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A New Era in Functional Genomics Using CRISPR/Cas9 Knockout Screening 使用CRISPR/Cas9基因敲除筛选功能基因组学的新时代
W. Cai, Weijing Li, Dan Yang, Hua‐An Xie, Jian Huang
In this commentary, we discussed the new exciting progress in CRISPR based screening technology field and highlight recent developments in the area of CRISPR-based functional genomics. High-throughput functional genomics using CRISPR-Cas9 revolutionized our ability to decipher cellular function in health and disease. Despite its limitations, the simplicity and effectiveness of CRISPR/Cas9 based screening, makes an enormous impact on genomic screening and thus scientific discovery.
在这篇评论中,我们讨论了基于CRISPR的筛选技术领域令人兴奋的新进展,并重点介绍了基于CRISPR的功能基因组学领域的最新进展。使用CRISPR-Cas9的高通量功能基因组学彻底改变了我们破译健康和疾病中细胞功能的能力。尽管存在局限性,但基于CRISPR/Cas9的筛选的简单性和有效性对基因组筛选和科学发现产生了巨大的影响。
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引用次数: 12
The Laws of the Ring: Governing Mechanisms, Diagnostic Standards, and Therapeutic Potentials for Human Constitutional Ring Chromosomes 环的规律:人类体质环染色体的调控机制、诊断标准和治疗潜力
P. Li, Q. Hu
Human constitutional ring chromosomes are a rare type of chromosome structural abnormalities. The cytogenomic analysis of ring chromosome cases revealed different genomic imbalances and ring structures, variable levels of dynamic mosaicism, and selective karyotype evolution in different tissues. This cytogenomic heterogeneity is likely correlated with variable clinical manifestations of generalized features of ‘ring chromosome syndrome’, chromosome-specific and segmental aneuploidy related phenotypes, and risks of infertility and various types of cancers. Better understanding of the ‘biologic law’ governing ring chromosome formation and its mitotic segregation can contribute to the ‘diagnostic law’ guiding toward best practice in genetic analyses and the ‘therapeutic law’ for evidence-based treatment and management of ring chromosome disorders. Collaborative efforts are needed to study the biological processes involving ring chromosome formation, mitotic segregation and cell-autonomous correction, to develop cytogenomic diagnostic standards, and to generate registry of ring chromosome cases with defined genomic structures and dynamic mosaicism and detailed clinical manifestations. These efforts could provide more reliable karyotype-phenotype correlations for developing chromosome-specific guidelines and recommendations for genetic counseling and clinical treatment.
人类体质环染色体是一种罕见的染色体结构异常类型。环状染色体病例的细胞基因组分析揭示了不同组织中不同的基因组失衡和环状结构、不同水平的动态镶嵌和选择性核型进化。这种细胞基因组异质性可能与“环染色体综合征”的广泛特征、染色体特异性和节段非整倍性相关表型的可变临床表现以及不孕和各种癌症的风险有关。更好地理解控制环染色体形成及其有丝分裂分离的“生物学定律”,有助于制定指导遗传分析最佳实践的“诊断定律”,以及循证治疗和管理环染色体疾病的“治疗定律”。需要合作研究涉及环染色体形成、有丝分裂分离和细胞自主校正的生物学过程,制定细胞基因组诊断标准,并建立具有明确基因组结构、动态镶嵌和详细临床表现的环染色体病例登记册。这些努力可以为制定染色体特异性指南和遗传咨询和临床治疗建议提供更可靠的核型-表型相关性。
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引用次数: 0
Mathematical (Quantitative) and Cell Linguistic (Qualitative) Evidence for Hypermetabolic Pathways as Potential Drug Targets 高代谢途径作为潜在药物靶点的数学(定量)和细胞语言学(定性)证据
Ji S
Objectives: According to the cell language theory first proposed in 1997, living cells use a molecular language whose structure is similar to (or isomorphic) with the structures of the human language with respect to the 10 out of the 13 design features established by linguists. One of the predictions of the cell language theory is that there should exist in the living cell what is referred to as ‘hypermetabolic pathways’ that correspond to texts in human language deemed essential for reasoning and computing. A mathematical method known as the Planck-Shannon plot is described that can be employed to identify the predicted hypermetabolic pathways that underlie human breast cancer and hence can serve as potential anti-cancer drug targets. Data and analytic method: The gene expression profile data measured with microarrays were provided by Perez- Ortin’s group in Valencia, Spain and Perou and his coworkers at Stanford University. The mRNA data were transformed into histograms which were then fitted to the Planck Distribution Equation (PDE y = ((A / (x + B)5 ) / (eC/ ( x + B) – 1)) , to generate the numerical values for the parameters, A, B and C, that quantitatively characterize the shape of each histogram and hence the information contained in the original mRNA data set. The fitting of mRNA data to PDE was performed by the Sovler program available in Excel. Results: The hypermetabolic pathways, both intra-organismic, and inter-organismic, that are predicted by the cell language theory can be identified with the PDE-based analysis of mRNA data. The intra-organismic hypermetabolic pathway identified with PDE consists of 3 or more traditional metabolic pathways, while the interorganismic hypermetabolic pathway consists of one traditional metabolic pathway whose activity is correlated among 3 or more organisms exhibiting a common phenotype, e.g., breast cancer. Conclusion: Ribonoscopy, defined as the genome-wide study of mRNA levels within an organism or between different organisms, when combined with the quantitative method of analysis afforded by the Planck Distribution Equation (PDE), can identify a novel class of metabolic structures referred to as “intra-organismic hypermetabolic pathways” and “inter-organismic hypermetabolic pathways” that can serve as potential targets of cancer drug therapy.
目的:根据1997年首次提出的细胞语言理论,在语言学家确定的13种设计特征中,活细胞使用的分子语言的结构与人类语言的结构相似(或同构)。细胞语言理论的一个预测是,活细胞中应该存在所谓的“高代谢途径”,它对应于人类语言中的文本,这些文本被认为是推理和计算所必需的。一种被称为普朗克-香农图的数学方法被描述为可以用来确定预测的人类乳腺癌的高代谢途径,因此可以作为潜在的抗癌药物靶点。数据和分析方法:用微阵列测量的基因表达谱数据由西班牙瓦伦西亚的Perez- Ortin小组和斯坦福大学的Perou及其同事提供。将mRNA数据转换成直方图,然后拟合到普朗克分布方程(PDE y = (A / (x + B)5) / (eC/ (x + B) - 1)),生成参数A、B和C的数值,定量表征每个直方图的形状,从而表征原始mRNA数据集中包含的信息。用Excel中的Sovler程序拟合mRNA数据与PDE。结果:细胞语言理论预测的生物体内和生物间的高代谢途径可以通过基于pde的mRNA数据分析来识别。PDE鉴定的生物内高代谢途径由3个或更多传统代谢途径组成,而生物间高代谢途径由一个传统代谢途径组成,其活性在3个或更多具有共同表型的生物体(如乳腺癌)之间相关。结论:核糖核酸检查被定义为对生物体内或不同生物体之间mRNA水平的全基因组研究,当与普朗克分布方程(PDE)提供的定量分析方法相结合时,可以识别一类新的代谢结构,称为“生物体内高代谢途径”和“生物体间高代谢途径”,可以作为癌症药物治疗的潜在靶点。
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引用次数: 3
Practical Advices About How To Handle Disease Progression During Osimertinib In EGFR-Mutant NSCLC Patients: Is It The Same Old Story? A Mini Review 关于如何在EGFR突变的NSCLC患者中使用奥西美替尼治疗疾病进展的实用建议:这是老故事吗?迷你评论
A. Cortellini, F. Buttitta, A. Marchetti, C. Ficorella
After the advent of third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), oncologists are called to face new challenges in everyday management of EGFR mutated non-small-cell-lungcancer (NSCLC) patients. These drugs, in particular Osimertinib (which is the only one currently available), represent an extraordinary innovation. But while raising the bar of expectations, they pose us new challenges. Mechanisms of resistance to Osimertinib are heterogeneous: from a "molecular point of view" they can be categorized in EGFR-dependent and independent ones. In recent years many clinical reports have shown interesting results with target treatments, mainly chosen on the basis of the "molecular resistance". However, in common practice clinicians and patients must face off with the reality and with limited treatment options. It may be helpful to classify different clinical patterns of disease progression during treatment with Osimertinib. Treating a localized progression to a single organ certainly differs from treating a wide dissemination of disease, as well as treating symptomatic progressions differs from treating non-symptomatic ones. This mini-review aims to analyse, with a very practical approach, current options for clinical management of EGFR mutant NSCLC patient at the time of disease progression during Osimertinib, by focusing particularly on maintenance strategies beyond progression.
在第三代表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)问世后,肿瘤学家被要求在EGFR突变的非小细胞肺癌(NSCLC)患者的日常管理中面临新的挑战。这些药物,特别是奥西美替尼(目前唯一可用的药物),代表了一项非凡的创新。但是,在提高期望值的同时,它们也给我们带来了新的挑战。对奥西美替尼的耐药性机制是异质性的:从“分子角度”来看,它们可以分为EGFR依赖性和非依赖性。近年来,许多临床报告显示,主要基于“分子耐药性”选择的靶向治疗取得了令人感兴趣的结果。然而,在常见的实践中,临床医生和患者必须面对现实,面对有限的治疗选择。在奥西美替尼治疗期间,对疾病进展的不同临床模式进行分类可能有帮助。治疗单个器官的局部进展肯定不同于治疗广泛传播的疾病,治疗有症状的进展也不同于治疗无症状的进展。这篇小型综述旨在通过一种非常实用的方法,通过特别关注进展之外的维持策略,分析奥西马尔蒂尼治疗期间EGFR突变NSCLC患者在疾病进展时的临床管理的当前选择。
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引用次数: 1
Caspase-Cleaved Cytokeratin 18 as a Potential Molecular Biomarker for Monitoring Chemotherapeutic Response in Breast Cancer Patients 半胱天冬氨酸叶片细胞角蛋白18作为一种潜在的分子生物标记物监测癌症患者的化疗反应
Y. Gemechu, D. Seifu, W. Tigneh, Labisso Wl
Background: Breast cancer is one of the most dreadful cancer types, with the highest mortality and morbidity in women in both low and high-income countries. Cytokeratins can be applied as noninvasive, efficient and satisfactory molecular tools to monitor and predict the response to chemotherapy for breast cancer. Objective: This study was intended to explore the potential application of ccCK18 as a molecular biomarker for monitoring and predicting the efficacy of chemotherapy on breast cancer patients. Methodology: A hospital-based prospective study was conducted on 40 breast cancer patients and 38 apparently healthy control individuals in Black Lion Specialized Hospital. Blood samples were obtained from study subjects and control groups before chemotherapy, at 4 and 6 hours after chemotherapy. An ELISA assay was applied to measure plasma caspase-cleaved Cytokeratin 18 (ccCK18). The association between expression of ccCK18 and the tumor metastasis and stages and grades were determined with ELISA. Different biochemical tests were also carried out to investigate the function of liver in relation to ccCK18 level with respect to cancer chemotherapy. Wilcoxon signed rank test, Spearman’s rho test and paired t-test were applied as statistical tools to determine association and correlation among different the study parameters. A p-value of <0.05 was considered as statistically significant. Results: The baseline levels of plasma ccCK-18 were significantly higher in patients with breast cancer than those in the control group (% CI= 95%, p<0.05). The level of ccCK-18 was also significantly increased at 6 hours after chemotherapy (p<0.05). Patients with pT3 tumor size displayed the highest median level compared to other tumor sizes. The ccCK-18 level was observed to be higher among patients with distant metastasis than in nonmetastatic patients. Lactate dehydrogenase (LDH) levels were also elevated at 6 hours, following chemotherapy. Plasma liver function tests (ALT, AST, ALP and total bilirubin) were normal before and after chemotherapy, indicating that there was no major liver damage following chemotherapy. Conclusion: ccCK-18 level in blood could be used as a molecular biomarker for monitoring the disease and predicting the response of patients to breast cancer chemotherapy, particularly in low settings; however, further studies with other protocols are warranted to tailor chemotherapy treatment in a better way.
背景:癌症是最可怕的癌症类型之一,在低收入和高收入国家,女性死亡率和发病率最高。细胞角蛋白可以作为一种无创、有效和令人满意的分子工具,用于监测和预测癌症化疗的反应。目的:本研究旨在探索ccCK18作为分子生物标志物在癌症患者化疗疗效监测和预测中的潜在应用。方法:在黑狮专科医院对40名癌症患者和38名明显健康的对照者进行了一项基于医院的前瞻性研究。在化疗前、化疗后4小时和6小时从研究受试者和对照组获得血样。应用ELISA法测定血浆胱天蛋白酶裂解的细胞角蛋白18(ccCK18)。用ELISA法测定ccCK18的表达与肿瘤转移、分期和分级的关系。通过不同的生化检测,探讨癌症化疗时肝功能与ccCK18水平的关系。采用Wilcoxon符号秩检验、Spearman rho检验和配对t检验作为统计工具,确定不同研究参数之间的相关性和相关性。p值<0.05被认为具有统计学意义。结果:癌症患者血浆ccCK-18的基线水平显著高于对照组(%CI=95%,p<0.05),化疗后6小时ccCK-18水平也显著升高(p<0.05),pT3肿瘤大小患者的中位水平高于其他肿瘤大小患者。观察到远处转移患者的ccCK-18水平高于非转移患者。化疗后6小时乳酸脱氢酶(LDH)水平也升高。化疗前后血浆肝功能测试(ALT、AST、ALP和总胆红素)正常,表明化疗后没有严重的肝损伤。结论:血ccCK-18水平可作为监测疾病和预测癌症化疗反应的分子生物标志物,特别是在低环境下;然而,有必要对其他方案进行进一步的研究,以更好的方式调整化疗治疗。
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引用次数: 3
Donepezil for Constipation in Lewy Body Disease: A Twelve-Month Follow-Up 多奈哌齐治疗路易体病便秘:12个月随访
Lepkowsky Cm
Previously, the acetylcholinesterase inhibitor Donepezil was used in a case study to address the symptoms of constipation, obstipation, and impaction in four patients with Lewy Body diseases. In patients with both Parkinson’s disease (PD) and Neurocognitive Disorder with Lewy Bodies (NCDLB), the use of Donepezil led to symptom reduction. After six months, the symptoms of the same patients were reviewed, with no loss of bowel motility nor emergence of new symptoms. After twelve months, another review of symptoms was conducted. The results indicate that Donepezil appears to be effective in reducing the symptoms of constipation, obstipation and impaction over an extended period of treatment.
此前,乙酰胆碱酯酶抑制剂多奈哌齐被用于一项病例研究,以解决4例路易体疾病患者的便秘、梗阻和嵌塞症状。在患有帕金森病(PD)和路易体神经认知障碍(NCDLB)的患者中,使用多奈哌齐可减轻症状。6个月后,对相同患者的症状进行复查,没有肠蠕动丧失,也没有出现新的症状。12个月后,对症状进行了另一次检查。结果表明,多奈哌齐似乎是有效的减轻便秘,便秘和嵌塞的症状在一个延长的治疗期。
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引用次数: 6
Fetal Chimerism and Fetal Thymic Transplantation 胎儿嵌合体与胎儿胸腺移植
N. Bhattacharya, P. Sengupta
Fetal tissue transplantation is an attractive field of modern medicine that can have immense application in treating several refractile conditions. Fetal tissue transplantation is an allogeneic transplantation procedure and like any allogeneic transplantation they contribute towards the formation of a chimera at the cellular and tissue level grossly and can be classified as a macro chimerism. The fetus during the time of pregnancy also takes part in microchimerism through fetomaternal cell trafficking where there is an exchange of the maternal and the fetal cells through the blood-placental barrier. Apart from the creation of a stable chimerism, fetal tissues also play a role in healing. Fetal thymic transplantation is one of the most exciting applications of regenerative medicine which has also been discussed briefly with some case studies.
胎儿组织移植是现代医学的一个有吸引力的领域,在治疗多种屈光性疾病方面有着巨大的应用。胎儿组织移植是一种异基因移植程序,与任何异基因移植一样,它们有助于在细胞和组织水平上形成嵌合体,可归类为宏嵌合体。胎儿在怀孕期间也通过胎儿细胞运输参与微嵌合体,其中母体和胎儿细胞通过血液-胎盘屏障进行交换。除了产生稳定的嵌合外,胎儿组织也在愈合中发挥作用。胎儿胸腺移植是再生医学最令人兴奋的应用之一,本文也通过一些案例研究对其进行了简要讨论。
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引用次数: 0
An Approach to Enhancing the Life Experience of Patients with Early Alzheimer s Disease 提高早期阿尔茨海默病患者生活体验的方法
Howe Eg
In this brief piece, I shall describe how providers seeing such patients may do this. I shall start with a case example involving a patient with who I carried out this intervention. The extent to which this emotionally moved her and gave her additional meaning in her life while, for her, both were still possible were marked, as I shall relate further, below, to say the least. I shall then refer to a small and very selected segment of the medical literature to suggest why provides might be warranted in anticipating that their inquiring and if wanted, then facilitating as I shall suggest, is likely to be beneficial, actually to both parties in most if not all cases. Finally, I shall discuss in more general terms the core, sequential steps that providers may take.
在这篇简短的文章中,我将描述医疗服务提供者如何看待这类患者。我将从一个病人的例子开始,我对他进行了这种干预。这件事在感情上感动了她,使她的生活有了额外的意义,而对她来说,这两件事都还可能发生,这一点是显而易见的,我将在下面进一步说明。然后,我将参考一小部分精选的医学文献,以说明为什么提供方可能有理由预测他们的询问,如果需要,那么我将建议,促进可能是有益的,实际上在大多数情况下,如果不是所有情况,对双方都是有益的。最后,我将以更一般的术语讨论提供者可能采取的核心顺序步骤。
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引用次数: 0
Impact of Climatic Fluctuation on Dengue Virus Etiology 气候变化对登革热病毒病原学的影响
K. Tilwani, G. Dave, Nadurbarkar
Aedes mosquito-body is the favored habitat for the member of Flaiviridae, the most famous member of the family, formerly known as Dengue virus (DENV). Dengue virus infection induces high fever in human and responsible for associated symptoms like skin rashes. In literature, it has been noted that the onset of dengue fever usually occurs in monsoon and winter seasons, which gradually declines with onset of summer. This season-coordinated trend has suggested positive association towards the climate and proliferation of Dengue virus. To investigate this hypothesis, this study has been proposed. In this study, the date-wise data for Dengue positive cases were obtained from the Government hospitals across Gujarat region. The data were further correlated with the climatic parameters for that date. The investigation suggests the strong correlation between climatic fluctuations. The correlation analysis of obtain data suggests the fluctuations in relative humidity, temperature and pressure during day and night has strong impact. We proposed Poisson regression model and Negative Binomial model for prediction.
伊蚊的身体是黄病毒科成员最喜欢的栖息地,黄病毒科是该科最著名的成员,以前被称为登革热病毒(DENV)。登革热病毒感染会引起人类高烧,并引起皮疹等相关症状。在文献中,人们注意到登革热的发病通常发生在季风和冬季,随着夏季的到来,登革热的发病率逐渐下降。这种季节协调的趋势表明,登革热病毒与气候和扩散之间存在积极联系。为了研究这一假设,提出了这项研究。在这项研究中,登革热阳性病例的日期数据是从古吉拉特邦地区的政府医院获得的。这些数据进一步与该日期的气候参数相关联。调查表明,气候波动之间有很强的相关性。对获得的数据进行相关性分析表明,昼夜相对湿度、温度和压力的波动具有较强的影响。我们提出了泊松回归模型和负二项式模型进行预测。
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引用次数: 3
Parkinson’s Disease: A Case Report of Motor Symptoms Resolution Following Antibiotic Treatment for Suspected Bacterial Osteomyelitis 帕金森病:疑似细菌性骨髓炎抗生素治疗后运动症状缓解一例报告
Leheste, Gottlieb Sf, Biegel Ca, Ramos Rl, G. Torres, G. Saggio
Background and case: The vast majority of Parkinson’s disease (PD) cases occur sporadically without any obvious etiological schema. That poses major hurdles to the discovery of effective preventative and treatment strategies. Here we are reporting the case of an 86-year-old Caucasian male, with a 21-year history of PD, who reports complete resolution of PD - related motor symptoms after treatment with antibiotics for suspected bacterial osteomyelitis.Results: After a right leg injury, the patient was prescribed a ten-day course of ciprofloxacin and a four-week course of dicloxacillin for suspected osteomyelitis. After completion of the antibiotics, the patient reported his pervasive motor symptoms as “completely resolved” which to this day have not returned.Conclusion: PD is a progressive, mostly idiopathic, neurodegenerative disorder with effective but limited treatment options and without compelling preventative strategies. Here we identify the first case indicating the resolution of PD-linked motor symptoms following an unrelated treatment course with antibiotics. This raises interesting questions about the use of antibiotics in PD and the potential of an etiological bacterial connection. The microbiome signature of PD is a current ‘hot topic’ of investigation and studies need to continue investigating bacteria as a possible causes of PD and antibiotics as effective treatment modalities.
背景和病例:绝大多数帕金森病(PD)病例是偶发性的,没有任何明显的病因模式。这对发现有效的预防和治疗策略构成了重大障碍。我们报告了一例86岁的白人男性,有21年的帕金森病史,在用抗生素治疗疑似细菌性骨髓炎后,帕金森病相关的运动症状完全缓解。结果:右腿受伤后,患者因疑似骨髓炎接受了为期10天的环丙沙星疗程和为期四周的双氯西林疗程。在完成抗生素治疗后,患者报告其普遍的运动症状“完全缓解”,至今仍未复发。结论:帕金森病是一种进行性的、主要是特发性的神经退行性疾病,治疗选择有效但有限,没有令人信服的预防策略。在这里,我们发现了第一个病例,表明在使用抗生素进行不相关的疗程后,PD相关的运动症状得到了解决。这引发了关于PD中抗生素的使用以及病原菌之间潜在联系的有趣问题。帕金森病的微生物组特征是目前研究的“热点”,研究需要继续研究细菌是帕金森病的可能原因,抗生素是有效的治疗方式。
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引用次数: 1
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Journal of molecular and genetic medicine : an international journal of biomedical research
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