Pancreatic ductal adenocarcinoma (PDAC) is a virulent disease which readily develops resistances to prevailing chemotherapies. PDAC is often not diagnosed until the disease presents in an inoperable ...late stage. Early detection of PDAC while there is still hope for effective treatment is critical to survival. Cancer cells experience a metabolic shift towards aerobic glycolysis as they develop. This atypical metabolism results in the production and export of lactic acid, which results in acidification of the extracellular tumor microenvironment. Thus, acidosis is a biomarker of cancer development. Our research program uses a technique called chemical exchange saturation transfer magnetic resonance imaging (acidoCEST MRI) to measure acidosis in the extracellular microenvironment. The work presented in this dissertation will focus on characterization of acidosis in PDAC using acidoCEST MRI. Chapter 1 reviews components of the tumor microenvironment that are affected by acidosis as well as briefly overviews aspects of the microenvironment of pancreatic cancer. Chapter 2 presents work analyzing the role of the glucose transporter GLUT3 in chemoresistance and acidosis of two pancreatic cancer cell lines. Chapter 3 explores the use of acidosis as a prognostic biomarker of pancreatic cancer development. Finally, chapter 4 highlights future studies which would be a natural continuation of the work in this dissertation or would contribute to the advancement of acidoCEST MRI as a research technique.
OBJECTIVE To create a cohort for cost-effective genetic research, the Mayo Genome Consortia (MayoGC) has been assembled with participants from research studies across Mayo Clinic with high-throughput ...genetic data and electronic medical record (EMR) data for phenotype extraction. PARTICIPANTS AND METHODS Eligible participants include those who gave general research consent in the contributing studies to share high-throughput genotyping data with other investigators. Herein, we describe the design of the MayoGC, including the current participating cohorts, expansion efforts, data processing, and study management and organization. A genome-wide association study to identify genetic variants associated with total bilirubin levels was conducted to test the genetic research capability of the MayoGC. RESULTS Genome-wide significant results were observed on 2q37 (top single nucleotide polymorphism, rs4148325; P =5.0 × 10−62 ) and 12p12 (top single nucleotide polymorphism, rs4363657; P =5.1 × 10−8 ) corresponding to a gene cluster of uridine 5′-diphospho-glucuronosyltransferases (the UGT1A cluster ) and solute carrier organic anion transporter family, member 1B1 ( SLCO1B1 ), respectively. CONCLUSION Genome-wide association studies have identified genetic variants associated with numerous phenotypes but have been historically limited by inadequate sample size due to costly genotyping and phenotyping. Large consortia with harmonized genotype data have been assembled to attain sufficient statistical power, but phenotyping remains a rate-limiting factor in gene discovery research efforts. The EMR consists of an abundance of phenotype data that can be extracted in a relatively quick and systematic manner. The MayoGC provides a model of a unique collaborative effort in the environment of a common EMR for the investigation of genetic determinants of diseases.
Although the supportive communication people receive from others during stressful times can be helpful, it can also result in negative outcomes. One explanation for these different effects might be ...how closely the support people receive matches their desires. This study extends optimal matching theory and examines how the discrepancy between the support people want and what they receive (called support gaps) corresponds with hurt feelings, perceived negative relational consequences, and esteem improvement. People can either receive less support than the desire (i.e., be under-benefited) or receive more support than they desire (i.e., be over-benefited), and these different types of support gaps produce distinct patterns of results. Specifically, action-facilitating support, which includes informational and tangible support, and nurturant support, which includes emotional, esteem, and network support, were studied. Results showed that being over-benefited in informational support and being under-benefited in emotional and esteem support is hurtful, and hurt corresponded with negative relational consequences and reduced esteem improvement. Implications for research on support gaps and hurt feelings are discussed.
The virulence factor mycolactone is responsible for the immunosuppression and tissue necrosis that characterise Buruli ulcer, a disease caused by infection with Mycobacterium ulcerans In this study, ...we confirm that Sec61, the protein-conducting channel that coordinates entry of secretory proteins into the endoplasmic reticulum, is a primary target of mycolactone, and characterise the nature of its inhibitory effect. We conclude that mycolactone constrains the ribosome-nascent-chain-Sec61 complex, consistent with its broad-ranging perturbation of the co-translational translocation of classical secretory proteins. In contrast, the effect of mycolactone on the post-translational ribosome-independent translocation of short secretory proteins through the Sec61 complex is dependent on both signal sequence hydrophobicity and the translocation competence of the mature domain. Changes to protease sensitivity strongly suggest that mycolactone acts by inducing a conformational change in the pore-forming Sec61α subunit. These findings establish that mycolactone inhibits Sec61-mediated protein translocation and highlight differences between the co- and post-translational routes that the Sec61 complex mediates. We propose that mycolactone also provides a useful tool for further delineating the molecular mechanisms of Sec61-dependent protein translocation.
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