638 research outputs found

    The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome.

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    Epigenetic mechanisms oversee epidermal homeostasis and oncogenesis. The identification of kinases controlling these processes has direct therapeutic implications. We show that ULK3 is a nuclear kinase with elevated expression levels in squamous cell carcinomas (SCCs) arising in multiple body sites, including skin and Head/Neck. ULK3 loss by gene silencing or deletion reduces proliferation and clonogenicity of human keratinocytes and SCC-derived cells and affects transcription impinging on stem cell-related and metabolism programs. Mechanistically, ULK3 directly binds and regulates the activity of two histone arginine methyltransferases, PRMT1 and PRMT5 (PRMT1/5), with ULK3 loss compromising PRMT1/5 chromatin association to specific genes and overall methylation of histone H4, a shared target of these enzymes. These findings are of translational significance, as downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in two orthotopic models of skin cancer

    Prediction of a gene regulatory network linked to prostate cancer from gene expression, microRNA and clinical data

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    Motivation: Cancer is a complex disease, triggered by mutations in multiple genes and pathways. There is a growing interest in the application of systems biology approaches to analyze various types of cancer-related data to understand the overwhelming complexity of changes induced by the disease

    Contrasting properties of particle-particle and hole-hole excitations in 206Tl and 210Bi nuclei

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    A complete-spectroscopy investigation of low-lying, low-spin states in the one-proton-hole and one-neutron-hole nucleus 206Tl has been performed by using thermal neutron capture and \u3b3-coincidence technique with the FIPPS Ge array at ILL Grenoble. The new experimental results, together with data for the one-proton-particle and one-neutron-particle nucleus 210Bi (taken from a previous study done at ILL in the EXILL campaign), allowed for an extensive comparison with predictions of shell-model calculations performed with realistic interactions. No phenomenological adjustments were introduced in the calculations. In 210Bi, state energies, transition multipolarities and decay branchings agree well with theory for the three well separated multiplets of states which dominate the low-lying excitations. On the contrary, in 206Tl significant discrepancies are observed: in the same energy region, six multiplets were identified, with a significant mixing among them being predicted, as a consequence of the smaller energy separation between the active orbitals. The discrepancies in 206Tl are attributed to the larger uncertainties in the determination of the off-diagonal matrix elements of the realistic shell-model interaction with respect to the calculated diagonal matrix elements, the only ones playing a major role in the case of 210Bi. The work points to the need of more advanced approaches in the construction of the realistic interactions

    Volatile lipophilic substances management in case of fatal sniffing.

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    Death due to inhalation of aliphatic hydrocarbons such as butane and propane is a particularly serious problem worldwide, resulting in several fatal cases of sniffing these volatile substances in order to "get high". Despite the number of cases published, there is not a unique approach to case management of fatal sniffing. In this paper we illustrate the volatile lipophilic substances management in a case of a prisoner died after sniffing a butane-propane gas mixture from prefilled camping stove gas canisters, discussing the comprehensive approach of the crime scene, the autopsy, histology and toxicology. A large set of accurate values of both butane and propane was obtained by gas chromatography-mass spectrometry analyzing the following post-mortem biological samples: peripheral blood, heart blood, vitreous humor, liver, lung, heart, brain/cerebral cortex, fat tissue, kidney, and allowed an in depth discussion about the cause of death. A key role is played by following the proper sampling approach during autopsy

    Antitumor activity and expression profiles of genes induced by sulforaphane in human melanoma cells

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    Purpose Human melanoma is a highly aggressive incurable cancer due to intrinsic cellular resistance to apoptosis, reprogramming, proliferation and survival during tumour progression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, plays a role in carcinogenesis in many cancer types. However, the cytotoxic molecular mechanisms and gene expression profiles promoted by SFN in human melanoma remain unknown. Methods Three different cell lines were used: two human melanoma A375 and 501MEL and human epidermal melanocytes (HEMa). Cell viability and proliferation, cell cycle analysis, cell migration and invasion and protein expression and phosphorylation status of Akt and p53 upon SFN treatment were determined. RNA-seq of A375 was performed at different time points after SFN treatment. Results We demonstrated that SFN strongly decreased cell viability and proliferation, induced G2/M cell cycle arrest, promoted apoptosis through the activation of caspases 3, 8, 9 and hampered migration and invasion abilities in the melanoma cell lines. Remarkably, HEMa cells were not affected by SFN treatment. Transcriptomic analysis revealed regulation of genes involved in response to stress, apoptosis/cell death and metabolic processes. SFN upregulated the expression of pro-apoptotic genes, such as p53, BAX, PUMA, FAS and MDM2; promoted cell cycle inhibition and growth arrest by upregulating EGR1, GADD45B, ATF3 and CDKN1A; and simultaneously acted as a potent inhibitor of genotoxicity by launching the stress-inducible protein network (HMOX1, HSPA1A, HSPA6, SOD1). Conclusion Overall, the data show that SFN cytotoxicity in melanoma derives from complex and concurrent mechanisms during carcinogenesis, which makes it a promising cancer prevention agent

    The results of arthroscopic anterior stabilisation of the shoulder using the bioknotless anchor system

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    <p>Abstract</p> <p>Background</p> <p>Shoulder instability is a common condition, particularly affecting a young, active population. Open capsulolabral repair is effective in the majority of cases, however arthroscopic techniques, particularly using suture anchors, are being used with increasing success.</p> <p>Methods</p> <p>15 patients with shoulder instability were operated on by a single surgeon (VK) using BioKnotless anchors (DePuy Mitek, Raynham, MA). The average length of follow-up was 21 months (17 to 31) with none lost to follow-up. Constant scores in both arms, patient satisfaction, activity levels and recurrence of instability was recorded.</p> <p>Results</p> <p>80% of patients were satisfied with their surgery. 1 patient suffered a further dislocation and another had recurrent symptomatic instability. The average constant score returned to 84% of that measured in the opposite (unaffected) shoulder. There were no specific post-operative complications encountered.</p> <p>Conclusion</p> <p>In terms of recurrence of symptoms, our results show success rates comparable to other methods of shoulder stabilisation. This technique is safe and surgeons familiar with shoulder arthroscopy will not encounter a steep learning curve. Shoulder function at approximately 2 years post repair was good or excellent in the majority of patients and it was observed that patient satisfaction was correlated more with return to usual activities than recurrence of symptoms.</p
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