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Paul Doetsch                                         Joanna Goldberg
Biochemistry                                          Pediatrics
DNA damage and retromutagenesis: A new paradigm for acquisition of antibiotic resistance in bacterial pathogens

Antibiotic resistance in disease causing bacteria is a major public health problem worldwide and presents serious challenges in the use of drugs to control bacterial infections and disease. Our current understanding of the causes of antibiotic resistance is limited and new approaches for elucidating its mechanisms are urgently needed. Recently, one of our groups reported a novel mechanism called transcriptional mutagenesis (TM) for explaining how bacteria (Escherichia coli) can escape growth restraints that is analogous and directly relevant to situations in which disease causing bacteria develop antibiotic resistance. This proposal brings together an interdisciplinary team of investigators from the fields of cancer research and infectious disease research and will apply the Escherichia coli TM experimental system to address how an important bacterial pathogen, Pseudomonas aeruginosa, develops antibiotic resistance in a laboratory setting. It is expected that the results of this project can be used to devise new effective therapeutic strategies to overcome antibiotic resistance in the control of bacterial disease.

Dabney Evans                                         Nadine Kaslow
Global Health                                           Psychiatry
“Maltratar não é direito”: Understanding the relationship between violence against women-related laws and perceptions of intimate partner violence among women in Santo André, Brazil

Femicide, or the murder of a woman because of her gender, is the most lethal form of violence against women (VAW). In March 2015, Brazil passed anti-femicide legislation to criminalize the gender-motivated killing of women and stiffen penalties for VAW. Brazil is characterized by a pervasive culture of violence and impunity, which may weaken the ability of the new anti-femicide law to protect women’s lives and improve gender equality. As global legislation to eradicate VAW is increasingly passed and implemented, it is essential to document how such laws impact the health and wellbeing of women whom these laws are meant to protect. The goal of the study is to assess the impact of VAW‐related laws on women who are at risk of violence as well as healthcare providers (HCPs) who deliver support services in public health posts in Santo André, Brazil. The proposed research will examine the cultural, clinical, and legal context surrounding VAW from the perspectives of women, Health Care Providers (HCPs), and existing regulatory frameworks. A comprehensive legal and policy analysis will examine relevant laws that address VAW at the international, federal, and local levels (Aim 1). Baseline qualitative data collected from women (Aim 2) and quantitative data gathered from HCPs (Aim 3) in the clinical setting will allow us to triangulate the impact of VAW laws on women’s health and health sector response, assess social and cultural norms that influence attitudes towards VAW in the community, and explore VAW-related knowledge.

Jun Kong                                                    Daniel Brat
Biomedical Informatics                             Pathology
Quantitative Three-Dimensional Understanding of Glioblastoma Tumor Micro-environment with Histopathological Imaging Volumes

Cancer is a complex disease that involves a three dimensional (3-D) dynamic interplay between cancer cells, immune cells, regions of tumor death, new blood vessels and normal cells. Our current understanding of this disease has relied heavily on the two-dimensional (2D) analysis due to the limitations of histologic sections and microscopic techniques. The quantitative analysis of cancer dynamics in 3-D could lead to enhanced understanding of growth properties. We are now ready to study human cancers more fully in 3-D, but need better tools. One approach we have been working on is to scan tissue sections from human cancers into digital images and process them with computer-based algorithms. Since the 2-D appearance and spatial profiles of histological structures in 3-D tissue space are highly dependent on the locations and angles of the cutting planes selected during tissue slide preparation stage, the resulting phenotypic and spatial information derived from 2-D imaging data is significantly altered from their 3-D representations in most cases. Stacking a large number of images precisely on top of one another can create a three dimensional view of cancer, but this is technically challenging to accomplish in high resolution, posing a serious challenge for 3-D tissue-based analyses. Our test case is human glioblastoma (GBM), since this cancer is rapidly fatal and depends on the 3-D Tumor Micro-Environment (TME) for its rapid clinical progression. We propose to investigate GBM evolution mechanisms by reconstructing and modeling a digital virtual 3-D tumor micro-environment. We will develop image processing methods for analysis of 3-D morphologic features and spatial profiles of pathologic hallmarks with 3-D pathologic imaging volumes. We will also develop computational methods for modeling the patterns of GBM TME evolution. Our proposed study is novel and interdisciplinary, exhibiting a strong potential of its application to a wide spectrum of cancers and diseases. In summary, we propose to reconstruct and model tumor evolution of the GBM TME in a 3-D tissue space with pathology analytics, computer-based image processing methods, and computational biology modeling.

Steven Yeh                                                Colleen Kraft
Ophthalmology                                          Pathology
Ebola Virus Persistence In Ocular Tissues and Fluids

The Ebola virus disease (EVD) outbreak of 2014-2015 in West Africa is the largest in history with over 28,000 cases and over 11,300 deaths. There are an estimated 15,000 EVD survivors in West Africa who are at risk for the post Ebola syndrome, a disease condition that includes arthritis, mental health issues, hearing loss and uveitis. Uveitis, an inflammatory condition of the eye, has been observed in 20-25% of EVD survivors and may lead to cataract and glaucoma, conditions that sometimes require surgery. Recently, we identified live Ebola virus in the ocular fluid of a repatriated United States health care worker who, after recovering from critical illness, developed severe, sight-threatening uveitis. Following his successful treatment, outreach efforts with the World Health Organization, eye care providers, and partnering institutions in West Africa have led to the identification of numerous EVD survivors with uveitis and structural eye issues that will require surgery to regain their vision. The purpose of this project is to determine the prevalence of live Ebola virus in eye fluid outside and inside the eyes of EVD survivors with uveitis and the timing of Ebola virus clearance from eye fluid if Ebola is present. These findings will be important to the safety of eye care providers performing cataract surgery and other ophthalmic procedures in West Africa and abroad in the future. This project will also aim to develop safe protocols for invasive ocular procedures for individuals involved in EVD survivor care.