugs based on the circadian timing system of individual patients, using dedicated circadian biomarker and drug delivery technologies.

Chronobiol Int. 2002 Jan;19(1):1-19.
From circadian rhythms to cancer chronotherapeutics.
Lévi F.
Author information
Mammalian circadian rhythms result from a complex organization involving molecular clocks within nearly all “normal” cells and a dedicated neuroanatomical system, which coordinates the so-called “peripheral oscillators.” The core of the central clock system is constituted by the suprachiasmatic nuclei that are located on the floor of the hypothalamus. Our understanding of the mechanisms of circadian rhythm generation and coordination processes has grown rapidly over the past few years. In parallel, we have learnt how to use the predictable changes in cellular metabolism or proliferation along the 24h time scale in order to improve treatment outcome for a variety of diseases, including cancer. The chronotherapeutics of malignant diseases has emerged as a result of a consistent development ranging from experimental, clinical, and technological prerequisites to multicenter clinical trials of chronomodulated delivery schedules. Indeed large dosing-time dependencies characterize the tolerability of anticancer agents in mice or rats, a better efficacy usually results from treatment administration near the least toxic circadian time in rodent tumor models. Programmable in time multichannel pumps have allowed to test the chronotherapy concepts in cancer patients and to implement chronomodulated delivery schedules in current practice. Clinical phase I and II trials have established the feasibility, the safety, and the activity of the chronotherapy schedules, so that this treatment method has undergone further evaluation in international multicenter phase III trials. Overall, more than 2,000 patients with metastatic disease have been registered in chronotherapy trials. Improved tolerability and/or better antitumor activity have been demonstrated in randomized multicenter studies involving large patient cohorts. The relation between circadian rhythmicity and quality of life and even survival has also been a puzzling finding over the recent years. An essential step toward further developments of circadian-timed therapy has been the recent constitution of a Chronotherapy cooperative group within the European Organization for Research and Treatment of Cancer. This group now involves over 40 institutions in 12 countries. It is conducting currently six trials and preparing four new studies. The 19 contributions in this special issue reflect the current status and perspectives of the several components of cancer chronotherapeutics.
[PubMed – indexed for MEDLINE]
Cancer Causes Control. 2006 May;17(4):611-21.
Chronotherapeutics: the relevance of timing in cancer therapy.
Lévi F.
Author information
Cell physiology is regulated along the 24-h time scale by a circadian timing system composed of molecular clocks within each cell and a central coordination system in the brain. The mammalian molecular clock is made of interconnected molecular loops involving at least 12 circadian genes. The cellular clocks are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker which also helps the organism adjust to environmental cycles. The rest-activity rhythm is a reliable marker of the circadian system function in both rodents and man. This circadian organization is responsible for predictable changes in the tolerability and efficacy of anticancer agents, and possibly also in tumor promotion or growth.
Expected least toxic times of chemotherapy were extrapolated from experimental models to human subjects with reference to the rest-activity cycle. The clinical relevance of the chronotherapy principle, i.e. treatment administration as a function of rhythms, has been demonstrated in randomized multicenter trials.
Chronotherapeutic schedules have been used to safely document the activity of the association of oxaliplatin, 5-FU and leucovorin against metastatic colorectal cancer and to set up a new medicosurgical management of this disease which achieved unprecedented long term survival.
The chronotherapy concept offers further promises for improving current cancer treatment options as well as for optimizing the development of new anticancer or supportive agents.
[PubMed – indexed for MEDLINE]

Mol Med. 2012 Dec 6;18:1249-60. doi: 10.2119/molmed.2012.00077.
Circadian rhythm disruption in cancer biology.
Savvidis C1, Koutsilieris M.
Author information
Circadian rhythms show universally a 24-h oscillation pattern in metabolic, physiological and behavioral functions of almost all species. This pattern is due to a fundamental adaptation to the rotation of Earth around its own axis. Molecular mechanisms of generation of circadian rhythms organize a biochemical network in suprachiasmatic nucleus and peripheral tissues, building cell autonomous clock pacemakers. Rhythmicity is observed in transcriptional expression of a wide range of clock-controlled genes that regulate a variety of normal cell functions, such as cell division and proliferation. Desynchrony of this rhythmicity seems to be implicated in several pathologic conditions, including tumorigenesis and progression of cancer. In 2007, the International Agency for Research on Cancer (IARC) categorized “shiftwork that involves circadian disruption [as] probably carcinogenic to humans” (Group 2A in the IARC classification system of carcinogenic potency of an agent) (Painting, Firefighting, and Shiftwork; IARC; 2007). This review discusses the potential relation between disruptions of normal circadian rhythms with genetic driving machinery of cancer. Elucidation of the role of clockwork disruption, such as exposure to light at night and sleep disruption, in cancer biology could be important in developing new targeted anticancer therapies, optimizing individualized chronotherapy and modifying lighting environment in workplaces or homes.
[PubMed – indexed for MEDLINE]
Free PMC Article

Chronobiol Int. 2012 Apr;29(3):227-51. doi: 10.3109/07420528.2012.658127.
Clock genes and clock-controlled genes in the regulation of metabolic rhythms.
Mazzoccoli G1, Pazienza V, Vinciguerra M.
Author information
Daily rotation of the Earth on its axis and yearly revolution around the Sun impose to living organisms adaptation to nyctohemeral and seasonal periodicity. Terrestrial life forms have developed endogenous molecular circadian clocks to synchronize their behavioral, biological, and metabolic rhythms to environmental cues, with the aim to perform at their best over a 24-h span. The coordinated circadian regulation of sleep/wake, rest/activity, fasting/feeding, and catabolic/anabolic cycles is crucial for optimal health. Circadian rhythms in gene expression synchronize biochemical processes and metabolic fluxes with the external environment, allowing the organism to function effectively in response to predictable physiological challenges. In mammals, this daily timekeeping is driven by the biological clocks of the circadian timing system, composed of master molecular oscillators within the suprachiasmatic nuclei of the hypothalamus, pacing self-sustained and cell-autonomous molecular oscillators in peripheral tissues through neural and humoral signals. Nutritional status is sensed by nuclear receptors and coreceptors, transcriptional regulatory proteins, and protein kinases, which synchronize metabolic gene expression and epigenetic modification, as well as energy production and expenditure, with behavioral and light-dark alternance. Physiological rhythmicity characterizes these biological processes and body functions, and multiple rhythms coexist presenting different phases, which may determine different ways of coordination among the circadian patterns, at both the cellular and whole-body levels. A complete loss of rhythmicity or a change of phase may alter the physiological array of rhythms, with the onset of chronodisruption or internal desynchronization, leading to metabolic derangement and disease, i.e., chronopathology.
[PubMed – indexed for MEDLINE]