Role of mitochondria in early molecular diagnosis and prognosis of cancer

Background:Earlier clinical detection of cancer may improve survival as well as offer opportunities for less invasive treatment options. This thesis explores whether the mitochondria and its related genes in the nuclear genome can be used as novel methods for the diagnosis and prognosis of cancers.Aims and Methods:Paper I: To investigate if mitochondrial dysfunction (characterized by mtDNA copy number variations) is associated with prevalent, incident cancer and cancer mortality – droplet digital PCR (ddPCR).Paper II: To investigate the potential causal relationship between mitochondrial dysfunction (characterized by genetic predispositions in all mitochondrial-related genes) and common cancer risks – Mendelian randomization, colocalization.Paper III: To investigate mitochondrial mutations as potential biomarkers for the early diagnosis of breast cancer – whole mitochondrial genome sequencing, bioinformatics, ddPCR.Paper IV: To investigate the mitochondrial-related gene expression signature as a prognostic model to predict the clinical outcome for breast cancer patients – machine learning.Results and conclusions:Paper I: We found that mtDNA-CN was significantly associated with prevalent and incident cancer as well as cancer mortality. However, these associations were cancer-type specific and need further investigation.Paper II: We identified potential causal relationships between mitochondrial-related genes and breast, prostate and lung cancer. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention.Paper III: We comprehensively characterized the mtDNA mutation landscape of breast cancer biopsies and matched baseline whole blood samples. Notably, we have identified and validated mt.16093T>C mutation, which was associated with a 67% increased risk of developing breast cancer, and could potentially be used as early breast cancer diagnostic biomarkers.Paper IV: We built a novel 14 genes mitochondrial signature model that could be an independent prognostic predictor and together with clinical variables as an improved model for predicting overall earlystage of breast cancer survival

Global Dynamics and Applications of an Epidemiological Model for Hepatitis C Virus Transmission in China

An epidemiological model is proposed and studied to understand the transmission dynamics and prevalence of HCV infection in China. Theoretical analysis indicates that the basic reproduction number R0 provides a threshold value determining whether the disease dies out or not. Two Lyapunov functions are constructed to prove the global asymptotic stability of the disease-free and the endemic equilibria, respectively. Based on data reported by the National Health and Family Planning Commission of China, the basic reproduction number is estimated as approximately R0=1.9897, which is much less than that for the model when a treatment strategy is not considered. An ever-increasing HCV infection is predicted in the near future. Numerical simulations, performed to investigate the potential effect of antiviral treatment, show that increasing the treatment cure rate and enlarging the treatment rate for patients at the chronic stage remain effective in reducing the number of new infections and the equilibrium prevalence. The finding suggests that treatment measures are significantly beneficial for disease control in terms of reducing new infections and, in particular, more attention should be paid to treatment for patients at the chronic stage

Learning-by-Doing in Non-Homogeneous Tasks: An Empirical Study of Content Creator Performance on A Music Streaming Platform

With the development of high-speed internet and better mobile connections, online streaming platforms with user-generated videos are becoming popular. The success of these platforms relies on content creators who can effectively enhance user engagement (e.g., subscribing to a content creator’s channel). As opposed to homogeneous production scenarios (e.g., assembling automobiles in a factory), creating user-generated videos is a more complex task in which learning might happen. In this study, we empirically test the effect of prior experience on content creators’ performance. Furthermore, we examine the role of specialization in learning. We use a dataset from NetEase Cloud Music, one of the most popular music streaming platforms in China, with 21,549 content creators and 252,762 user-generated videos. The findings indicate that: (1) prior experience has a positive effect on creators’ performance; (2) specialized experience across distinct video categories has a nonlinear effect on creators’ performance. These results have implications for improving user engagement for online user-generated video streaming platforms

Research on One Novel Logging Interpretation Method of CBM Reservoir

Coalbed methane (CBM) is a kind of natural gas which is stored in the micropores and fractures of the “coal seam” and has not been transported out of the source rock. Conventional logging technology plays an important role in coalbed methane exploration and development. By analyzing the response characteristics of conventional logging of coalbed methane, coal bearing strata are accurately determined. Two methods of statistical model and volume model are established to analyze and calculate industrial components. Based on the study of adsorption isotherm and correlation between logging parameters and coal core gas content, the calculation method of coal seam gas content is determined In practices, the calculation accuracy of industrial components and gas content of coal seam has been significantly improved. Abstract: coalbed methane (CBM) is a kind of natural gas which is stored in the micropores and fractures of “coal seam” and has not been transported out of the source rock. Conventional logging technology plays an important role in coalbed methane exploration and development. By analyzing the response characteristics of conventional logging of coalbed methane, coal bearing strata are accurately determined. Two methods of statistical model and volume model are established to analyze and calculate industrial components. Based on the study of adsorption isotherm and correlation between logging parameters and coal core gas content, the calculation method of coal seam gas content is determined In practice, the calculation accuracy of industrial components and gas content of coal seam has been significantly improved

Distinct composition and amplification dynamics of transposable elements in sacred lotus (Nelumbo nucifera Gaertn.)

Sacred lotus (Nelumbo nucifera Gaertn.) is a basal eudicot plant with a unique lifestyle, physiological features, and evolutionary characteristics. Here we report the unique profile of transposable elements (TEs) in the genome, using a manually curated repeat library. TEs account for 59% of the genome, and hAT (Ac/Ds) elements alone represent 8%, more than in any other known plant genome. About 18% of the lotus genome is comprised of Copia LTR retrotransposons, and over 25% of them are associated with non-canonical termini (non-TGCA). Such high abundance of non-canonical LTR retrotransposons has not been reported for any other organism. TEs are very abundant in genic regions, with retrotransposons enriched in introns and DNA transposons primarily in flanking regions of genes. The recent insertion of TEs in introns has led to significant intron size expansion, with a total of 200 Mb in the 28 455 genes. This is accompanied by declining TE activity in intergenic regions, suggesting distinct control efficacy of TE amplification in different genomic compartments. Despite the prevalence of TEs in genic regions, some genes are associated with fewer TEs, such as those involved in fruit ripening and stress responses. Other genes are enriched with TEs, and genes in epigenetic pathways are the most associated with TEs in introns, indicating a dynamic interaction between TEs and the host surveillance machinery. The dramatic differential abundance of TEs with genes involved in different biological processes as well as the variation of target preference of different TEs suggests the composition and activity of TEs influence the path of evolution

Glycogen synthase kinase-3β inhibition induces nuclear factor-κB-mediated apoptosis in pediatric acute lymphocyte leukemia cells

<p>Abstract</p> <p>Background</p> <p>Molecular therapies that target genetic abnormalities in leukemic cells and their affected signaling pathways have been emerging in pediatric acute lymphoblastic leukemia (ALL). Glycogen synthase kinase-3β (GSK-3β) has recently been found to positively regulate the activity of nuclear factor-κB (NF-κB). Here, we investigated the relationship between GSK-3β inhibition and NF-κB in apoptosis of pediatric primary leukemia cells obtained from 39 newly diagnosed ALL children in China.</p> <p>Methods</p> <p>Bone marrow mononuclear cells (BMMC) were isolated by density gradient centrifugation from the heparinized aspirates of children with ALL. We used immunofluorescence staining to detect nuclear GSK-3β in these cells. After treatment with chemically distinct GSK-3β inhibitors in vitro, NF-κB transcriptional activity was identified by means of western blotting and electrophoretic mobility shift assay (EMSA). NF-κB-mediated apoptosis was detected by Annexin V-PE/7-AAD double-staining flow cytometry. The expression level of the <it>survivin </it>gene was detected by reverse-transcriptase polymerase chain reaction (RT-PCR).</p> <p>Results</p> <p>GSK-3β significantly accumulates in the nuclei of ALL cells than in the nuclei of control cells. Cell death induced by GSK-3β inhibition in ALL cells was mediated by a downregulation of NF-κB p65 transcriptional activity. GSK-3β inhibition significantly decreased the expression of the NF-κB target gene <it>survivin</it>.</p> <p>Conclusions</p> <p>These results indicate that inhibition of GSK-3β downregulates the NF-κB activation pathway, leading to suppression of the expression of an NF-κB-regulated gene and promotion of apoptosis in ALL cells in vitro. Furthermore, our findings suggest that GSK-3β or NF-κB is a potential therapeutic target in the treatment of pediatric ALL.</p