How hypothermia induces the UPR

How hypothermia induces the UPR and ER hormesis is unknown. One possibility is that it is simply due to aberrant folding of as yet unknown proteins at low temperatures. Alternatively, hypothermia may induce cold shock proteins such as the RNA binding motif protein 3 (RBM3), which has recently been shown to confer neuroprotection by increasing structural plasticity at the level of synapses ().
In 1971, US President Nixon announced the “war on cancer”. This declaration not only sparked global interest in this devastating disease but also fuelled large investments. Interdisciplinary and international consortia in academic and commercial cancer research and drug development were fostered around the world. Some 40years later, our understanding of the cellular and molecular pathophysiology of many cancer entities has tremendously increased (). This impressive knowledge has led to the establishment of cancer prevention programs, early diagnostics and more effective treatment strategies. However, despite astonishing improvements in certain entities such as cervical, -prostate, and breast cancer, the war on cancer has not been won (). In the US, a total of 1,658,370 new cancer cases and 589,430 cancer deaths are anticipated to occur in 2015 (). Due to the growth and aging of the world population, cancer becomes a global economic problem. In Europe more than US$ 67 billion are spent for cancer patients each year ().
Patients with B-precursor acute lymphoblastic leukemia (BPL) are often treated with TBI-based conditioning, followed by hematopoietic stem-cell transplantation (HSCT). However, the leukemic relapse in high-risk BPL patients remained the major cause of patient mortality (). The incidence of post-HSTC relapse correlated with the level of residual leukemia burden prior to total body irradiation (TBI), indicating the radiation-resistant population of BPL 5-ht receptors may have contributed to the relapse. STAT-3 signaling pathway, along with PI3-K and NFkB pathways, regulates the cell survival after exposure to radiation-induced oxidative stress (), therefore contributes to the radiation resistance of BPL cells. Spleen tyrosine kinase (SYK), a key regulator of STAT-3, was chosen as the main target of reducing the radiation resistance (). The authors identified C61, a small-molecule chemical compound inhibitor for SYK phosphorylation, which sensitized the resistant BPL cells toward radiation. Despite the high selectivity and potent inhibition of C61 against SYK phosphorylation, the in vivo performance of C61 is still limited by pharmacokinetic problems. The low molecular weight of C61 is expected to have short blood circulation and quickly be cleared through the kidney (). The in vivo stability of C61 against various proteases needs to be addressed. In the current issue of , Uckun et al. used liposome nanoparticles to encapsulate C61, increased its blood retention and preserved its integrity for proper function (). The liposome formulation could also alleviate the potential toxic side effects of free C61 (). In their recent work published in , Uckun et al. first studied the correlation between SYK-STAT3 pathway and incidence of relapse in primary ALL samples. The results confirmed that SYK was a key regulator for STAT3 regulation, while patients with early relapse had significantly higher expression levels of SYK-STAT3 genes. The authors then confirmed with in vitro that C61-liposome in combination with low-dose TBI, could deplete leukemia-initiating BPL cells. The xenograft model study showed promising results that the C61-liposome+TBI regimen resulted in a median EFS time of >150days and a remarkable 150-day leukemia-free survival of 80±10%. The authors then evaluated the treatment efficacy in CD22ΔE12xBCR-ABL double transgenic (Tg) model of advanced murine BPL. The combination regiment had the longest duration of remission (54±27days) compared to TBI (7±4days, p=0.021) or C61-liposome (0±0days, p=0.0016). The median OS times were 112days for C61-LNP+TBI but only 4days for CON (Log-rank test, P<0.0001), 3days for C61-LNP alone (P<0.0001), and 14days for TBI alone (P=0.0002).