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31.
A. Ari Hakimi Ying-Bei Chen James Wren Mithat Gonen Omar Abdel-Wahab Adriana Heguy Han Liu Shugaku Takeda Satish K. Tickoo Victor E. Reuter Martin H. Voss Robert J. Motzer Jonathan A. Coleman Emily H. Cheng Paul Russo James J. Hsieh 《European urology》2013
Background
Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.Objective
To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.Design, setting, and participants
Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded.Outcome measurements and statistical analysis
The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]).Results and limitations
PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III–IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events.Conclusions
Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted. 相似文献32.
Tetsuro Tago Jun Toyohara Kenji Ishii 《Journal of labelled compounds & radiopharmaceuticals》2020,63(2):85-95
Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family because of its characteristics, namely, its cytoplasmic localization and ubiquitin binding. HDAC6 has been implicated in cancer metastasis and neurodegeneration. In the present study, we performed radiosynthesis and biological evaluation of a fluorine-18–labeled ligand [18F] 3 , which is an analog of the HDAC6-selective inhibitor tubastatin A, for positron emission tomography (PET) imaging. [18F] 3 was synthesized by a two-step reaction composed of 18F-fluorination and formation of a hydroxamic acid group. IC50 values of 3 against HDAC1 and HDAC6 activities were 996 nM and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [18F] 3 . Furthermore, bone radioactivity was stable at around 2% ID/g after injection, suggesting high tolerance to defluorination. Regarding metabolic stability, 70% of the compound was observed as the unchanged form at 30 minutes post injection in mouse plasma. A small animal PET study in mice showed that pretreatment with cyclosporine A had no effect on initial brain uptake of [18F] 3 , suggesting low brain uptake of [18F] 3 was not caused by the P-glycoprotein–mediated efflux. While PET imaging using [18F] 3 has a limitation with respect to neurodegenerative diseases, further studies evaluating its utility for certain cancers are worth evaluating. 相似文献
33.
PAN Dong DU Ya Rong LI Rong SHEN Ai Hua LIU Xiao Dong LI Chuan Yuan HU Bu Rong 《Biomedical and environmental sciences : BES》2022,35(3):194-205
Objective SET8 is a member of the SET domain-containing family and the only known lysine methyltransferase(KMT) that monomethylates lysine 20 of histone H4(H4 K20 me1). SET8 has been implicated in many essential cellular processes, including cell cycle regulation, DNA replication, DNA damage response, and carcinogenesis. There is no conclusive evidence, however, regarding the effect of SET8 on radiotherapy. In the current study we determined the efficacy of SET8 inhibition on radiotherapy of tum... 相似文献
34.
目的探讨丙戊酸(VPA)联合伏立诺他(SAHA)增强阿糖胞苷(Ara-c)对人Dami白血病细胞株的杀伤作用,并探讨其分子学机制。方法设空白对照组、Ara-c组、VPA组、SAHA组、VPA+Ara-c组、SAHA+Ara-c组,VPA+SAHA+Ara-c组,分别作用于对数生长期的Dami白血病细胞,MTT比色法检测药物对细胞的生长抑制作用;用PI法通过流式细胞仪检测细胞周期;RT-PCR方法检测转录因子GATA-1、胞苷脱氨酶(CDA)及脱氧胞苷激酶(DCK)mRNA水平的变化。结果 VPA和SAHA共同联合Ara-c用药组细胞生长抑制率明显高于VPA联合Ara-c组及SAHA联合Ara-c组,各组间相比,具有显著性差异。Dami细胞经过VPA和SAHA处理后均出现细胞周期阻滞现象,主要阻滞在G1期,与对照组相比差异有显著性(P0.05);VPA和SAHA联合用药组G1期细胞所占比例高于SAHA组(P0.05),与VPA组差异无显著性(P0.05)。VPA组、SAHA组、VPA和SAHA联合用药组GATA-1和CDA mRNA表达水平均低于对照组(P0.05),各组间差异无显著性(P0.05);VPA组DCK mRNA表达水平高对照组(P0.05)、SAHA组与对照组比较差异无显著性(P0.05)、VPA和SAHA联合用药组DCK mRNA表达水平高于VPA组和SAHA组(P0.05)。结论 VPA联合SAHA可增强阿糖胞苷对Dami白血病细胞的杀伤作用,可能是通过增加DCK的表达,从而增加阿糖胞苷体内活性代谢产物所致。 相似文献
35.
Paulina Misztak Patrycja Pańczyszyn-Trzewik Magdalena Sowa-Kućma 《Pharmacological reports : PR》2018,70(2):398-408
Major depressive disorder (MDD) represents approximately 40% of the disability caused by mental illnesses globally. The poorly understood pathophysiology and limited efficiency of pharmacological treatment (based primarily on the principles of the monoaminergic hypothesis) make depression a serious medical, public and socio-economical problem. An increasing number of studies suggest that epigenetic modifications (alterations in gene expression that are not due to changes in DNA sequence) in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of mental disorders. Accordingly, chromatin-based epigenetic regulation seems to be a promising direction for the development of new, more effective antidepressant drugs. Recently, several inhibitors of histone deacetylases (HDAC) have been extensively studied in the context of antidepressant action. So far, none of them has been used to treat depression in humans due to the low selectivity for specific HDAC isoforms, and consequently, a risk of serious adverse events. In this review, we focus on the HDAC inhibitors (HDACi) with the greatest antidepressant efficacy and their activity in the preclinical studies. Moreover, we discuss their potential therapeutic usefulness in depression and the main limitations. 相似文献
36.
Background
Even after several novel therapeutic approaches, the number of people with diabetic nephropathy (DN) still continues to increase globally, this suggest to find novel therapeutic strategies to prevent it completely. Recent reports, are indicating the ubiquitin proteasome system alterations in DN. Recently, we also showed that, histone H2AK119 mono-ubiquitination (H2AK119-Ub) found to regulate Set7, a key epigenetic enzyme in the development of renal fibrosis under type 1 diabetic condition. Hence, we aimed to study the role of a known 20 s proteasome inhibitor Aspirin, on histone ubiquitination in the progression of DN.Methods
Male Wistar rats were rendered diabetic using a single dose of Streptozotocin (55 mg kg?1, ip). After 4 weeks, diabetic animals were grouped into respective groups and the drug, aspirin, low dose (25 mg kg?1 day?1), high dose (50 mg kg?1 day?1) was administered through po route. At the end of the study, kidneys from all the groups were collected and processed separately for glomerular isolation, protein isolation, and for histopathological studies.Results
Aspirin administration, reduced the protein expression of Mysm1, increased the protein expression of H2AK119-Ub and thereby reduced the Set7 protein expression in glomeruli isolated from diabetic animals and prevented renal fibrosis.Conclusions
In conclusion, our results are clearly indicating that, aspirin prevents renal fibrosis in diabetic animals through decreasing the expression of Mysm1, increasing the expression of H2AK119-Ub and thereby decreasing the protein expression of Set7, which is a novel mechanism. Moreover, this mechanism may lay down a novel strategy to prevent DN completely in future. 相似文献37.
Iris Šalamon Arčan Katarina Kouter Alja Videtič Paska 《World Journal of Psychiatry》2022,12(9):1150-1168
Depressive disorder is a complex, heterogeneous disease that affects approximately 280 million people worldwide. Environmental, genetic, and neurobiological factors contribute to the depressive state. Since the nervous system is susceptible to shifts in activity of epigenetic modifiers, these allow for significant plasticity and response to rapid changes in the environment. Among the most studied epigenetic modifications in depressive disorder is DNA methylation, with findings centered on the brain-derived neurotrophic factor gene, the glucocorticoid receptor gene, and the serotonin transporter gene. In order to identify biomarkers that would be useful in clinical settings, for diagnosis and for treatment response, further research on antidepressants and alterations they cause in the epigenetic landscape throughout the genome is needed. Studies on cornerstone antidepressants, such as selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, norepinephrine, and dopamine reuptake inhibitors and their effects on depressive disorder are available, but systematic conclusions on their effects are still hard to draw due to the highly heterogeneous nature of the studies. In addition, two novel drugs, ketamine and esketamine, are being investigated particularly in association with treatment of resistant depression, which is one of the hot topics of contemporary research and the field of precision psychiatry. 相似文献
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