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Engineering technology for accessible precision therapeutics and diagnosticsBlumenfeld, Nicole Rose January 2020 (has links)
Over the last two decades, the concept of precision medicine has remained more of a promise than a reality. While there has been significant advancement in the field in terms of scientific discovery, precision medicine has yet to truly permeate standard clinical practice. There are a few individual examples, such as the treatment of breast cancer, in which the precision medicine approach has been ubiquitously adopted, but for most applications it remains exploratory. This barrier can arguably be attributed to the lack of accessible technology. That is, highly laborious, costly, and time-consuming methods that inhibit the integration of precision medicine techniques into the current clinical paradigm. In this dissertation, we aim to develop new technology, for both therapeutics and diagnostics, that would enable access to precision medicine by considering factors such as scalability, manufacturability, cost, turnaround time and integration.
In Aim 1, we developed a direct tissue engineering approach to increase endogenous brown fat for the treatment of obesity. This method capitalized on the use of brown adipose tissue (BAT), a highly metabolic tissue that expends energy via uncoupled respiration and has been shown to correlate with a lean phenotype and decreased risk of metabolic disease. Existing methods that seek to increase BAT mass include either the use of pharmacologic agents, which often exhibit detrimental off-target effects, or cold exposure, which is obviously unsustainable in practice. Cell therapies that involve the isolation of adipocyte progenitor cells have also been explored but are not easily scaled and are difficult to implement. Here, we developed a method to convert a patient’s own white adipose tissue (WAT) en masse to thermogenic BAT in a single ex vivo step, followed by reimplantation back into the patient. We demonstrated that this method, called exBAT, was able to convert full fragments of WAT to a BAT-like tissue, which sustained its phenotype up to 8-weeks after reimplantation in a mouse model. Further, allogeneic transplantation of exBAT in a diet-induced obesity mouse model exhibited a trend toward weight loss which should further be explored with additional dosing experiments. This method is highly scalable, patient-specific, and easily implemented with current clinical practice and has the potential to provide a precise method to combat the growing challenge of obesity.
In Aim 2, we shifted our focus to the development of a point-of-care (POC) diagnostic device for precision oncology. Here, we developed a device capable of performing a POC liquid biopsy for the detection of resistance mutations in non-small cell lung cancer (NSCLC). While liquid biopsies, which seek to identify tumor fragments in a patient’s blood, hold significant promise and advantages over traditional tissue biopsies, there are still several challenges including long turnaround time, high cost, and challenges with sensitivity. We sought to build a fully integrated device that can reduce the turnaround time for liquid biopsies from 2 weeks to one hour, enabling much higher throughput for important genotyping tests in NSCLC patients, and thereby enabling faster access to treatment. We demonstrated the ability to isolate plasma from undiluted whole blood at the POC, purify and concentrate circulating nucleic acids, and perform detection of low variant allelic frequency (VAF) mutations down to 1% in a microfluidic chip using a low-cost thermocycler. The device was initially designed to identify the presence or absence of T790M mutations, an important gatekeeper mutation with a clear clinical use case that confers sensitivity toward specific tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. However, the device can be easily extrapolated toward any type of molecular profiling and has the potential to significantly increase access to precision oncology diagnostics and therapeutics.
Finally, in Aim 3, we sought to develop a molecular diagnostic for detection of SARS-CoV-2 that would provide a qualitative result in less than 15 minutes at the POC. As the COVID-19 pandemic has continued to spread rapidly throughout the world, there is still an unmet need for high-throughput, ultrafast diagnostics that are sensitive, specific and accessible to all. To meet this challenge, we developed a molecular diagnostic that performs RT-PCR off of crude lysate from patient specimens in 15 minutes or less. To achieve this, we built upon previously demonstrated photothermal amplification techniques and extended its capabilities to perform ultrafast RT-PCR using a low-power infrared LED. We also sought to integrate sample preparation methods for both nasopharyngeal (NP) swabs and saliva samples to eliminate the need for labor-intensive RNA extraction and enable full automation for POC testing. Testing of our device using purified SARS-CoV-2 RNA showed high sensitivity and a limit of detection down to 500 copies/mL. We also demonstrated preliminary results showing the ability to detect SARS-CoV-2 RNA in unpurified saliva and further testing of clinical specimens in the POC device is ongoing. With a significantly faster and low-cost test that maintains gold-standard sensitivity and specificity, this device has the potential to drastically increase testing throughput and help contain the spread of COVID-19.
Underlying this work is the development of accessible technology for precision medicine. Aim 1 focuses on a simple, patient-specific tissue engineering approach to treating obesity, which is significantly more scalable than other cell and tissue engineering methods. Aim 2 demonstrates the ability to perform a highly sensitive liquid biopsy at the POC down to 1% VAF. Aim 3 demonstrates a new POC diagnostic for SARS-CoV-2 that provides a result in less than 15 minutes. Both Aims 2 and 3 focus on the development of POC diagnostics and were designed to be user-friendly, scalable, and easily integrated into current clinical paradigms. In Appendix I, we expand the discussion of POC diagnostics and present a design framework based on cost and budget constraints that was used for the development of these POC devices. Overall, the sum of this work illustrates examples of thoughtful engineering for the development of impactful new technologies for precision therapeutics and diagnostics.
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Epigenetic targeting of metabolic and lineage abnormality in cancerKaragiannis, Dimitrios January 2023 (has links)
Chromatin regulation is a major aspect of cancer development, progression, and treatment. Several small molecule inhibitors of chromatin regulators are currently used for treatment of certain hematological malignancies. However, there is still opportunity for many more patients to benefit from therapeutic approaches that target chromatin regulation, especially in the context of solid tumors. A critical unmet need is the identification of robust biomarkers that can guide the application of epigenetic inhibitors in a precise and personalized manner. In my dissertation, I aim to address this important knowledge gap by studying how perturbation of chromatin can target metabolic and lineage abnormalities in solid tumors for therapeutic benefit.
To do this, I have focused on genetic and pharmacological perturbations of chromatin pathways in two cancer models: (1) lung adenocarcinoma (LUAD) with NRF2 activation and (2) neuroendocrine esophageal carcinoma (NEC). In the study on NRF2-active LUAD, we found that histone deacetylase (HDAC) inhibitors can be repurposed to reprogram the epigenomic and metabolic landscape, which leads to specific and potent anti-tumor effects in the context of NRF2 activation. Specifically, we employed a chromatin-focused genetic screen to identify dependencies on chromatin regulators. The screen revealed an NRF2-specific dependency on class I histone deacetylases.
Experiments in mouse and human LUAD cell lines in vitro and in vivo indicated an NRF2-specific sensitivity to the class I HDAC inhibitor Romidepsin. Mechanistically, profiling of histone acetylation and gene expression upon Romidepsin treatment revealed a relative loss of histone H4 acetylation at promoters which was associated with reduced gene expression. Many downregulated genes were more essential for the survival of NRF2 hyperactive cancer cells, including genes involved in glutamine and serine metabolism, c-Myc and several of its targets involved in purine and pyrimidine synthesis. These transcriptional changes had corresponding effects on altering the metabolic pathways that NRF2-active cells selectively require for survival.
In the study on neuroendocrine esophageal carcinoma (NEC), we identified a crucial role for epigenetic regulation of lineage fate through transcriptional control of the key epidermal transcription factor p63. This project originated from data from my collaborators that indicates a role for p63 in the suppression of basal-to-neuroendocrine identity transition in the developing esophagus. Consistently, I found that p63 is silenced in NEC through a non-genetic mechanism. Reintroducing p63 isoforms in a human NEC cell line showed that ΔNp63α was sufficient to restore squamous marker expression. An epigenetic drug screen assessing p63 gene expression and subsequent validation experiments revealed that inhibition of EZH2, a histone methyltransferase, induced expression of ΔNp63α and genes related to the squamous identity. Analysis of the chromatin state in the TP63 locus showed that EZH2 inhibition led to a loss histone H3 methylation and a gain of histone H3 acetylation and its reader BRD4. These results support the hypothesis that the squamous identity can be reactivated epigenetically in NEC through de-repression of ΔNp63α as a potential therapeutic strategy.
Together, these studies contribute to our understanding of the transcriptional response to chromatin perturbation and show that this can be leveraged to modulate cell metabolism and identity, as well as to achieve therapeutic benefit in new contexts of cancer.
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Biological markers of weight loss and muscle protein metabolism in early non-small cell lung cancerMehrfar, Parisa. January 2008 (has links)
No description available.
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The effect of reconstruction algorithms (iterative versus filtered backprojection) on the diagnosis of single pulmonary nodules using Thallium-201 and Technetium-99m MIBI SPECTAmbayi, Rudo 04 1900 (has links)
Thesis (MScMed)--Stellenbosch University, 2004. / Copy not signed by author. / ENGLISH ABSTRACT: This study involved 33 patients, 19 men and 14 women. The age range was wide (20-90
years) and median age was 57 years. These patients had a single pulmonary nodule (SPN)
defined radiologically as a well defined, round or oval intrapulmonary lung lesion not
associated with atelectasis or adenopathy on chest radiography or computed tomography.
Patients were investigated with Tc-99m MIBI and TI-201 (25 patients) and with Tc-99m
MIBI alone (8 patients). Single photon emission computed tomography images were
reconstructed using both iterative reconstruction (Ordered Subsets - Expectation
Maximisation: aSEM) and filtered backprojection (FBP), on the Hermes system.
Transverse, coronal and sagittal slices were displayed on the screen using a grey scale.
The aSEM and FBP images for each study were co-registered semi-automatically using
the multimodality programme on the Hermes. The best slice for the lesion was chosen
according to the best view used to locate the SPN on chest radiograph. Regions of interest
(Ral) were drawn manually outside the outer margin of the detected lesion, first on the
aSEM image. This was automatically mirrored on the co-registered FBP image.
For most patients, the background was automatically mirrored horizontally on the
contralateral side, again, first on the OSEM then automatically on the FBP image.
Automatic vertical mirroring or manual horizontal mirroring was used when background
was found to be in a visually 'hot' area like the heart or vertebrae. The average counts
and standard deviation of the Ral and background were generated automatically.
Semi-quantitative image analysis was done by calculating the signal-to-noise ratio (SNR)
and tumour-to-background (TIB) ratio using the following formulae:
SNR = Mean counts ROI(lesion) - Mean counts background
Standard deviation background
TIB rati.o = -M---e-a-n-'--c-o--u-n-'t-s- ROI(lesion)
Mean counts background
Detection was found to be the same for the two reconstruction algorithms, that is, every
lesion detected by using OSEM could also be detected by using FBP.
However lesion detection did differ between Tl-201 and Tc-99m-MIBI.
Sensitivity and specificity were calculated for different thresholds of SNR and TIB ratios.
Receiver operating characteristics (ROC) curves were drawn to represent the different
sensitivities and specificities at each threshold. Tuberculosis (TB) was not included in
this analysis as uptake of Tl-20l was found to be significantly high and comparable to
that of malignant nodules. However the effect of OSEM and FBP on the 'positive' TB
nodules was assessed separately. By calculating the area under the ROC curves, TI-201
using OSEM was shown to be more accurate at differentiating malignant nodules from
benign ones than FBP. Although this difference was not statistically significant (p=0.1 0),
there was a clear tendency. The two reconstruction algorithms were found to be almost
equally accurate, when using Tc-99m-MIBI, the difference between them being
considerably insignificant.
In conclusion, it was shown that there is a tendency that OSEM outperforms FBP for
studies using Tl-201 but not for Tc-99m-MIBI. / AFRIKAANSE OPSOMMING: Hierdie studie sluit 33 pasiënte in, 19 mans en 14 vroue. Die ouderdomme wissel tussen
20 en 90 jaar met 'n gemiddelde ouderdom van 57 jaar. Elkeen van die pasiënte het 'n
enkel longnodule (SPN) op borskas X-straal en/of rekenaar tomografie getoon, wat
radiologies gedefinieer word as 'n goed omskrewe, ronde of ovaal intrapulmonale
longletsel wat nie met atelektase of adenopatie geassosieer is nie.
Pasiënte is met Tc-99m MIDI en TI-201 (25 pasiënte) of slegs met Tc-99m MIBI (8
pasiënte) ondersoek. Enkelfoton emissie rekenaar tomografiese (EFERT) beelde is met
beide iteratiewe rekonstruksie (Ordered Subsets - Expectation Maximisation: OSEM) en
gefilterde terugprojeksie (FBP) met die Hermes sisteem gerekonstrueer.
Transvers, koronale en sagittale snitte is in grysskaal op die sisteem vertoon. Die OSEM
en FBP beelde vir elke studie is semi-outomaties gekoregistreer met behulp van die
multimodaliteitsprogram op die Hermes. Die optimale snit vir elke letsel is gekies
volgens die beste aansig op die borskas X-straalom die SPN te lokaliseer. Gebiede van
belang (ROl) is met die hand buite-om die buitenste rand van die letsel getrek op die
OSEM beeld en daarna outomaties in die ooreenstemmende area op die gekoregistreerde
FPB beeld geplaas.
Vir die meeste pasiënte is die agtergrond outomaties as horisontale spieëlbeeld op die
kontralaterale kant geplaas, eers op die OSEM en dan outomaties op die FBP beeld. 'n
Outomatiese vertikale spieëlbeeld of manuele horisontale verskuiwing van die
agtergrondsarea is gedoen indien die agtergrond oorvleuel het met 'n 'warm' area soos
die hart of werwels. Die gemiddelde tellings en standaardafwyking van die ROl en
agtergrond is outomaties gegenereer.
Semi-kwantitatiewe beeldanalise is gedoen deur berekening van die sein-tot-agtergrond
verhouding (signal-to-noise ratio - SNR) en tumor-tot-agtergrond (TIB) verhouding met
behulp van die volgende formules:
SNR = gemiddelde tellings ROI(letsel) - gemiddelde tellings agtergrond
Standaard afwyking van agtergrond
TIB rati.o = -g=em--id-d-e-l-d-e--te=ll-in-g-s__R:_O-I(-le-t-s'e-l)
gemiddelde tellings agtergrond
Opsporing is soortgelyk bevind vir die twee rekonstruksie algoritmes, dit wil sê elke
letselopgespoor met behulp van OSEM kon ook met FBP opgespoor word.
Letselwaameming het egter verskil tussen TI-201 en Tc-99m-MIBI.
Sensitiwiteit en spesifisiteit is vir verskillende drempels van SNR en TIB verhoudings
bereken. 'Receiver operating characteristics' (ROC) kurwes is getrek om die verskillende
sensitiwiteite en spesifisiteite by elke drempel te verteenwoordig. Tuberkulose (TB) is nie
in hierdie analise ingesluit nie aangesien opname van Tl-201 beduidend hoog en
vergelykbaar met die van maligne nodules was. Die effek van OSEM en FBP op die
'positiewe' TB nodules is egter apart beoordeel. Deur berekening van die area onder die
ROC kurwes, is getoon dat OSEM van Tl-201 tomografiese data meer akkuraat as FBP
was om maligne van benigne nodules te onderskei. Alhoewel hierdie verskil nie statisties
betekenisvol was nie (p=0.10), is daar wel 'n duidelike neiging gevind. Die twee
rekonstruksie algoritmes was byna ewe akkuraat wanneer Tc-99m-MIBI gebruik is, met
duidelik geen betekenisvolle verskil tussen die algoritmes nie.
Gevo lgtrekking
In hierdie studie is dit getoon dat daar 'n neiging is dat OSEM beter vaar as FBP vir
studies met tallium-201 maar nie vir Tc-99m-MIBI nie.
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Phytochemical screening, cytotoxicity and anticancer activity of Lobostemon fruticosus extracts on human lung cancer cell lineNdlovu, Lungile Melly 03 1900 (has links)
A dissertation submitted to the Faculty of Science, University of Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. March 2015 / Lung cancer is currently the most deadly form of cancer due to the fact that metastasis occurs in the lymph nodes making it difficult to remove by surgical means. Chemotherapy has been the most successful method of treatment, although it has been harmful to human health as a consequence of non-specific cytotoxicity. There has been, therefore, a growing interest in cancer research to develop alternative cancer treatments, which are less toxic. Currently plant-derived drugs are perceived to be more effective as they display both cytotoxic activity and are less harmful to overall human health. Thus the aim of the study was to determine the cytotoxic effects of the plant Lobostemon fruticosus on A549 cells. The IC50 of the methanol and butanol extracts of L. fruticosus were obtained at 40 μg/ml and 50 μg/ml, respectively. DNA fragmentation was observed after 48 hour exposure to treatments, indicating that the plant extracts induced apoptosis. Cell cycle analysis indicated that the plant extracts inhibited cell cycle progression at the sub-G0 phase, which indicated that the cells had undergone apoptosis. RT-PCR showed that the expression of p53 was down-regulated; however, p21 and Bax were up-regulated in all treatments. LC-MS identified that the compounds from the plant extracts are known apoptotic inducers. The results lead to the conclusion that the extracts of L. fruticosus, induce cell death in A549 cells. The plant extracts induced a p53-independent apoptotic mechanism, which was mediated by Bax and p21.
Key words: Lobostemon fruticosus, camptothecin, taxol, Non-small cell lung cancer (NSCLC)
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Phantom Study Incorporating A Diode Array Into The Treatment Planning System For Patient-Specific Quality AssuranceUnknown Date (has links)
The purpose of this research is to accurately match the calculation environment, i.e. the treatment planning system (TPS) with the measurement environment (using a 2-D diode array) for lung Stereotactic Body Radiation Therapy (SBRT) patient-specific quality assurance (QA). Furthermore, a new phantom was studied in which the 2-D array and heterogeneities were incorporated into the patient-specific QA process for lung SBRT.
Dual source dual energy computerized tomography (DSCT) and single energy computerized tomography (SECT) were used to model phantoms incorporating a 2-D diode array into the TPS. A water-equivalent and a heterogeneous phantom (simulating the thoracic region of a patient) were studied. Monte Carlo and pencil beam dose distributions were compared to the measured distributions. Composite and individual fields were analyzed for normally incident and planned gantry angle deliveries. The distributions were compared using γ-analysis for criteria 3% 3mm, 2% 2mm, and 1% 1mm.
The Monte Carlo calculations for the DSCT modeled phantoms (incorporating the array) showed an increase in the passing percentage magnitude for 46.4 % of the fields at 3% 3mm, 85.7% at 2% 2mm, and 92.9% at 1% 1mm. The Monte Carlo calculations gave no agreement for the same γ-analysis criteria using the SECT.
Pencil beam calculations resulted in lower passing percentages when the diode array was incorporated in the TPS. The DSCT modeled phantoms (incorporating the array) exhibited decrease in the passing percentage magnitude for 85.7% of the fields at 3% 3mm, 82.1% at 2% 2mm, and 71.4% at 1% 1mm. In SECT modeled phantoms (incorporating the array), a decrease in passing percentage magnitude were found for 92.9% of the fields at 3% 3mm, 89.3% at 2% 2mm, and 82.1% at 1% 1mm.
In conclusion, this study demonstrates that including the diode array in the TPS results in increased passing percentages when using a DSCT system with a Monte Carlo algorithm for patient-specific lung SBRT QA. Furthermore, as recommended by task groups (e.g. TG 65, TG 101, TG 244) of the American Association of Physicists in Medicine (AAPM), pencil beam algorithms should be avoided in the presence of heterogeneous materials, including a diode array. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection
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Comparison of treatment plans calculated using ray tracing and Monte Carlo algorithms for lung cancer patients having undergone radiotherapy with cyberknifeUnknown Date (has links)
The purpose of this research is to determine the feasibility of introducing the Monte Carlo (MC) dose calculation algorithm into the clinical practice. Unlike the Ray Tracing (RT) algorithm, the MC algorithm is not affected by the tissue inhomogeneities, which are significant inside the chest cavity. A retrospective study was completed for 102 plans calculated using both the RT and MC algorithms. The D95 of the PTV was 26% lower for the MC calculation. The first parameter of conformality, as defined as the ratio of the Prescription Isodose Volume to the PTV Volume was on average 1.27 for RT and 0.67 for MC. The results confirm that the RT algorithm significantly overestimates the dosages delivered confirming previous analyses. Correlations indicate that these overestimates are largest for small PTV and/or when the ratio of the volume of lung tissue to the PTV approaches 1. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2014. / FAU Electronic Theses and Dissertations Collection
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Predictive biomarkers of the efficacy of epidermal growth factor receptor tyrosine kinase Inhibitors in treating advanced non-small cell lung cancer: a systematic review of randomized controlled trials = 表皮生长因子受体酪氨酸激酶抑制剂治疗晚期非小细胞肺癌的疗效预测生物标志物 : 随机对照试验的系统综述. / 表皮生长因子受体酪氨酸激酶抑制剂治疗晚期非小细胞肺癌的疗效预测生物标志物: 随机对照试验的系统综述 / Predictive biomarkers of the efficacy of epidermal growth factor receptor tyrosine kinase Inhibitors in treating advanced non-small cell lung cancer: a systematic review of randomized controlled trials = Biao pi sheng zhang yin zi shou ti luo an suan ji mei yi zhi ji zhi liao wan qi fei xiao xi bao fei ai de liao xiao yu ce sheng wu biao zhi wu : sui ji dui zhao shi yan de xi tong zong shu. / Biao pi sheng zhang yin zi shou ti luo an suan ji mei yi zhi ji zhi liao wan qi fei xiao xi bao fei ai de liao xiao yu ce sheng wu biao zhi wu: sui ji dui zhao shi yan de xi tong zong shuJanuary 2014 (has links)
目的: 尽管过去几十年癌症的化疗取得了很大进步,但晚期非小细胞肺癌的预后仍然较差。表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR TKIs)给晚期非小细胞肺癌的患者带来了新的希望。然而,EGFR TKIs的总体效果有限,且不良反应较多,价格也较昂贵。如果能找到EGFR TKIs的疗效预测因子,则该治疗就可以只给予那些最有可能从中获益的人,从而提高成本效果,并使治疗变得更加个体化。 / 已有单组研究在接受EGFR TKIs治疗的患者中对有或没有某个标志物的人的预后进行了比较,发现EGFR基因突变、EGFR基因拷贝数增加、EGFR蛋白表达和KRAS基因突变这4个生物标志物可能能够预测EGFR TKIs的疗效。然而,此类研究的方法学是有缺陷的。要确定以上生物标志物是否有预测作用,应该在评估EGFR TKIs疗效的随机对照试验中作亚组分析,对该治疗在有某个生物标志物及没有某个生物标志物的患者中的疗效进行比较,检测治疗与生物标记物的交互作用。 / 但是,现有的随机对照试验通常样本量较小,统计效能不足,难以从中得到确定的结论。因此,我们做了一个随机对照试验的系统综述,以总结现有的最佳证据,对EGFR TKIs与上述4个生物标志物的交互作用进行评估。 / 方法: 我们检索了PubMed,EMBASE,考科蓝图书馆,中国生物医学文献数据库(中文),万方数据库(中文),美国临床肿瘤学会和欧洲肿瘤学会的会议摘要,以及相关原始研究、系统综述与Meta分析、临床指南、共识及专家意见的参考文献。检索时间截至2012年6月。合格研究为非重复、提供了具体数据且符合下列所有条件的研究:1)研究对象:晚期非小细胞肺癌患者;2)干预措施:EGFR TKIs单药治疗或联合其他药物治疗;3)对照措施:安慰剂对照,空白对照或化疗,或者它们任一种加上干预组的基线治疗;4)结局指标:无进展生存期和/或总生存期;5)研究设计:随机对照试验;6)根据上述任一种或多种生物标志物的状态作了亚组分析。 / 两名研究者平行独立地从合格研究中提取了患者特征、治疗方案、结局、生物标志物分析和方法学质量等方面的资料。对每一个研究,我们都根据生物标志物阳性亚组的风险比(hazard ratio)和阴性亚组的风险比计算了一个风险比之比(ratio of hazard ratios)来测量该标志物对疗效的预测能力或者说治疗与该生物标志物的交互作用。然后,采用随机效应模型对来自不同研究的风险比之比进行Meta分析;采用Cochran Q检验和I²评估研究间的异质性;通过敏感性分析考察原始研究的方法学质量等因素对结果的影响;采用Begg漏斗图和Egger检验来检测发表偏倚存在的可能性。 / 结果: 共有18个合格研究入选。可用于各个生物标志物分析的患者数量从1763到3246不等。原始研究普遍对关于方法学质量的信息报告得不够充分;有的研究可能存在重要偏倚。与安慰剂相比,EGFR TKIs可以有效延长无进展生存期和总生存期,但对总生存期的效果相对较小。除了在EGFR基因突变的患者中EGFR TKIs延长无进展生存期的效果明显好于化疗外,其它情形下,不管是无进展生存期还是总生存期,EGFR TKIs与化疗的效果均相当。 / 以无进展生存期为结局的风险比之比,在EGFR基因突变状态不同的亚组间(野生型亚组为参照)为0.37(95% 置信区间[CI]:0.22-0.60,P < 0.0001),EGFR基因拷贝数状态不同的亚组间(未增加的亚组为参照)为0.72(95% CI:0.52-0.99,P = 0.04),EGFR蛋白表达状态不同的亚组间(无表达的亚组为参照)为0.99(95% CI:0.78-1.26,P = 0.93),KRAS基因突变状态不同的亚组间(野生型亚组为参照)为1.35(95% CI:1.02-1.80,P = 0.04)。这些结果提示EGFR TKIs治疗与EGFR基因突变,EGFR基因拷贝数及KRAS基因突变之间可能存在交互作用。以总生存期为结局的风险比之比,在EGFR基因突变、EGFR基因拷贝数、EGFR蛋白表达及KRAS基因突变状态不同的亚组间分别为0.84(95% CI:0.64-1.11,P = 0.22)、0.92(95% CI:0.69-1.23,P = 0.57)、0.86(95% CI:0.70-1.05,P = 0.14)和1.37(95% CI:0.89-2.10,P = 0.15)。 / 就统计学显著性、异质性和稳定性而言,关于其它3个生物标志物的结果不如EGFR基因突变的相关结果确定,关于总生存期的结果不如无进展生存期的相关结果确定。没有证据表明本研究中存在发表偏倚。 / 结论: EGFR基因突变可用于确定哪些患者更有可能从EGFR TKIs治疗中获益。EGFR基因拷贝数增加和KRAS基因突变可能也有类似用途,但它们与治疗的交互作用是独立存在的还是由于它们与EGFR基因突变的相关性而获得的,目前尚不清楚。在EGFR野生型的患者中,选择化疗似乎比EGFR TKIs更好,因为它的副作用相对较少,且更为便宜。 / 本研究的结果为当前的临床指南提供了全面的证据支持。其它3个标志物在EGFR野生型患者中的预测价值可能还值得进一步的探讨,但我们更建议未来的研究在探讨治疗与生物标志物的交互作用时进行多因素分析。 / Objective: Despite the many new progresses in chemotherapy, the prognosis of advanced non-small cell lung cancer (NSCLC) remains poor. The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) seems to offer new promises for advanced NSCLC patients. However, EGFR TKIs have a limited overall efficacy, clear adverse events and large costs. It has become particularly appealing to identify, through new biomarkers, patients who are more likely to benefit from the treatment so that the treatment can be more personalized and effective. / EGFR mutations, EGFR gene copy number gain, EGFR protein expression and KRAS mutations were indicated as potential predictive biomarkers for the efficacy of the treatment in single-arm studies that compared survival of treated patients with and without a biomarker. However, such comparisons are flawed and the appropriate study design to evaluate the value of a biomarker in predicting efficacy which is known as interaction in epidemiology is the randomized controlled trial with stratified analysis that compared the efficacy of EGFR TKIs between patients with and without the biomarker. / As trials in this field are usually small in sample size and insufficiently powered for drawing a robust conclusion, we conducted this systematic review to summarize the evidence from all relevant randomized controlled trials that have data for investigating the interaction between EGFR TKIs and the 4 biomarkers. / Methods: PubMed, EMBASE, the Cochrane Library, Chinese Biomedical Literature Database (in Chinese), Wanfang Data (in Chinese), the abstracts of conferences of the American Society of Clinical Oncology and European Society of Medical Oncology, the reference list of relevant original studies, systematic reviews and meta-analyses, guidelines, consensus, and expert opinions were searched up to June 2012. / Eligible studies had to be non-duplicate, extractable studies meeting all the following criteria: 1) Population: patients with advanced NSCLC; 2) Intervention: EGFR TKIs alone or EGFR TKIs plus other treatments; 3) Control: placebo, no treatment, or chemotherapy, with or without the baseline treatments in the intervention arm; 4) Outcome: progression-free survival and/or overall survival; 5) Study design: randomized controlled trial; 6) Subgroup analyses were conducted according to the status of one or more of the 4 biomarkers. / Data on patients’ characteristics, treatment protocols, outcomes, biomarker analysis and methodological quality were extracted by two researchers independently. Within a study, we defined the measure of the value of a biomarker in predicting efficacy or biomarker-treatment interaction as the hazard ratio in patients with the biomarker relative to that in those without the marker. The ratio of hazard ratios from relevant studies was then combined by using the random-effect model. / Heterogeneity among studies was assessed by the Cochran’ Q test and I². Sensitivity analyses were conducted to examine the impact of factors such as methodological quality on the results. Begg’s funnel plots and Egger’s tests were used to examine the possibility of publication bias. / Results: Eighteen studies were included. The number of patients available for analyses on different biomarkers varied from 1,763 to 3,246. Data on the methodological quality of included studies are generally under-reported. Some studies seemed to have important biases. EGFR TKIs are in general effective in increasing progression-free and overall survival as compared with placebo although the effect size is smaller for overall survival than for progression free survival. EGFR TKIs are comparable to chemotherapy in their effect in prolonging both progression-free and overall survival, except in EGFR mutation group in which EGFR TKIs seem much more effective than chemotherapy in prolonging progression-free survival. / Importantly, for progression-free survival, the summary ratio of hazard ratios was 0.37 (95% confidence interval [CI]: 0.22-0.60, P < 0.0001) for EGFR mutations (versus wild-type), 0.72 (95% CI: 0.52-0.99, P = 0.04) for EGFR gene copy number gain (versus no gain), 0.99 (95% CI: 0.78-1.26, P = 0.93) for EGFR protein expression (versus negative), and 1.35 (95% CI: 1.02-1.80, P = 0.04) for KRAS mutations (versus wild-type), indicating interaction may exist between EGFR TKIs and EGFR mutation, EGFR gene copy number and KRAS mutations. For overall survival, the summary ratio of hazard ratios for EGFR mutations, EGFR gene copy number gain, EGFR protein expression and KRAS mutations was 0.84 (95% CI: 0.64-1.11, P = 0.22), 0.92 (95% CI: 0.69-1.23, P = 0.57), 0.86 (95% CI: 0.70-1.05, P = 0.14) and 1.37 (95% CI: 0.89-2.10, P =0.15), respectively. / In general, the results on EGFR gene copy number gain, KRAS mutations and EGFR protein expression were less certain than those on EGFR mutations in terms of statistical significance, consistency and robustness, and the results on overall survival were less certain than those on progression-free survival. Publication bias did not seem present in the study. / Conclusions: EGFR mutations and possibly EGFR-GCN and KRAS mutations can help identify who are more likely to benefit from EGFR TKIs treatment. However, it is not clear whether the interaction with EGFR-GCN and KRAS mutations are independent or obtained through their relation with EGFR mutations. Furthermore, in EGFR wild-type patients, given that chemotherapy is cheaper and of fewer side effects, chemotherapy seems clearly a better choice than EGFR TKIs. / Our findings provided the most comprehensive evidence for the recommendations of current guidelines. Although the predictive value of the other 3 biomarkers in wild-type EGFR patients may be worth further investigation, we suggest that multivariate analyses are explored in future studies of biomarker-treatment interactions. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Yang, Zuyao. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 88-104). / Abstracts also in Chinese. / Yang, Zuyao.
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Radiotherapy dose-fractionations and outcomes in cancer patientsRamroth, Johanna Rankin January 2017 (has links)
Radiotherapy cures many cancers, but the optimum total doses and fractionations used to treat different cancer types remain uncertain. While conventional fractionation (≈2 Gy per fraction) is common in many countries, UK practice has been highly variable. This thesis compared different curative-intent radiotherapy dose-fractionations used in non-small cell lung and breast cancer. These two cancers together make up over a quarter of UK cancer incidence and mortality, and radiotherapy can increase cure rates of both cancers. Two studies were conducted: (A) A meta-analysis of randomised radiotherapy trials in non-small cell lung cancer and (B) A cohort study of non-small cell lung and breast cancer radiotherapy in the Thames Valley. For the meta-analysis, a systematic search was conducted. Eligible studies were randomised comparisons of two or more radiotherapy regimens. Median survival ratios were calculated for each comparison and pooled. 3,795 patients in 25 randomised comparisons of radiotherapy dose were studied. When radiotherapy was given alone, the higher dose within-trial resulted in increased survival (median survival ratio 1.13, 95% confidence interval 1.04-1.22). When radiotherapy was given with concurrent chemotherapy, the higher dose within-trial resulted in decreased survival (median survival ratio 0.83, 95% confidence interval 0.71-0.97). For the cohort study, multiple Public Health England data sources were combined to obtain information on radiotherapy, patient characteristics, and outcomes. Multivariable Cox regressions were conducted separately by cancer site. 324 non-small cell lung, 8,879 invasive breast, and 477 ductal carcinoma in situ patients were studied. In analyses of both non-small cell lung and invasive breast cancer, increasing radiotherapy dose was associated with improved survival in some treatment centres, while in other centres the opposite was true. These opposite trends by treatment centre were unlikely to be explained by chance, and they suggest that differences in patient selection were driving results. There were insufficient events among ductal carcinoma in situ patients to assess associations. Findings from the meta-analysis support consideration of further radiotherapy dose escalation trials, making use of modern methods to reduce toxicity. Findings from the cohort study suggest that it is not possible to use observational studies to examine causal effects of radiotherapy dose-fractionation. This thesis therefore shows the continued importance of conducting sufficiently large randomised trials to ascertain optimal dose-fractionation in radiotherapy.
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The positive role of thromboxane A2 (TxA2) and Its receptor in lung cancer cell growth induced by smoking carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK). / CUHK electronic theses & dissertations collectionJanuary 2012 (has links)
肺癌是一個世界性的健康難題。大量研究證據顯示,煙草及其致癌物NNK對環氧酶(COX)-2及其下游產物具有促進效應。血栓素(TxA)2是COX-2的關鍵性下游產物之一,該論文闡述了TxA2在NNK導致的肺癌增長中的可能作用。 / 我們發現相对于非吸烟者,吸煙者肺癌組織表达更高水平的TxA2合酶(TxAS)。NNK可以刺激培養的肺癌細胞TxA2合成。用TxAS抑制劑和TxA2受體(TP)拮抗劑分別阻抑TxA2的合成與功能可以引起細胞凋亡,從而有效抑制NNK導致的細胞增殖效應。在TxA2合成受抑制的情況下,TP激動劑U46619幾乎可以重建NNK效應,說明TP在NNK效應中的重要作用。研究還顯示,激活的TP可以通過PI3K/Akt和ERK通路進一步激活CREB,從而參與NNK對肺癌細胞的促生長效應。 / 緊接著,我們的研究顯示TP 可以調節NNK對COX-2 和TxA2的誘導,而且發現NNK刺激的TxA2合成主要依賴於COX-2活性。COX-2和TxA2功能抑製劑對NNK的促細胞生長作用具有相似的抑制效用。考慮到TP是TxA2的功能受體,該資料說明TP在NNK處理的肺癌細胞中傳遞了上游因子COX-2的促腫瘤作用。在使用COX-2小干擾RNA(siRNA)抑制NNK作用的情況下,TP激動劑U46619幾乎可以恢復NNK的效應證實了TP的傳遞者角色。研究還發現 TPα而不是TPβ在培養的肺癌細胞系中廣泛表達,並且過表達TPα具有促進腫瘤生長的作用。在用NNK處理細胞的條件下,TPα還具有促COX-2表達和TxA2生成的作用。 / 我們的研究進一步發現,在吸煙者肺癌組織中TPα表達增高,這與TxAS的表達相似。与此结果相一致,在經NNK處理的A/J小鼠肺癌組織中,TxAS和TP表達水準也是明顯上升的。在細胞培養實驗中,NNK能夠提高TxAS蛋白和信使RNA(mRNA)的表達水準。但是,在TP的兩個亞型TPα和TPβ中, NNK僅能促進TPα的蛋白表達,對它們的mRNA均無影響。NNK對TxAS的促表達作用是核轉錄因數(NF)-κB依賴性的。其他的幾個關鍵轉錄因數,諸如特異性蛋白(SP)-1,CREB和活化受體 (PPAR)γ均未參與NNK對TxAS和TPα的表達促進作用。進一步的,轉錄後機理被證實參與了NNK對TPα的作用。TPα而不是TPβ經鑒別在NNK的促NF-κB 激活 和 促TxAS 表達效應中起正向調節作用。 / 總之, 我們的研究說明TxA2相關通路在NNK的促肺癌細胞生長效應中起正向調節作用。我們的研究揭示了TPα的自我激活環路。通過該環路,TxA2,或者說TxAS和TPα參與了NNK的肺癌促生長效應。因此,我們的研究為肺癌的防治了提供了一個新的方向,即靶向TxAS和TPα是一種可能有效的策略。 / Lung cancer concerns a world-wide health problem. There is considerable evidence of that tobacco smoke and its carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK) have the potential effects on the production of cyclooxygenase (COX)-2 and its downstream products in tumor cells. This thesis is constructed to describe the study focused on the role of thromboxane A2 (TxA2), one of the key downstream products of COX-2, in NNK-induced lung tumor growth. / We found that as compared to non-smokers, lung cancer tissues obtained from smokers tended to express more TxA2 synthase (TxAS). Moreover, NNK could stimulate TxA2 synthesis in lung cancer cells. Blockade of TxA2 synthesis and action by TxAS inhibitor and TxA2 receptor (TP) antagonist completely blocked NNK-promoted cell proliferation via inducing apoptosis. Moreover, TP agonist U46619 reconstituted a near full proliferative response to NNK when TxAS was inhibited, affirming the role of TP in NNK-induced cell growth. Furthermore, we revealed that the activated TP may then activate CREB through PI3K/Akt and ERK pathways, thereby contributing to the NNK-induced lung cancer cell growth. / We subsequently showed that TP could modulate the induction of COX-2 and TxA2 by NNK. The synthesis of TxA2 stimulated by NNK was found to be mainly dependent on COX-2 activity. Intriguingly, there are similar inhibitory effects on NNK-induced cell growth between pharmacological inhibition of COX-2 and the blockade of TxA2 synthesis and action. Because TP is the natural receptor of TxA2, these results suggest that TP may function as a mediator for the tumor-promoting effects of COX-2 upon NNK treatment, which was confirmed by the data showing that U46619 almost restored NNK effects in the presence of COX-2-siRNA. Importantly, TPα, but not TPβ was found to be widely expressed in lung cancer cells and be able to promote tumor growth, COX-2 expression and TxA2 synthesis upon NNK treatment. / We further demonstrated that in lung tumor tissues obtained from smoker, TPα protein was increased, which was similar to the change in TxAS protein. The increased levels of TxAS and TP proteins were also found in lung cancer tissues of A/J mice treated with NNK. In cell culture experiments, NNK could increase TxAS at both protein and mRNA levels. However, TPα rather than TPβ was increased by NNK at protein but not mRNA level. NNK-stimulated TxAS expression was dependent on nuclear factor (NF)-κB signaling. Other key transcriptional factors, such as specificity protein(SP)-1, CREB and peroxisome proliferator-activated receptor-gamma (PPARγ), were not involved in NNK-induced TxAS and TPα expression. Further experiments revealed that post-transcriptional mechanisms were responsible for NNK-induced TPα expression. TPα rather than TPβ was finally identified to have a positive role in NNK-induced NF-κB activation and TxAS expression. / Taken together, our study suggests that TxA2 pathway has a positive role in NNK-induced lung cancer cell growth. An auto-positive feedback loop of TPα activation to facilitate lung tumor growth in the presence of NNK is delineated by these results. Therefore, targeting TxAS or/and TPα may represent a promising strategy for prevention and treatment of lung cancer. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Huang, Runyue. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 119-146). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.I / 摘要 / Publications / Acknowledgement / Abbreviations / Table of contents / Chapter Chapter 1 --- General introduction--Tobacco smoking, COX-2 pathway and cancer / Chapter 1.1 --- Abstract --- p.1 / Chapter 1.2 --- Introduction --- p.2 / Chapter 1.3 --- Cyclooxygenase and prostanoids --- p.5 / Chapter 1.4 --- The effects of tobacco smoking on COX-2 pathway, and the related pathologies --- p.8 / Chapter 1.4.1 --- Smoking, PGE2, inflammation and immunosupression --- p.8 / Chapter 1.4.2 --- Smoking, TxA2, platelet activation, cell contraction and angiogenesis --- p.11 / Chapter 1.4.3 --- Smoking and PGI2 --- p.16 / Chapter 1.5 --- The role of cyclooxygenase-2 pathway in the progression of tobacco smoke-related cancers --- p.19 / Chapter 1.5.1 --- Lung cancer --- p.19 / Chapter 1.5.2 --- Gastrointestinal cancer --- p.23 / Chapter 1.5.3 --- Bladder cancer --- p.24 / Chapter 1.5.4 --- Head and neck squamous cell carcinoma --- p.25 / Chapter 1.5.5 --- The signaling mechanisms underlying the induction of COX-2 by smoking in tumors --- p.26 / Chapter 1.6 --- Summary, future directions and key questions --- p.28 / Chapter Chapter 2 --- NNK induces lung cancer cell growth by stimulating TxA2 and its receptor / Chapter 2.1 --- Abstract --- p.32 / Chapter 2.2 --- Introduction --- p.33 / Chapter 2.3 --- Materials and Methods --- p.35 / Chapter 2.3.1 --- Cell lines and cell culture --- p.35 / Chapter 2.3.2 --- Chemicals and drug treatment --- p.35 / Chapter 2.3.3 --- Thromboxane B2 EIA assay --- p.36 / Chapter 2.3.4 --- MTT assay --- p.36 / Chapter 2.3.5 --- BrdU cell proliferation assay --- p.37 / Chapter 2.3.6 --- Flow cytometry for analysis of apoptosis --- p.37 / Chapter 2.3.7 --- Transfection of cells with CREB siRNA --- p.38 / Chapter 2.3.8 --- Western blot analysis and antibodies --- p.38 / Chapter 2.3.9 --- Statistical analysis --- p.39 / Chapter 2.4 --- Results --- p.41 / Chapter 2.4.1 --- High expression of TxAS in lung cancer tissues of smoker --- p.41 / Chapter 2.4.2 --- NNK stimulated TxA2 synthesis in lung cancer cells --- p.43 / Chapter 2.4.3 --- Blockade of TxA2 synthesis and action prevented NNK-induced cell growth --- p.44 / Chapter 2.4.4 --- TxA2 mimetic U46619 reconstituted NNK-enhanced cell proliferation under TxA2-inhibited condition --- p.47 / Chapter 2.4.5 --- Blockade of TxA2 synthesis or action induced the apoptosis of the NNK-exposed cells --- p.47 / Chapter 2.4.6 --- CREB is accountable for the key role of TxA2 in NNK-enhanced cell proliferation --- p.49 / Chapter 2.4.7 --- PI3K/Akt and ERK rather than JNK and p38 pathways were mediated by TxA2 in the NNK-exposed cells --- p.52 / Chapter 2.4.8 --- CREB is located downstream of the PI3K/Akt and ERK pathways in NNK-treated cells --- p.53 / Chapter 2.5 --- Discussion --- p.55 / Chapter Chapter 3 --- The positive role of TPα in the induction of COX-2, TxA2 and cell growth by NNK in human lung cancer cells / Chapter 3.1 --- Abstract --- p.62 / Chapter 3.2 --- Introduction --- p.63 / Chapter 3.3 --- Materials and methods --- p.65 / Chapter 3.3.1 --- Cell culture and chemicals --- p.65 / Chapter 3.3.2 --- Transient transfections --- p.66 / Chapter 3.3.3 --- TxB2 measurement --- p.66 / Chapter 3.3.4 --- Cell growth detection --- p.67 / Chapter 3.3.5 --- Analysis of apoptosis --- p.67 / Chapter 3.3.6 --- Western blot analysis and antibodies --- p.67 / Chapter 3.3.7 --- Statistical analysis --- p.68 / Chapter 3.4 --- Results --- p.70 / Chapter 3.4.1 --- Examination of TP as the modulator for induction of COX-2 and TxA2 by NNK --- p.70 / Chapter 3.4.2 --- The TxA2 generated in cells treated with NNK is mainly dependent on COX-2 activity --- p.72 / Chapter 3.4.3 --- Examination of TP as the key mediator for the tumor-promoting effect of COX-2 --- p.72 / Chapter 3.4.4 --- The expression and action of α and β isoforms of TP in human lung cancer cells --- p.77 / Chapter 3.4.5 --- the identification of positive role of TPα in NNK-induced COX-2, TxA2 and cell growth in lung cancer cells --- p.79 / Chapter 3.5 --- Discussion --- p.81 / Chapter Chapter 4 --- TP-α facilitates lung tumor growth through an autoregulatory feedback mechanism / Chapter 4.1 --- Abstract --- p.88 / Chapter 4.2 --- Introduction --- p.89 / Chapter 4.3 --- Materials and methods --- p.91 / Chapter 4.3.1 --- Human lung tissue and immunohistochemical analysis --- p.91 / Chapter 4.3.2 --- Animal treatment --- p.91 / Chapter 4.3.3 --- Cell culture and chemicals --- p.92 / Chapter 4.3.4 --- Transient transfection --- p.93 / Chapter 4.3.5 --- Real-time PCR --- p.93 / Chapter 4.3.6 --- Western blot analysis and antibodies --- p.94 / Chapter 4.3.7 --- Statistical analysis --- p.95 / Chapter 4.4 --- Results --- p.96 / Chapter 4.4.1 --- The effects of smoking on the expression of TP in human lung cancer tissue --- p.96 / Chapter 4.4.2 --- The effects of NNK on the expression of TxAS and TP in lung tissues of A/J mice --- p.98 / Chapter 4.4.3 --- The effects of NNK on the expression of TxAS and TPα in lung cancer cells --- p.99 / Chapter 4.4.4 --- Identification of the roles of NF-κB, CREB and SP1 in NNK-induced TxAS and TPα expression --- p.101 / Chapter 4.4.5 --- The negative role of PPARγ in NNK-induced TxAS and TPα expression --- p.104 / Chapter 4.4.6 --- NNK-induced TPα expression via post-transcriptional mechanism --- p.105 / Chapter 4.4.7 --- Examination of TPα auto-activation mechanism in lung cancer cells stimulated with NNK --- p.106 / Chapter 4.5 --- Discussion --- p.109 / Chapter Chapter 5 --- Conclusion and future works / Chapter 5.1 --- Conclusion --- p.114 / Chapter 5.2 --- Future works --- p.115 / Chapter 5.2.1 --- The possible role of miR-34c in the auto-regulatory loop of TxAS expression or TPα activation --- p.116 / Chapter 5.2.2 --- The possible role of FOXO3a in the auto-regulatory loop of TxAS expression or TPα activation --- p.116 / References --- p.119
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