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With the development of energy-storage devices, separator is encountered by several challenges including adequate safety, higher current density and superior stability. Tissue paper, composed of packed cellulose fibers, possesses lower production cost, more easily accessibility, superior wettability and outstanding thermostability, thus being prospective as a substrate of high performance separator. To address structure collapse phenomenon occurred in conventional coating layer after long term electrolyte swelling, nano-SiO2 hybrid crosslinked network was constructed on tissue paper through chemical reactions between polymer poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and hyperbranched polyethyleneimine (PEI) in this work. The influences of crosslinking degree on physical properties and electrochemical performance were studied thoroughly. It can be found that when the crosslinking ratio of PVDF-HFP and PEI fixed at 10:1, the crosslinked composite separator displays excellent electrolyte uptake and wettability, superior ionic conductivity, better interfacial compatibility as well as higher Li+ transference number (0.56), thus offering battery with prominent rate capabilities. Besides, this crosslinked composite separator exhibits satisfying dimensional stability even treated at 250 oC, better flame retardancy, enhanced mechanical behavior, wider electrochemical window and outstanding cycle stability. Accordingly, tissue paper-based crosslinked composite separator can meet higher requirements put forward by high power lithium ion battery.

It is well established that ferroptosis is primarily controlled by glutathione peroxidase 4 (GPX4). Surprisingly, we observed that p53 activation modulates ferroptotic responses without apparent effects on GPX4 function. Instead, ALOX12 inactivation diminishes p53-mediated ferroptosis induced by reactive oxygen species stress and abrogates p53-dependent inhibition of tumour growth in xenograft models, suggesting that ALOX12 is critical for p53-mediated ferroptosis. The ALOX12 gene resides on human chromosome 17p13.1, a hotspot of monoallelic deletion in human cancers. Loss of one Alox12 allele is sufficient to accelerate tumorigenesis in Eμ-Myc lymphoma models. Moreover, ALOX12 missense mutations from human cancers abrogate its ability to oxygenate polyunsaturated fatty acids and to induce p53-mediated ferroptosis. Notably, ALOX12 is dispensable for ferroptosis induced by erastin or GPX4 inhibitors; conversely, ACSL4 is required for ferroptosis upon GPX4 inhibition but dispensable for p53-mediated ferroptosis. Thus, our study identifies an ALOX12-mediated, ACSL4-independent ferroptosis pathway that is critical for p53-dependent tumour suppression.

// Ning Kon 1,* , Donglai Wang 1,* , Tongyuan Li 1 , Le Jiang 1 , Li Qiang 2,3,** and Wei Gu 1,3 1 Institute for Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, New York, USA 2 Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA 3 Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, New York, USA * These two authors contributed equally to this work ** This author is listed as a co-corresponding author Correspondence to: Wei Gu, email: // Keywords : p53; Mdmx; Mdm4; metabolism; adipose tissues Received : September 26, 2017 Accepted : December 08, 2017 Published : January 02, 2018 Abstract Although cell-cycle arrest, senescence and apoptosis remain as major canonical activities of p53 in tumor suppression, the emerging role of p53 in metabolism has been a topic of great interest. Nevertheless, it is not completely understood how p53-mediated metabolic activities are regulated in vivo and whether this part of the activities has an independent role beyond tumor suppression. Mdmx (also called Mdm4), like Mdm2, acts as a major suppressor of p53 but the embryonic lethality of mdmx-null mice creates difficulties to evaluate its physiological significance in metabolism. Here, we report that the embryonic lethality caused by the deficiency of mdmx , in contrast to the case for mdm2 , is fully rescued in the background of p53 3KR/3KR , an acetylation-defective mutant unable to induce cell-cycle arrest, senescence and apoptosis. p53 3KR/3KR /mdmx -/- mice are healthy but skinny without obvious developmental defects. p53 3KR/3KR /mdmx -/- mice are resistant to fat accumulation in adipose tissues upon high fat diet. Notably, the levels of p53 protein are only slightly increased and can be further induced upon DNA damage in p53 3KR/3KR /mdmx -/- mice, suggesting that Mdmx is only partially required for p53 degradation in vivo . Further analyses indicate that the anti-obesity phenotypes in p53 3KR/3KR /mdmx -/- mice are caused by activation of lipid oxidation and thermogenic programs in adipose tissues. These results demonstrate the specific effects of the p53/Mdmx axis in lipid metabolism and adipose tissue remodeling and reveal a surprising role of Mdmx inhibition in anti-obesity effects beyond, commonly expected, tumor suppression. Thus, our study has significant implications regarding Mdmx inhibitors in the treatment of obesity related diseases.

Purpose We aimed to evaluate the role of cone-beam computed tomography (CT) performed as an adjunct to angiography for the determination of feeding vessels responsible for bleeding during arterial embolization for massive hemoptysis. Methods In this retrospective study, 23 patients with massive hemoptysis who underwent cone-beam CT evaluation prior to arterial embolization from December 2014 to December 2017 were included. During the angiographic session, two interventional radiologists selected the possible feeding vessels that were likely to supply the bleeding target lesions. Contrast-enhanced cone-beam CT was performed at the indefinite feeding arteries as an adjunct to angiography to determine whether the artery was a real feeding vessel, based on whether the target lesion was detected in the perfused territory of the study artery on images. Results Selective cone-beam CT was successfully performed in 21 patients, at 26 possible feeding vessels that were detected by selective angiography. Cone-beam CT determined the feeding vessel in 24 arteries (92.3%) in 19 patients (90.5%). As a result of cone-beam CT findings, 16 of 24 study arteries were judged as definitively not feeding vessels (66.7%) and the remaining 8 study arteries were judged as definitively feeding vessels (33.3%). In 2 of 26 study arteries cone-beam CT could not determine the feeding vessel (7.7%). Conclusion Cone-beam CT performed as an adjunctive technique to angiography is sufficient to provide adequate information for confident determination of the feeding vessel, which is essential for the operators to perform accurate embolization during arterial embolization for massive hemoptysis.

It is well established that the p53 tumor suppressor plays a crucial role in controlling cell proliferation and apoptosis upon various types of stress. There is increasing evidence showing that p53 is also critically involved in various metabolic pathways, both in tumor and normal cells. Here, we have identified a novel p53 metabolic target pantothenate kinase-1 (PANK1) via ChIP-on-chip. PanK1 catalyzes the rate-limiting step for CoA synthesis and, therefore, controls intracellular CoA content; Pank1-knockout mice exhibit defect in β-oxidation and gluconeogenesis in the liver after starvation due to insufficient CoA levels. We demonstrated that PANK1 gene is a direct transcriptional target of p53. Although DNA damage-induced p53 upregulates PanK1 expression, depletion of PanK1 expression does not affect p53-dependent growth arrest or apoptosis. Interestingly, upon glucose starvation, PanK1 expression is significantly reduced in HCT116 p53 (-/-) but not in HCT116 p53 (+/+) cells, suggesting that p53 is required to maintain PanK1 expression under metabolic stress conditions. Moreover, by using p53-mutant mice, we observed that, similar to the case in Pank1-knockout mice, gluconeogenesis is partially impaired in p53-null mice. Together, our findings show that p53 plays an important role in regulating energy homeostasis through transcriptional control of PANK1, independent of its canonical functions in apoptosis and cell cycle arrest.

Cell-cycle arrest, apoptosis, and senescence are widely accepted as major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53K117R) or three (p533KR; K117R+K161R+K162R) of the critical p53 acetylation sites. While p53K117R/K117R cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p533KR/3KR cells. Surprisingly, unlike p53-null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53K117R/K117R or p533KR/3KR animals. Notably, p533KR retains the ability to modulate energy metabolism and reactive oxygen species (ROS) production by regulating metabolic p53 target genes. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppression of early-onset spontaneous tumorigenesis.

Human DDX11 and DDX12 are closely related genes encoding the helicases ChlR1 and ChlR2, which belong to the CHL1 DNA helicase family. Recently, it was shown that human ChlR1 interacts with components of the cohesin complex and is required for proper centromeric cohesion. To establish the function of ChlR1 in development we made a mutant mouse lacking Ddx11, the single mouse ChlR gene. The absence of Ddx11 resulted in embryonic lethality at E10.5. The mutant embryos were smaller in size, malformed and exhibited sparse cellularity in comparison to normal or heterozygous litter mates. Importantly, loss of Ddx11 resulted in the inability to form a proper placenta, indicating that ChlR1 is essential for placental formation. Detailed analysis of cells isolated from Ddx11-/- embryos revealed a G2/M cell cycle delay, an increased frequency of chromosome missegregation, decreased chromosome cohesion, and increased aneuploidy. To examine whether ChlR proteins are required for arm cohesion and for loading of the cohesin complex, further studies were preformed in ChlR1 siRNA treated cells. These studies revealed that ChlR1 is required for proper sister chromatid arm cohesion and that cohesin complexes bind more loosely to chromatin in the absence of ChlR1. Taken together, these studies provide the first data indicating that the ChlR1 helicase is essential for proper binding of the cohesin complex to both the centromere and the chromosome arms, and indicate that ChlR1 is essential for embryonic development and the prevention of aneuploidy in mammals.

The CDK11(p110) protein kinases are part of large-molecular-weight complexes that also contain RNA polymerase II, transcriptional elongation factors, and general pre-mRNA splicing factors. CDK11(p110) isoforms may therefore couple transcription and pre-mRNA splicing by their effect(s) on certain proteins required for these processes. The CDK11(p58) kinase isoform is generated from the CDK11(p110) mRNA through the use of an internal ribosome entry site in a mitosis-specific manner, suggesting that this kinase may regulate the cell cycle during mitosis. The in vivo role and necessity of CDK11(p110/p58) kinase function during mammalian development were examined by generating CDK11(p110/p58)-null mice through targeted disruption of the corresponding gene using homologous recombination. While heterozygous mice develop normally, disruption of both CDK11(p110/p58) alleles results in early embryonic lethality due to apoptosis of the blastocyst cells between 3.5 and 4 days postcoitus. Cells within these embryos exhibit both proliferative defect(s) and a mitotic arrest. These results are consistent with the proposed cellular functions of the CDK11(p110/p58) kinases and confirm that the CDK11(p110/p58) kinases are essential for cellular viability as well as normal early embryonic development.

Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 suppresses tumor formation. Nevertheless, it remains unclear how these p53 responses are differentially controlled in vivo and whether they are absolutely required for tumor suppression. p53 is regulated by an exquisite network of fine-tuning mechanisms that ensure proper responses to the various stress signals encountered by cells. In broad terms, p53 activities are controlled via protein levels, coactivator/corepressor recruitment, and a diverse array of post-translational modifications that includes acetylation, ubiquitination, phosphorylation, methylation, sumoylation, and neddylation. p53 was the first non-histone protein shown to be regulated functionally by acetylation and deacetylation and subsequent work has established that acetylation plays a major role in controlling promoter-specific activation of p53 targets during stress responses. We and others recently showed that p53 is acetylated at K120 by Tip60/MOF, while K164 is acetylated by CBP and p300, but not Tip60/MOF. Both sites are mutated in human tumors and well conserved in all species known to encode p53. Interestingly, K120 acetylation is crucial for p53-mediated apoptosis but has no obvious effect on cell cycle arrest, while simultaneous loss of acetylation at all major sites abolishes the ability of p53 to induce both cell cycle arrest and apoptosis, suggesting that acetylation is essential for both p53-mediated processes. Nevertheless, the role of acetylation in the most critical aspect of p53 function, its capacity to suppress tumor formation, has not been addressed. To investigate whether p53 acetylation is important for tumor suppression, we generated p53-mutant mice (p53K117R/K117R) in which K117 (K120 in human) is replaced by arginine. In these animals, p53-mediated apoptosis is abrogated but p53-dependent cell cycle arrest and senescence remain intact. We also established mice (p533KR/3KR) in which the three acetylation sites of the DNA-binding domain (K117, K161, K162) were simultaneously replaced by arginine. Significantly, loss of acetylation at these three sites completely abolished the ability of p53 to mediate cell cycle arrest, apoptosis, and senescence in vivo. To evaluate whether these p53-dependent processes are required for tumor suppression, we monitored tumor formation in cohorts of p53 acetylation-deficient mice. Although p53-null mice rapidly develop spontaneous thymic lymphomas, neither p53K117R/K117R nor p533KR/3KR mice are prone to early-onset tumorigenesis. Since tumor suppression can be mediated by a p53 polypeptide (e.g., p533KR) that lacks the ability to induce p53-dependent cell cycle arrest, apoptosis, and senescence, these results indicate that other aspects of p53 function are sufficient to suppress tumor formation. Notably, p533KR retains the ability to modulate energy metabolism and reactive oxygen species (ROS) production by regulating metabolic target expression. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppression of early-onset spontaneous tumorigenesis. Our study thus reveals that current views regarding the mechanism of p53-mediated tumor suppression should be reconsidered. Citation Format: Tongyuan Li, Ning Kon, Le Jiang, Ying Zhao, Richard Baer, Wei Gu. Tumor suppression in the absence of p53-mediated cell cycle arrest, apoptosis, and senescence. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY02-02. doi:10.1158/1538-7445.AM2013-SY02-02