Genetic and mechanistic determinants of prostate cancer progression and metastasis

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2007.Includes bibliographical references.In order to study a complex biological phenomenon such as tumor cell metastasis, one must focus on examining discrete aspects of the process which are amenable to experimentation. In this thesis, I made use of xenograft and spontaneous in vivo mouse models of prostate cancer to approach this problem from two perspectives. First, I sought to identify genes which were involved with metastasis. Second, I focused on the mechanistic elements involved with tumor cell intravasation into lymphatics. The results from this work have shown that loss of Protein 4.1B, a 4.1/ezrin/radixin/moesin (FERM) domain-containing cytoskeletal protein, is a frequent event in prostate cancer. The significance of this finding was confirmed by experimental ablation of 4.1B, which enhanced tumor progression and metastasis, at least in part, by protecting cells against apoptosis. This thesis has also shown that metastatic dissemination to lymph nodes is mediated primarily by peritumoral lymphatic vessels, which surround the tumor at the invasive margins. In contrast, inhibition of intratumoral lymphatics did not affect metastatic spread, indicating that these vessels were unnecessary for tumor cell dissemination.(cont.) The genetic and mechanistic findings from this thesis were consistent across both model systems examined, and are also in concordance with observations made in human clinical prostate cancer. Thus, the results of this work have contributed small pieces of knowledge to our overall understanding of how tumors initiate, and frequently complete, the elaborate and often lethal process of spreading throughout the body.by Sunny Y. Wong.Ph.D

Loss of Gata6 causes dilation of the hair follicle canal and sebaceous duct

The uppermost aspect of the hair follicle, known as the infundibulum or hair canal, provides a passageway for hair shaft egress and sebum secretion. Recent studies have indicated that the infundibulum and sebaceous ducts are lined by molecularly distinct differentiated cells expressing markers including Keratin 79 and Gata6. Here, we ablated Gata6 from the skin and observed dilation of both the hair canal and sebaceous ducts, independent of gender and hair cycle stage. Constitutive loss of Gata6 yielded only a mild delay in depilation‐induced entry into anagen, while unperturbed mutant mice possessed overtly normal skin and hair. Furthermore, we noted that Keratin 79 and Gata6 expression and localization did not depend upon each other. Our findings implicate Gata6 in maintaining the upper hair follicle and suggest that regulation of this transcription factor may be compromised in pathologies such as acne or infundibular cystic diseases that are characterized by abnormal expansion of this follicular domain.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149235/1/exd13757_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149235/2/exd13757-sup-0001-FigS1-S9.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149235/3/exd13757.pd

Infrared Nonlinear Optics

Contains report on one research project.U.S. Air Force - Office of Scientific Research (Contract F49620-80-C-0008

Infrared Nonlinear Optics

Contains report on one research project.U.S. Air Force - Office of Scientific Research (Contract F49620-84-C-0010

Infrared Nonlinear Optics

Contains a report on one research project.U.S. Air Force - Office of Scientific Research (Contract F49620-80-C-008

Infrared Nonlinear Optics

Contains reports on four research projects.DARPA/Universities Research Initiative (Contract NOOO14-46-K-0760)SDI/IST managed by the Naval Research Laboratory (Contract N00014-87-K-2031

Infrared Nonlinear Optics

Contains reports on six research projects.Defense Advanced Research Projects Agency Universities Research Initiative (Contract N00014-46-K-0760)Strategic Defense Initiative/Innovative Science & Technology, managed by the U.S. Naval Research Laboratory (Contract N00014-87-K-2031)National Science Foundation (Grant EET-87-18417

Initiation of warfarin is associated with decreased mortality in patients with infective endocarditis: A population-based cohort study.

The use of warfarin to prevent thromboembolism in patients with infective endocarditis (IE) remains controversial due to potentially increased bleeding risks. Population-based retrospective cohort study. Patients aged 18 or older and diagnosed with IE in Hong Kong between January 1st, 1997 and August 31st, 2020 were included. Patients with use of any anticoagulant 30 days before IE diagnosis were excluded. Patients initiated on warfarin within 14 days of IE diagnosis and patients without warfarin use were matched for baseline characteristics using 1:1 propensity score matching. Warfarin use within 14 days of IE diagnosis. Patients were followed up to 90 days for the outcomes of ischemic stroke, all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding. Cox regression was used to determine hazard ratios (HRs) [95 % confidence intervals (CIs)] between treatment groups. Fine-Gray competing risk regression with all-cause mortality as the competing event was performed as a sensitivity analysis. In addition to 90-day analyses, landmark analyses were performed at 30 days of follow-up. The matched cohort consisted of 675 warfarin users (57.0 % male, age 59 ± 16 years) and 675 warfarin non-users (53.5 % male, age 61 ± 19 years). Warfarin users had a 50 % decreased 90-day risk in all-cause mortality (HR:0.50 [0.39-0.65]), without significantly different 90-day risks of ischemic stroke (HR:1.04 [0.70-1.53]), intracranial hemorrhage (HR:1.25 [0.77-2.04]), and gastrointestinal bleeding (HR:1.04 [0.60-1.78]). Thirty-day landmark analysis showed similar results. Competing risk regression showed significantly higher 30-day cumulative incidence of intracranial hemorrhage in warfarin users (sub-HR:3.34 [1.34-8.31]), but not at 90-day (sub-HR:1.63 [0.95-2.81]). Results from Fine-Gray regression were otherwise congruent with those from Cox regression. Warfarin initiated within 14 days of IE diagnosis was associated with significantly decreased risks of mortality but higher risks of intracranial hemorrhage, with similar risks of ischemic stroke and gastrointestinal bleeding, compared with non-use of warfarin with 14 days of IE diagnosis. Question: Is warfarin, initiated within 14 days of a diagnosis of infective endocarditis (IE), efficacious and safe? In this propensity score-matched, population-based, prospective cohort study from Hong Kong, warfarin use within 14 days of IE diagnosis was associated with a 50 % decrease in the risk of all-cause mortality, albeit with higher risk of intracranial hemorrhage, and without significant differences in the risk of ischaemic stroke and gastrointestinal bleeding. Meaning: In patients with IE, warfarin use within 14 days of diagnosis may have mortality benefits, despite increased risks of intracranial hemorrhage. [Abstract copyright: Copyright © 2023. Published by Elsevier Ltd.

Disease Burden of Clostridium difficile Infections in Adults, Hong Kong, China, 2006-2014

Cross-sectional studies suggest an increasing trend in incidence and relatively low recurrence rates of Clostridium difficile infections in Asia than in Europe and North America. The temporal trend of C. difficile infection in Asia is not completely understood. We conducted a territory-wide population-based observational study to investigate the burden and clinical outcomes in Hong Kong, China, over a 9-year period. A total of 15,753 cases were identified, including 14,402 (91.4%) healthcare-associated cases and 817 (5.1%) community-associated cases. After adjustment for diagnostic test, we found that incidence increased from 15.41 cases/100,000 persons in 2006 to 36.31 cases/100,000 persons in 2014, an annual increase of 26%. This increase was associated with elderly patients, for whom incidence increased 3-fold over the period. Recurrence at 60 days increased from 5.7% in 2006 to 9.1% in 2014 (p<0.001). Our data suggest the need for further surveillance, especially in Asia, which contains ≈60% of the world’s population