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关键词： 血液肿瘤   骨髓细胞   细胞形态学   免疫表型   遗传学   分子生物学  

摘要： 血液肿瘤是一种常见的恶性肿瘤,我国已将其列入重点防治的十大恶性肿瘤之一。白血病占恶性肿瘤总发病数的5%左右,发病以儿童和青年居多,在我国各年龄组恶性肿瘤的死亡率中占第六位(男性)和第八位(女性),在儿童及35岁以下的人群中则占第一位。实验室检测技术是其诊断的重要手段,目前检测方法有很多,快速、廉价、准确的使用方法是临床所期待的。笔者就血液肿瘤实验室检测技术现状进行综述。

关键词： 自闭症谱系障碍   表观遗传学   危险因素  

摘要： 自闭症谱系障碍(autism spectrum disorders, ASD)是一种神经发育障碍,目前ASD的病因尚不明确,但涉及多种因素和基因与环境的相互作用。文章综述了表观遗传对ASD可能的危险因素,如产前因素、环境因素,同时也提到表观遗传机制对ASD的影响,如DNA甲基化。这些危险因素与表观遗传机制可能会在干预ASD与降低风险中提供方向。

关键词： 白血病   B细胞   儿童   细胞遗传学分析   预后  

摘要： 目的探讨初发儿童急性B淋巴细胞白血病(B-ALL)的细胞遗传学特征及首次治疗反应相关影响因素。方法回顾性收集2019年4月至2021年9月厦门大学附属第一医院收治的49例初发B-ALL患儿资料,获得患儿临床特征、细胞遗传学和分子生物学检查结果、治疗前后临床指标等数据。按照儿童ALL诊疗规范(2018版),进行基因分型和首次诱导化疗后临床危险度分层及化疗方案制订。分析B-ALL患儿不同基因分型与临床指标的关系,采用Spearman等级相关分析法分析临床危险度分层与各指标的相关性。结果49例患儿中位年龄3.0岁(四分位数间距:3.2岁),男性32例(65.3%),女性17例(34.7%),男女比1.88∶1。治疗前基因突变35例(71.4%),无突变14例(28.6%)。基因突变35例中,E2A-PBX15例(10.2%),其中伴费城染色体(Ph)样1例;IKZF1缺失8例(16.3%),其中伴Ph样4例,伴Ph阳性1例,伴MLL重排1例;MLL重排3例(6.1%);单独Ph样12例(24.5%);TEL-AML16例(12.2%),其中伴Ph样2例;单独Ph阳性1例(2.0%)。临床危险度分层高危7例(14.3%),中危28例(57.1%),低危14例(28.6%)。诱导化疗前基因突变患者临床危险度高、中危患者比例[20.0%(7/35)比0.0%(0/14)、62.9%(22/35)比42.9%(6/14)]及诱导化疗第33天基因突变情况发生改变患者比例[42.9%(15/35)比0.0%(0/14)]均高于治疗前基因未突变患者(均P<0.01),诱导化疗前是否基因突变与性别、初诊时白细胞计数、激素敏感性、诱导化疗第15天至第19天骨髓微小残留病(MRD)、诱导化疗第33天MRD均不相关(均P>0.05)。患儿临床危险度分层与初诊时白细胞计数(r=0.392,P=0.005)、中性粒细胞计数(r=0.453,P=0.001)、淋巴细胞计数(r=0.418,P=0.001)、单核细胞计数(r=0.359,P=0.017)、血尿酸水平(r=0.378,P=0.007)、治疗前(r=0.316,P=0.027)和诱导化疗第15天至第19天(r=0.399,P=0.005)及诱导化疗第33天骨髓幼稚淋巴细胞比例(r=0.408,P=0.028)以及诱导化疗第33天骨髓MRD≥0.0001患儿比例(χ^(2)=15.42,P<0.001)、治疗前基因突变患儿比例(χ^(2)=9.10,P=0.005)均相关。结论B-ALL患儿初发时血液中高水平的白细胞、中性粒细胞、淋巴细胞、单核细胞、幼稚淋巴细胞、血尿酸以及化疗第15天至第19天,第33天幼稚淋巴细胞、化疗第33天MRD、基因型与治疗反应不佳可能相关。临床危险度分层与基因突变情况相关,基因突变可能是B-ALL患儿治疗反应重要指标。

关键词： 课程思政   医学遗传学   立德树人   医学教育   探索与实践   教学改革  

摘要： 医学遗传学是一门连接基础医学理论和临床实践之间的桥梁课程,同时也是一门迅猛发展的前沿课程,其主要研究遗传因素在人类疾病发生、发展过程中的作用及可能的一些预防治疗手段。教育的根本任务是立德树人,课程思政是高校做好立德树人的重要途径。因此,笔者通过深入挖掘医学遗传学课程教学内容中包含的思政元素,将其与医学遗传学专业知识教学有机地结合起来,以达到新时期医学教育全方位教学育人的目标。文章拟结合医学遗传学课程的教学内容特点,探索在专业课堂教学中融入课程思政教育的效果和意义。

关键词： 产前诊断   胎儿遗传学   低深度全基因组测序   CNVs  

摘要： 低深度全基因组测序技术是基于下一代测序技术,对样本DNA进行全基因组水平的检测,将测序结果与人类参考基因组碱基序列进行比对,通过生物信息分析以发行受检样本存在的致病性基因组拷贝数变异(CNVs)。孕期对胎儿是否患染色体疾病进行检查是确保胎儿健康的重要措施。孕11~13周+6天的B超检查和孕15~20周的唐氏血清学筛查以及无创DNA检测都是筛查胎儿染色体疾病的重要方法。本文对近年来胎儿遗传学诊断中应用低深度全基因组测序技术的发展进行综述、分类介绍。

关键词： 遗传学计算   方法   运用范围   新发现  

摘要： 遗传学计算题中,不同的题目或许可以运用相同的计算方法,而同一道题目也或许可以用多种方法解答。通过两个例题的一题多解,探讨了遗传学计算中常用的几种方法的运用范围,以及自由组合定律中计算淘汰类问题的新发现,希望能给基础薄弱学生一些实际指导,以及给教师教学一定参考。

摘要： Diverse plant fungal pathogens that cause worldwide crop losses are understudied due to various technical challenges. With the increasing availability of sequenced whole genomes of these non-model fungi, effective genetic analysis methods are highly desirable. My PhD projects focus on the establishment of a new gene discovery pipeline, which combines a fast forward genetic screening in large scale with high-throughput next-generation sequencing. I applied this pipeline in the notorious soilborne phytopathogen, Sclerotinia sclerotiorum, and identified 32 mutants with various developmental and growth deficiencies. Detailed molecular studies of three melanisation-deficient mutants provide a proof of concept for the effectiveness of our method. Furthermore, using this forward genetic approach, a RAS-GTPase activating protein, SsGAP1, was identified, which plays essential roles in sclerotia formation, compound appressoria production and virulence. To find the responsible RAS-GTPase being activated by SsGAP1 through mutant phenotypes comparison, I knocked down two RAS-GTPases, SsRAS1 and SsRAS2, respectively. My results revealed that both SsRAS1 and SsRAS2 are required for vegetative growth, sclerotia formation, compound appressoria production and virulence. As RNA can move from plant hosts to associating eukaryotic pathogens, trans-species RNAi pathway has been employed for pathogen control through host-induced gene silencing (HIGS). Thereby, I tested whether these RAS signaling genes can be used as HIGS targets to control stem rot caused by S. scleortiorum. Here, when I infiltrated tobacco leaves with Agrobacterium with RNAi constructs targeting SsGAP1 and SsRAS1, I observed reduced virulence. Taken together, my forward genetics gene discovery pipeline in S. sclerotiorum is highly effective in identifying novel HIGS targets to control fungal diseases caused by S. sclerotiorum. As RAS signaling is conserved in eukaryotes, these RAS signaling genes may also have the poten

摘要： Bioorthogonal chemistry offers versatile strategies for monitoring and modulating biomolecules in their native environments through abiotic chemical reactions. Bioorthogonal catalysis via transition metal catalysts (TMCs) provides the controlled activation of anticancer therapeutics, which mimics the enzymatic amplifications. However, the direct use of TMCs in living systems faces challenges such as instability, poor solubility, and low biocompatibility. Engineering the structure of TMCs can partially solve the problems, but the rapid clearance of small molecules hurdles the in vivo applications. Therefore, embedding TMCs in/onto nanomaterials to obtain bioorthogonal nanozymes enhances stability, solubility, biocompatibility, and the presence of the catalysts in biological environments for drug activation. In this thesis, I screened a library of surface-functionalized gold nanoparticles (AuNPs) to check their effect on immune cells. I chose the positively charged with hydrophilic headgroup one to hydrophobic TMCs. AuNPs insulate the catalyst from the deactivating environment. The surface ligands of AuNPs were further engineered to generate stimuli-responsive nanozymes by harnessing the formation and proteolysis of the protein corona. Moreover, the cationic-charged nanozyme exhibited prolonged stability both in vitro and in vivo, allowing for localized drug activation. The localized cancer therapy mediated by nanozymes efficiently reduced the growth of aggressive breast cancer and avoided acute liver damage, a common off-target effect of chemotherapy. The nanozymes were also applied for anticancer immunotherapy by polarizing macrophages to anticancer phenotype through activating the precursor of an immune modulator. Other than gold nanoparticles, I functionalized zinc sulfite nanoparticles as the scaffold to integrate degradability and enhanced catalysis for anticancer drug activation. I also developed a scalable polymeric-based nanozyme that resisted serum poisoning

摘要： Grayia is a genus of relatively large (1.5 - 2.5 m) aquatic Afrotropical snakes. Recent molecular phylogenies recovered Grayia in its own distinct subfamily (Grayiinae), which was strongly supported as the sister group to Colubrinae. Because tropical African snakes are generally understudied, the relationships within Grayia are poorly known. Due to high degrees of intra- and interspecies variation, identification is often difficult and previous studies involving Grayia included misidentified specimens in other genera. The goal of this study is to create a phylogenetic tree that can be used to understand the relationships and taxonomy of Grayia via an integrative taxonomic approach that combines molecular and morphological data. Two nuclear (BDNF, NT3) and four mitochondrial genes (COI, cyt b, 16S and ND4) were used to construct phylogenetic trees with Maximum likelihood and Bayesian inference methods; outgroups included the genera Calamaria, Sibynophis, and Masticophis. The phylogenetic trees recovered two clades, Grayia caesar + G. tholloni and G. ornata + G. smithii, which the time-calibrated BEAST analysis estimated to have diverged from each other in the mid-Oligocene. Grayia ornata was found to consist of two distinct subclades, one from west and one from east, of the Congo and Ubangi Rivers. This suggests that these large rivers may be more of a barrier than previously believed. Molecular and morphological evidence supports a new cryptic species of Grayia from the upper and middle Congo River and its tributaries. This new species is estimated to have diverged from its nearest sister species, G. ornata, in the mid- to late Mioceneâwhich coincides with the divergence dates of sister taxa within other Central African snake genera (Boaedon [Family Lamprophiidae], Atheris [Family Viperidae], and Polemon [Family Lamprophiidae]).

摘要： The analysis of tumour tissues with modern analytic technologies has shown that most cancer types are composed of multiple subpopulations with distinct molecular signatures. Correct identification of molecular subtypes can predict response to a particular drug. As a result, targeted treatments have emerged as an important tool for disease management, resulting in some striking successes. The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly dysregulated pathways in cancer and the target of many new drugs. One of these, capivasertib, is a potent and selective inhibitor of AKT. In Phase I trials of capivasertib, patients in some arms were screened for activating PIK3CA mutations expected to render them sensitive. However, even among this genetically pre-selected cohort, the overall response rate was limited to approximately 30%. Alternative mass spectrometry (MS)-based approaches to quantify proteins and metabolites can offer a "real-time" portrait of the cellular processes that are active in a specific cancer. The purpose of our project is to link MS analyses with genetic and clinical information to create more comprehensive molecular profiles, and to assess whether these may be useful for patient selection and treatment planning. Results Chapter 1 describes the development and validation of a new proteomics workflow encompassing both targeted and global proteomics approaches. The methods were applied to comprehensively analyze volume-limited stored tumour slices from PIK3CA-mutated tumours of patients in a Phase II clinical trial of capivasertib. Patients were coded as "clinical benefit" or "no clinical benefit" based on their time to progression after starting the drug. AKT expression was not associated with capivasertib treatment benefit in this cohort. However, the global proteomic analysis revealed significant protein expression differences, leading to the hypothesis that increased activation of translational control pathways may be associ