There is increasing interest in the role of epigenetic and transcriptional dysregulation in the pathogenesis of a range of human diseases, not just in the best-studied example of cancer. It is, however, quite difficult for an individual investigator to perform these studies, as they involve genome-wide molecular assays combined with sophisticated computational analytical approaches of very large datasets that may be generated from various resources and technologies. In 2008, the Albert Einstein College of Medicine in New York, USA established a Center for Epigenomics to facilitate the research programs of its investigators, providing shared resources for genome-wide assays and for data analysis. As a result, several avenues of research are now expanding, with cancer epigenomics being complemented by studies of the epigenomics of infectious disease and a neuroepigenomics program.
The enzyme catechol-O-methyltransferase (COMT) transfers a methyl group from S-adenosylmethionine to the benzene ring of catecholamines including the neurotransmitters dopamine, epinephrine and norepinephrine. This methylation results in the degradation of catecholamines. The involvement of the COMT gene in the metabolic pathway of these neurotransmitters has made it an attractive candidate gene for many psychiatric disorders. This review focuses on the association between the genetic polymorphisms of COMT gene and psychiatric disorders.
Using the type III restriction-modification enzyme EcoP15I, we isolated sequences flanking sites digested by the methylation-sensitive HpaII enzyme or its methylation-insensitive MspI isoschizomer for massively parallel sequencing. A novel data transformation allows us to normalise HpaII by MspI counts, resulting in more accurate quantification of methylation at >1.8 million loci in the human genome. This HELP-tagging assay is not sensitive to sequence polymorphism or base composition and allows exploration of both CG-rich and depleted genomic contexts.
To observe and analyze the mutation phenomenon of 17 STR loci of PowerPlex 18D Kit in paternity test of Yunnan population.The DNA was extracted by Chelex-100 method. The PowerPlex 18D Kit was used to test 1,483 cases and their conclusions of paternity tests were verified.In the 1,483 cases, 1,047 were parental triplet and 436 were uniparental diad. A total of 2,530 times of meiosis was observed. One STR locus mutation was observed in 24 cases. And 11 mutation loci were found in the 17 STR loci.STR loci mutation is a common phenomenon. We should collect the data of STR loci mutation, choose other good polymorphism, low mutation rate of genetic markers, to ensure that the results are accurate and reliable.
Abstract KRAS mutations are frequently found in various types of cancers with an overall mutation frequency of 19.3%. G12C mutation of KRAS (KRASG12C) represents 11.4% of all KRAS mutations in cancer. Targeting KRAS mutations as a cancer treatment strategy has long been investigated for over 30 years already but still remains unconquered field. XNW14010 is a highly selective KRASG12C inhibitor that is rationally designed from AMG510, another proven covalent inhibitor of KRASG12C with potential antineoplastic activity. Compared to AMG510, XNW14010 demonstrated a better pharmaceutical potential and a better safety profile. XNW14010 does not have an axial chiral center shown in AMG510, thus the production cost of this agent could be vastly reduced. The in vitro efficacy of XNW14010 was tested in a variety of cancer cell lines with either wild type KRAS or different mutant KRAS, including lung cancer, colorectal cancer, and pancreatic cancer. The result shows that XNW14010 potently inhibits the activity of KRASG12C, but not wild type KRAS or KRAS bearing other mutations. Specifically, in a pancreatic cancer cell line MIA PaCa-2, which bears KRASG12C, the IC50 of XNW14010 is 26 nM. Furthermore, XNW14010 demonstrated a much less plasma protein binding (PPB) than AMG510 (50.4% versus 93.2%, respectively), suggesting much great potential to penetrating into tumor tissue for XNW14010 compared to AMG510. XNW14010 exhibited comparable or superior pharmacokinetic characteristics compared to AMG510 after oral administration in animal studies. More interestingly, XNW14010 has an improved brain penetration capability. The brain/plasma ratio of XNW14010 exposure is two folds as high as that of AMG510 and the Cmax of XNW14010 in brain tissue is also much higher. XNW14010 had a wider therapeutic window and good tolerance compared to AMG510, both in mouse and dog models, suggesting potentially better safety profile in humans. We also compared the antineoplastic activity of XNW14010 with that of AMG510 in vivo in Xenograft mouse models including lung cancer, colorectal cancer, and pancreatic cancer. The results demonstrated that XNW14010 has comparable antineoplastic activities to AMG510 when administered at the same doses. In pancreatic cancer, the total growth inhibition (TGI) is 90% when administered at the dose of 10 mg/kg QD. Given the better PPB, superior brain penetrating capacity, and similar antineoplastic activitie of XNW14010 compared to AMG510 in non-clinical studies, XNW14010 is expected to be a potent therapeutic candidate in treating cancers bearing KRASG12C, including pancreatic cancer. Citation Format: Yonghan Hu, Xin Li, Bin Huang, Liang Kong, Meijie Le, Yan Li, Cungang Liu, Xiaojun Liu, Bin Qian, Jing Qiang, Qifeng Shi, Wengui Wang, Yuchuan Wu, Zhenwei Wu, Linfeng Xu, Jinfeng Zhao. XNW14010:A highly selective KRASG12C inhibitor with potent efficacy in animal model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A071.
Long-span bridges are subjected to wind and temperature actions. Wind action is generally the governing load of long-span bridges in design, while temperature action is also significant. Accurate separation of typhoon- and temperature-induced responses is thus necessary for in-depth investigation of their effects and comprehensive evaluation of structural performance. This paper separates the temperature- and typhoon-induced responses of the Qingzhou Bridge by using a unified global analysis approach. The field-monitored meteorological data and structural responses collected from the structural health monitoring system installed on the bridge are analyzed in detail, with emphasis on the comparison of those during typhoon Higos (Signal No. 9) and a typical sunny day after the typhoon. Results show that the quasi-static variation of displacement and stress responses are higher on a typical sunny day than those during the typhoon period, which is out of intuition. Through the unified analysis, the temperature-induced responses are calculated, and the typhoon-induced responses can be separated. The temperature- and typhoon-induced longitudinal displacement, mid-span deflection, and stress of the girder are compared. The temperature-induced response accounts for a large part of the total quasi-static recording either on a typical sunny day or during the typhoon period, whereas typhoon caused significant dynamic responses. The typhoon-induced quasi-static and dynamic responses are also in good agreement with the wind tunnel test results. This case study demonstrates the effectiveness of the unified global analysis in separating the temperature effect.
Objective: To study the feasibility of using oral muomembranous cells as contrast sample for chimerism testing after allogeneic peripheral blood stem cell transplantation(allo-PBSCT)when the contrast sample before operation isn't available.Methods: 2 samples,one from peripheral blood of donor,the other from that of acceptor before allo-PBSCT and the peripheral blood and oral muomembranous cells from acceptor after allo-PBSCT were collected,the DNA was extracted and analyzed by PCR-STR technique.Results: The genotype of the acceptor's peripheral blood before allo-PBSCT and oral muomembranous cells after allo-PBSCT was identical.The genotype of peripheral blood from the acceptor after allo-PBSCT and that of peripheral blood from the donor was identical.Conclusion: The genotype of oral muomembranous cells after allo-PBSCT may stand for the samples before operation,thus it can be used as contrast sample for chimerism testing,especially when the contrast sample before operation isn't available.
Abstract Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, is a member of the STE20 family of serine/threonine kinases, and restrictedly expressed in hematopoietic cells. In T cells, HPK1 negatively regulated TCR signaling by phosphorylating the adaptor protein SLP76 on Ser376, which leads to the dissociation of the SLP-76/LAT signalosomes and downregulation of T cell priming and activation. HPK1 knockout (KO) or kinase-inactive (KI) mice spontaneously reject tumors with an enhanced immune response compared to wild-type ones. Thus, HPK1 is a novel immuno-oncology (I/O) target. In this work, we described the discovery of a potent HPK1 inhibitor starting from comprehensive SAR-based design with guidance from X-ray crystallography and computational modeling. These efforts led to identification of the potent azaindole inhibitor XNW21015, with excellent kinase selectivity and promising PK profile of low clearance and sufficient exposure for in vivo animal studies. XNW21015 dose-dependently inhibited phosphorylation of SLP76(Ser376) in vitro and in vivo in response to anti-CD3 agonist antibody, with concomitant enhancement in T cell activation. Oral administration of XNW21015 in mouse syngeneic tumor models showed favorable PK profile and robust anti-tumor activity as both single agent and in combination with immune checkpoint inhibitors. In a humanized PDX (patient-derived xenograft) model, XNW21015 enhanced tumor-infiltrated lymphocytes (TIL). In summary, we have discovered a novel, highly potent and selective HPK1 inhibitor XNW21015 as promising small molecule I/O agent, as monotherapy or in combination with immune checkpoint inhibitors. Citation Format: Yuchuan Wu, Rui Hao, Xi Chen, Xiao Liu, Yonghua Xie, Shihua Wang, Bingquan Gao, Jichun Wen, Zhenwei Wu, Wengui Wang, Haiyang Wei, Yonghan Hu, Xiaojun Liu, Meijie Le, Jing Qiang. Discovery of XNW21015, a novel, potent HPK1 inhibitor with excellent immune modulatory activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1821.
Abstract Objectives: To compare the clinical efficacy and safety of single-use and reusable digital flexible ureteroscopy for the treatment of lower pole stones. Methods :We enrolled 135 patients underwent reusable flexible ureteroscopy (FURS) and 78 patients underwent single-use digital FURS. Demographic,clinical variables,anatomical parameters of the lower calyx and perioperative indicators were compared in the two groups. Results : 36 patients in the infundibuloureter angle (IPA) ＜45° subgroup had a mini-percutaneous nephrolithotomy (mini-PCNL), including 25 patients in the reusable FURS group and 11 patients in the single-use FURS group.The demographic and clinical variables in the two FURS groups were comparable.There was no statistical difference in the success rate of stone searching( P >0.05). In terms of the success rate of lithotripsy,there was also no statistical difference in the IPA ≥45°subgroup( P >0.05),whereas single-use FURS was superior in the IPA<45°subgroup(χ2=6.513, P =0.011).The length of the working fiber in the reusable FURS and single-use FURS groups was 3.20±0.68 mm and 1.75±0.47 mm, respectively(t=18.297, P <0.05).The use of a stone basket in the reusable FURS (31/135,23.0%) was significantly higher than that in the single-use FURS(8/78,10.3%) (χ2=5.336, P =0.021).Compared with the reusable FURS group, the single-use FURS group had shorter operation times( P <0.05) and higher stone-free rate(SFR) (χ2=4.230, P=0.040).There was no statistical difference in the intraoperative transfer of mini-PCNL and postoperative complications between the two groups( P >0.05). Conclusions :Single-use and reusable FURS are alternative methods for removal of lower pole stones (i.e., 2 cm or less). Single-use FURS has a high success rate of lithotripsy,shorter operation time,and high stone-free rate.
Alzheimer's disease (AD), the most common age-dependent neurodegenerative disorder, produces a progressive decline in cognitive function. The metabolic mechanism of AD has emerged in recent years. In this study, we used multivariate analyses of gas c
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