Personalized Therapy for Metastatic Melanoma: Could Timing Be Everything?

Abstract

There is ample evidence that immune-related processes in humans are under temporal regulation. The circadian variation of humoral and cellular immunity is well documented and appears to be hormonally modulated via the hypothalamic–pituitary–adrenal axis. In advanced melanoma, it has recently been demonstrated that systemic immunity is repolarized toward a global state of chronic inflammation (Th2 dominance) and appears to be governed by infradian biorhythms of cytokines and immune cell subsets, which extend beyond the 24-h circadian variability reported in healthy volunteers. It is suggested that synchronizing administration of lymphodepleting chemotherapy (temozolomide) with these endogenous (individualized) immune dynamics (biorhythms) in patients with advanced/metastatic melanoma improves clinical outcomes compared with temozolomide used in a conventional ‘random delivery’ fashion.

Transgenerational effects of neonatal hypoxia‐ischemia in progeny

“…For example, the observed behavioral deficits of the next generation could be due to epigenetic modifications arising from cross‐talk among the nervous, endocrine, and reproductive systems. There is evidence that throughout development, there is cross‐talk among the nervous, endocrine, digestive, immune, and reproductive systems (Marchetti et al, 1990) and that the nervous system and endocrine system are seamlessly integrated and interact, especially in response to environmental stress (Dronca et al, 2012).…”

About 4-day rhythm of proliferative activity of fibroblast-like cell cultures isn’t endogenous and don’t depend from the variations of Earth’s magnetic field

“…Previously, we have shown that ex vivo production of pro-inflammatory and anti-inflammatory cytokines by spleen cells has a 4-day rhythm 21 . Infradian rhythms of cytokine concentration were detected in the blood of patients with melanoma 9 . There were more stable biorhythms of a larger number of immune parameters [such as IL-12p70, IL-1RA, IL-9, IL-10, IL-13, IL-15, IL-17, G-CSF, VEGF, Th1 cells (CD4 + TIM3 + ), Th2 cells (CD4 + CD294 + ), Tregs (CD4 + CD25 + FoxP3 + ), type 1 dendritic cells (CD11c + HLA-DR + ), type 2 dendritic cells (CD123 + HLA-DR + ), type 1 macrophages (CD14 + CD197 + ) and type 2 macrophages (CD14 + CD206 + )] in patients with metastatic melanoma 9 .…”

“…Infradian about 4-day fluctuations were found in many biological parameters: concentrations of melatonin, glucocorticoid and sex hormones 1 – 6 , motor activity 7 , immune system 8 , 9 , mitotic activity of cells 10 , 11 . Based on the facts that (1) 4-day rhythms are preserved during the removal both of the testes and adrenal glands 12 , and (2) hibernating hedgehogs with reduced hormonal activity had the stable rhythms of spontaneous short-term arousals 13 , it can be argued that the formation of this infradian rhythm is not associated with hormonal regulation.…”

About 4-day Rhythm of Proliferative Activity of Fibroblast-like Cell Cultures Depends on the Environmental Factor

“…Infradian about 4-day uctuations were found in many biological parameters: concentrations of melatonin, glucocorticoid and sex hormones [1][2][3][4][5][6], motor activity [7], immune system [8,9], mitotic activity of cells [10,11]. Based on the facts that 1) 4-day rhythms are preserved during the removal both of the testes and adrenal glands [12], and 2) hibernating hedgehogs with reduced hormonal activity had the stable rhythms of spontaneous short-term arousals [13], it can be argued that the formation of this infradian rhythm is not associated with hormonal regulation.…”