Programmed death-ligand 1 (PD-L1) is a type 1 transmembrane protein that has been reported to play a vital role in mediating suppressed immunity. The interaction between PD-L1 and PD-1 delivers a negative signal that reduces the proliferation of these T cells and induces apoptosis at the same time. Antibodies that can block the Programmed death-ligand 1 (PD-L1) on tumor cells have been shown to alleviate cancer-induced immunosuppression. While antibodies have a great potential in various therapeutic uses, many drawbacks such as the high cost of production, huge molecular size, and poor permeability impose restrictions on the extensive use of full-length antibodies. These limitations have necessitated research for finding alternatives to antibodies, such as peptides, that have lower molecular weight and similar properties as antibodies but do not have the lengthy and complicated approach of producing antibodies. In this study, a novel approach based on molecular interactions of the PD1-PD-L1 complex was developed to design peptides against PD-L1 using Knob-Socket model as basis. Three generations of peptides, α-helix, over-packed and salt bridge function peptides, were designed. All designed peptides were docked in the Molecular Operating Environment (MOE) and the AutoDock Vina software for the docking energy and the detail interaction information. Synthesis and characterization of selected peptides were performed after simulation studies. Surface Plasmon Resonance (SPR) studies showed that α-helix and over-packed peptides can’t bind to the PD-L1 protein with no response on sensorgrams, while peptides with salt bridge function had a higher binding response than those two generations of peptides. In confocal microscopic studies, PD-L1 positive breast cancer cell line MDA-MB-231 was used to determine the binding specificity of the salt bridge function peptides to PD-L1 in vitro, while another breast cancer cell line (MCF-7, without PD-L1) was used as a control. After incubation with peptides, significant fluorescence intensities were detected on the MDA-MB-231 cells, while only background fluorescence was observed on MCF-7 cells. In conclusion, this study demonstrated that peptides against PD-L1 designed using the Knob-Socket model and molecular interaction between PD-L1-PD1 complex showed feasibility to bind specifically with PD-L1 receptors.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18290号 / 工博第3882号 / 新制||工||1596(附属図書館) / 31148 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 秋吉 一成, 教授 澤本 光男, 教授 松原 誠二郎 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第20056号 / 医科博第74号 / 新制||医科||5(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 浅野 雅秀, 教授 岩井 一宏, 教授 生田 宏一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(薬科学) / 乙第13086号 / 論薬科博第2号 / 新制||薬科||9(附属図書館) / (主査)教授 竹本 佳司, 教授 高須 清誠, 教授 川端 猛夫 / 学位規則第4条第2項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21302号 / 医博第4391号 / 新制||医||1030(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 椛島 健治, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

The virus SARS-CoV-2 gave rise to a global pandemic and several vaccines, whose efficiency needed to be evaluated, have been developed. Our immune system is regulated by several mechanisms that activate and inhibit immune response. PD-1 and its ligand PD-L1 are immune inhibitors with a possible correlation between the potency of the immune response and the number of inhibitors. The hypothesis of this study is that individuals with a lower antibody response after vaccination have higher levels of PD-1/PD-L1. Using an ELISA, the concentration of the proteins was measured from blood plasma from 19 individuals from the CoVacc Cohort, with known antibody response after one as well as two doses of vaccine. The study found a significant correlation between the inhibitors PD-1 and PD-L1 after both the first and the second dose. No correlation was found between the response of antibodies and PD-1/PD-L1 and the hypothesis is therefore rejected. It is possible that the interval between each dose of vaccine and the collection of blood plasma was not optimized for this study. It is also possible that the number of individuals that were included in this study was too low. Considering this result, more research should be conducted on the subject before an absolute conclusion can be drawn. / Viruset SARS-Cov-2 gav upphov till en global pandemi och flera vacciner vars effektbehövde utvärderas har utvecklats. Vårt immunförsvar regleras av flera mekanismersom samverkar genom att aktivera respektive hämma immunförsvaret. PD-1 och dessligand PD-L1 är immuninhibitorer med en möjlig korrelation mellan styrkan hosimmunsvaret och mängden inhibitorer. Hypotesen för denna studie är att individermed ett lägre antikroppssvar efter vaccination har högre nivåer av PD-1 och PD-L1.Med hjälp av en ELISA mättes koncentrationen av PD-1 och PD-L1 med blodplasmafrån 19 individer ur CoVacc kohorten med kända antikroppsnivåer som fått enrespektive två doser av vaccin mot COVID-19. Studien fann en signifikant korrelationmellan hämmarna PD-1 och PD-L1 både efter första och andra dosen. Ingenkorrelation hittades mellan antikroppsresponsen och nivåerna av PD-1 och PD-L1 ochhypotesen förkastas därför. Det är möjligt att tidpunkten för provtagning eftervaccindoserna inte valdes optimalt för denna undersökning. Det är också möjligt attför få individer ingick i studien. Mot bakgrund av detta bör mer forskning göras i ämnetinnan en absolut slutsats kan dras.

No description available.

Introduction Aspirin has been associated with a reduction in mortality in patients diagnosed with colorectal cancer (CRC). A possible mechanism for this is related to the programmed cell death 1 (PD-1) immune checkpoint pathway. Aspirin may have a synergistic effect with PD-1 inhibitors via inhibition of prostaglandin E2 (PGE2) production, which can reverse the ability of tumor cells to evade the immune system. This appears to be strongest in cancers that express PI3 kinase (PI3K) signaling activity, which aspirin downregulates. However, the benefit of pre-diagnosis aspirin use on CRC overall survival (OS) and cancer-specific survival is still controversial, and most studies have been performed in racially homogenous populations. Our study examines the effect of pre-diagnosis aspirin therapy on OS in a racially diverse group of patients with CRC. Methods This is a retrospective chart review of 782 patients diagnosed with CRC from January 2007 to December 2020. Kaplan-Meier curve was created to study the association of aspirin exposure compared to no exposure on OS. In addition, univariate and multivariate binary logistic regression analyses were done to investigate potential predictors of survival. Results Of the 782 patients with CRC, 55.1% were males, 22.2% whites, 58.5% Asians, and 17.7% Pacific-Islanders. Moreover, 38.4% of the patients had a history of aspirin use, 79% of them used it for more than one year. There were more patients with hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), and chronic kidney disease (CKD) among those with a history of aspirin use. There was no difference in one, three, and five-year OS among aspirin users compared to non-users, p-value = 0.63. Age, grade, and stage were potential predictors of worsened OS. However, treatment with chemotherapy and CKD were potential predictors of worsened OS on univariate analysis only. No significant association was noticed with gender, tumor location, or other associated comorbidities. Conclusion The effect of pre-diagnosis aspirin use on CRC survival is not clear. In this retrospective analysis of a racially diverse population of CRC patients, we found that aspirin use was not associated with improved OS. Therefore, physicians should be careful about using aspirin as adjuvant therapy in CRC patients until high-quality prospective data are available, given the potential associated complications.

Polychlorinated biphenyls are a ubiquitous environmental contaminant that can be found today throughout the world in soils and sediments, lakes and rivers, and flora and fauna. PCBs have percolated throughout the food chain, so that almost every human being has a detectable amount of the contaminant within their blood stream. Existing remediation methods include incineration, dredging and landfilling, and microbial degradation, but all of these methods have drawbacks that limit their effectiveness as treatment options. Recently, the use of zero-valent metals as a means of reductive dechlorination has been explored. Using a combination of zero-valent magnesium and catalytic palladium, a successful bimetallic system capable of degrading PCBs has been created and optimized. Determining the mechanism for the reductive dechlorination has proven to be an arduous task, but experimental evidence has suggested three possible radical-type mechanisms for the use Mg/Pd specifically in methanol (as compared to aqueous systems). These possible mechanisms differ in the type of hydrogen species that replaces the chlorine atom on the PCB. Thermodynamic information has also aided in narrowing down which of the suggested pathways is most likely. It appears likely that the hydrogen involved in the dechlorination has the form of a "hydride-like" radical, which is a form of electron-rich atomic hydrogen. According to the literature, Pd catalysts create this species within the first few subsurface layers of the palladium in the presence of molecular hydrogen. Further work will be necessary to confirm that the "hydride-like" radical is actually the species involved in the dechlorination.