In this study, luteinized human granulosa cells (GC) obtained during in vitro fertilization procedures were used as a model system to evaluate the effects of ethanol (EtOH), a well‐known reproductive toxin, on epidermal growth factor (EGF) and gonadotropin‐stimulated steroidogenesis. Our results demonstrate that the basal progesterone (P4) and estradiol (E2) secretion by human GC in vitro was dependent on the ovarian stimulation protocol. EGF significantly enhanced P4, but not E2, secretion in human GC from clomiphene citrate (CC), human menopausal gonadotropin (hMG), and hMG/gonadotropin‐releasing hormone agonist (GnRH‐a)‐treated patients. The effects of EGF plus luteinizing hormone (LH) were additive in cells from the CC group, but less than additive in hMG and hMG/GnRH‐a groups. EtOH at 20 mM or more inhibited EGF stimulated P4 secretion in human GC from all three patient groups. EtOH inhibited P4 secretion stimulated by EGF and LH cotreatment in the CC and hMG/GnRH‐a groups, but not in human GC from the hMG‐treated patients. These results suggest that basal and EGF or LH‐stimulated P4 secretion by human GC, as well as the effects of EtOH, are profoundly influenced by the follicle's hormonal milieu.

Indiana University-Purdue University Indianapolis (IUPUI) / Diabetes occurs as a result of the failure of pancreatic insulin-producing β cells. The preservation or renewal of β cells is a strategy that can prevent diabetes by targeted manipulation of mechanisms associated with autoimmune β cell destruction or β cell regeneration. ErbB signaling, specifically epidermal growth factor receptor (EGFR) signaling, is associated with cell survival, growth, and proliferation. Thus, we investigated the role of the ErbB inhibitor, mitogen-inducible gene 6 (mig6), in pancreas development and in the progression to diabetes. Using morpholino knockdown in a zebrafish model of development, we discovered that mig6 is required for the generation of α and β cells as well as the formation of the exocrine pancreas. We suspect that the loss of mig6 function causes premature differentiation of ductal progenitor cells, and acts as a switch between progenitor differentiation and endocrine transdifferentiation. Furthermore, we established a pancreas-specific mig6 knockout mouse that maintained glucose tolerance and had a higher β cell mass after chemically-induced β cell injury by way of increased β cell proliferation. Our data suggests that mig6 is required during pancreas development and may be employed as a switch to direct the production of new β cells, but that during adulthood, it is detrimental to the recovery of β cell mass, making it a therapeutic target for β cell preservation after the onset of diabetes.

No description available.

Thesis advisor: Jianmin Gao / Protein-protein interactions (PPIs) are essential for all biological functions. Developing peptides that disrupt these PPIs is an avid research effort, as peptides possess several advantages over small molecules and monoclonal antibodies. Peptide phage display is a useful tool in identifying peptides for targeting PPIs. This technology displays up to 10^10 unique polypeptides on the surface of bacteriophage, which after several rounds of panning enriches high affinity peptide sequences towards a target protein. Phage display is classically done on immobilized discrete protein; however, we propose to use this technology to identify peptides ligands for overexpressed oncogenic proteins on live cells in-vitro. This is a more accurate representation of the therapeutic target landscape and resembles how the peptide will interact with the receptor in-vivo. Several groups have explored live cell panning, such as Ruoslahti et al. and Cieslewicz et al., and while they demonstrate the capabilities of in-vitro style phage display, there are areas for improvement. We intend to improve on this previous work by 1. Identifying a peptide ligand against specific receptor/protein, and 2. By incorporating the use of covalent phage libraries to elucidate a high affinity binder. This work will be accomplished using the mammalian epidermal oncogenic cell line, A431, that is known to overexpress epidermal growth factor receptor (EGFR). Epidermal growth factor receptor (EGFR) is responsible for cellular proliferation, survival, differentiation and metastasis, which makes it an attractive target to inhibit oncogenic proliferation. Despite successfully marketed monoclonal antibodies and tyrosine kinase inhibitors, EGFR can mutate and develop resistance as diseases progress; this phenomenon, in addition to the benefits of peptides as therapeutics, are driving factors for pursuing this project. Despite our best efforts using non-covalent phage libraries to identify a viable ligand, screening against EGFR extracellular domain (ECD) has proven to be more difficult than anticipated. We hypothesize that non-covalent phage libraries do not possess any sequences with a high enough binding affinity for this protein, and that the use of covalent libraries will be needed to pull out a positive hit. Due to these findings, we have successfully constructed two phage libraries, a ACX7C and a ACX7C-TEV, where the latter introduced a TEV protease cleavage site on the C’-terminal side of the randomized amino acids suitable for covalent warhead modification and screening. Further, we have begun work on constructing an EGF-displaying phage construct to aid in optimizing a live cell panning protocol. In the future, we plan to evaluate ligand affinity and protein density, as well as determine the optimal covalent warhead/peptide combination for live cell screenings. With this information, we intend to apply this to other oncogenic cell lines, such as MCF-10CA1a, to identify potent peptide ligands for overexpressed oncogenic proteins. / Thesis (MS) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

No description available.

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.

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 2000. / Typescript. Bibliography: leaves 92-100.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains x, 160 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.