ABSTRACT
Through this project we will determine the role of the mammary tissue microbiome in breast cancer development using 16S ribosomal RNA sequencing and dual-transcriptomic sequencing. In the first two years of this project we have selected and received 165 samples from the Susan G. Komen and Indiana University Simon Cancer Center TissueBanks. We completed 16S rRNA sequencing on DNA isolated from all samples in this cohort and note a distinct microbial compositional signature that is associated with breast cancer development. We anticipate submitting this work for publication by February 2021. Due to COVID-19, the RNA isolations from these samples have been delayed until we can return to campus. We anticipate completing RNA isolations in Summer 2021 and will begin our analysis of the RNA sequencing data in Fall 2021. Regardless of these delays, the project is well underway. Results from this work will be key in characterizing host-microbiome cross-talk in the pathogenesis of breast tumor development.
ABSTRACT
On 1 October 2019, the People's Republic of China (PRC) celebrated its 70th birthday, thus marking another important landmark of modern China under the leadership of the Chinese Communist Party (CCP). In commemorating the event, the Chinese government held a grand military parade with some 15,000 troops, more than 160 aircraft, and 580 active weapon systems during the event, including the latest generation nuclear missile systems such as the Dongfeng-41 mobile intercontinental ballistic missile. As the South China Morning Post reported, citing one insider, "the parade, which aims to showcase President Xi's achievement in military modernization and reforms in both hardware and software will carry a lot of political meaning." Given ongoing social protests in Hong Kong and problems in western societies at that time (such as Brexit talks in the UK and political opposition to President Trump in the United States) the contrast could not have been more stark: A powerful and prosperous China celebrates its international success while many western societies fail and flounder amidst their own domestic problems.
ABSTRACT
Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) builds upon the radio sensitivity of prostate cancer with the specific expression of PSMA. We hypothesize that there are patient (germline) and/or tumor molecular characteristics such as DNA repair defects and active AR signaling as well as clinical characteristics that are associated with response (or lack thereof) to PSMA-TRT. We hypothesize that quantitative molecular imaging assessment of PSMA expression will be associated with response to PSMA-TRT. We also hypothesize that PSMA-TRT generates an immune response that may be identified and associated with patient outcome. In this proposal, we will utilize our retrospective and prospective data and sample sets to: (i) assess genomic biomarkers and gene expression changes associated with outcome from anti-PSMA targeted radionuclide therapy;(ii) assess clinical parameters associated with outcome from anti-PSMA-TRT;(iii) assess PSMA expression as determined by PSMA molecular imaging associated with response to anti-PSMA-TRT;and (iv) evaluate generation of an immune response following anti-PSMA-TRT in association with clinical outcome. This project addresses the overarching challenge to develop effective new treatments and address mechanisms of resistance and particularly addresses the Focus Areas of Imaging and Targeted Radionuclide Therapy and Therapy and Mechanisms of Resistance and Response.
ABSTRACT
Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) builds upon the radiosensitivity of prostate cancer with the specific expression of PSMA. We hypothesize that there are patient (germline) and/or tumor molecular characteristics such as DNA repair defects and active AR signaling as well as clinical characteristics that are associated with response (or lack thereof) to PSMA-TRT. We hypothesize that quantitative molecular imaging assessment of PSMA expression will be associated with response to PSMA-TRT. We also hypothesize that PSMA-TRT generates an immune response that may be identified and associated with patient outcome. In this proposal, we will utilize our retrospective and prospective data and sample sets to: (i) assess genomic biomarkers and gene expression changes associated with outcome from anti-PSMA targeted radionuclide therapy;(ii) assess clinical parameters associated with outcome from anti-PSMA- TRT;(iii) assess PSMA expression as determined by PSMA molecular imaging associated with response to anti-PSMA TRT;and (iv) evaluate generation of an immune response following anti-PSMA-TRT in association with clinical outcome. This project addresses the overarching challenge to develop effective new treatments and address mechanisms of resistance and particularly addresses the Focus Areas of Imaging and Targeted Radionuclide Therapy and Therapy and Mechanisms of Resistance and Response.
ABSTRACT
We and others previously described an enrichment for somatic and germline alterations in DNA damage repair (DDR) genes among men with metastatic prostate cancer. Several recent clinical studies have indicated many of these patients could benefit from precision medicine strategies with PARP inhibitors and DNA damaging agents. In this project, our teams would investigate genomic, transcriptomic and protein related functional signatures for a more accurate sub-classification of prostate cancers associated to DDR defects, aiming for a more precise patient care. The project is divided in 3 main aims: 1) testing the prognostic value of somatic DDR defects in a retrospective cohort of tumor biopsies, 2) developing multi-omics signatures based on prospective analyses of metastatic biopsies and 3) clinical validation of these biomarkers in a clinical trial using carboplatin as DNA damaging chemotherapy.
ABSTRACT
A large body of evidence suggests that people experiencing a single or repetitive TBI in civilian and military settings may have an increased risk of late-life cognitive decline or neurodegenerative disease, including Alzheimers disease (AD) and AD-related dementias(ADRD). But the specific clinical features and neuropathological substrates of TBI-associated dementia, as well as the mechanisms underlying this apparent association, are less clear. This project leverages the extensive existing resources of the Framingham Heart Study (FHS),which includes access to a long-committed community-based study sample, as well as health, lifestyle, biomarker, genetic, cognitive, neuroimaging and neuropathological data. We are combining these existing resources with new self-report TBI and military service data. This study will comprehensively characterize the role of TBI and military service on key AD/ADRD outcomes, and identify genetic and non-genetic factors that modify these relationships.
ABSTRACT
Hemorrhagic fever with renal syndrome (HFRS) is a deadly disease caused by a several species of widely distributed (throughout Eurasia) Old World hantaviruses. Most prominent are Hantaan (HTNV) and Seoul (SEOV) viruses in Asia and Puumala (PUUV) virus in Europe. Worldwide it isestimated that between 60,000-100,000 cases occur annually with a small percentage of these cases resulting in death. As a starting point for an effective vaccine against these HFRS-causing viruses, we will use a different, nonpathogenic virus, vesicular stomatitis virus (VSV), to express a protein from HTNV or PUUV by producing a recombinant VSV (rVSV). Although the VSV virus does normally cause disease in humans and the genetically altered vaccine rVSVs tested thus far also appear safe in normal animals, when VSV itself or some rVSVs enter the central nervous system or are used to infect animals that have immune deficiencies, severe disease or death can result. Due to the concerns raised by these findings we are also engineering rVSVs that are designed to be safer and less likely to cause disease even if they enter the CNS or infect a severely immunocompromised individual.
ABSTRACT
Preclinical and clinical studies suggest that exercise therapy may slow the progression of Parkinsons disease (PD) however overall results are inconclusive. The present application seeks to use an optimized preclinical model of PD to examine whether exercise therapy can protect against alpha-synuclein accumulation and the subsequent loss of neurons in PD, the mechanism whereby the effects of exercise may occur and the effect on behavior affected in PD including motor, cognitive, and neuropsychiatric function. We have completed the behavioral analyses of the first rat cohort and established a treadmill exercise-induced signal of improvement in spontaneous activity and decreased anxiety. We also have observed that treadmill exercise may improve deficits in forelimb movement initiation induced by synucleinopathy. Results from this research could help individuals afflicted by PD. If exercise is truly disease-modifying then it would provide a much needed, non-invasive, nonpharmacological, low-cost therapeutic strategy for PD patients and at risk populations, including military veterans. Exercise therapy could be made readily available through hospitals and VA systems across the country.
ABSTRACT
The shortage of police officers in the United States has become a crisis. Many officers leave the force after only a few years, and police departments struggle to find qualified applicants to fill rapidly increasing openings. This thesis asks what police leaders can do to solve their staffing problems. The research looks to the armed forces recruitment methodology and the private sectors use of analytics to address strategic problems, and analyzes two police departments that have been able to reduce the number of open positions through an integrated approach to recruiting, retention, and force management. The research finds that traditional methods are no longer effective;modern recruiting requires departments to adapt to new and changing environments and generations. Recruitment advertising must be honest and targeted to the right audience, and must use the most appropriate medium for the message. To promote retention, police leaders must go beyond offering competitive compensation;equally as important, they must consider how they engage with and connect to their employees. Further, successful force management requires leaders to determine which positions must truly be filled by sworn officers and which can be filled by appropriately skilled civilians. To address staffing challenges, police leaders must start with retention and force management to determine what and who they need, and then enhance their recruiting efforts to complete the triad and fill their open spots.
ABSTRACT
Preclinical and clinical studies suggest that exercise therapy may slow the progression of Parkinsons disease (PD) however overall results are inconclusive. The present application seeks to use an optimized preclinical model of PD to examine whether exercise therapy can protect against alpha-synuclein accumulation and the subsequent loss of neurons in PD, the mechanism whereby the effects of exercise may occur and the effect on behavior affected in PD including motor, cognitive, and neuropsychiatric function. We have completed the behavioral analyses of the first rat cohort and established a treadmill exercise-induced signal of improvement in spontaneous activity and decreased anxiety. We also have observed that treadmill exercise may improve deficits in forelimb movement initiation induced by synucleinopathy. Results from this research couldhelp individuals afflicted by PD. If exercise is truly disease-modifying then it would provide a much needed, non-invasive, nonpharmacological, low-cost therapeutic strategy for PD patients and at risk populations, including military veterans. Exercise therapy could be made readily available through hospitals and VA systems across the country.
ABSTRACT
Background: Retrospective studies suggest that traumatic brain injury (TBI) increases the risk of Alzheimers disease (AD) four-fold. This has not been supported by recent PET imaging studies including our previous work in Vietnam War veterans. PET scanning to measure the proteins Amyloid and Tau are the key predictors of future AD. It is these abnormal protein deposits that define AD. However, PET TBI studies have had small cohorts and have not used the latest generation of more sensitive imaging biomarkers. Hypothesis: That individuals with traumatic brain injury (TBI) have a higher prevalence of AD related pathology and neurodegeneration compared to age matched controls. Study Design: We will use the latest generation of PET imaging and 7 Tesla MRI to measure AD pathology and chronic traumatic brain damage. We will study 150 elderly TBI subjects and 100 age-matched controls. In addition, psychological testing will be carried out such that the imaging results can be tested for correlation with clinical endpoints. Progress: The Covid 19 pandemic and administrative and ethics requirements have delayed aspects of the study, in particular the 7T MRI imaging. Never-the-less, due to co-funding from the Australian NHMRC and the participating institutions good progress has been made. To date 41 Vietnam war veterans, 84 persons with moderate or severe TBI due to motor vehicle accident and 40 age matched controls have been studied. Comparative cognitive and scanning data from 275 cognitively normal controls, 114 persons with mild cognitive impairment and 102 persons with mild Alzheimers disease was obtained from the AIBL study of ageing. Results: Analysis to date shows no increase in amyloid or tau in veterans or motor vehicle accident victims with TBI compared to controls. 7T MRI has not been acquired but all approvals for this are now in place and all participants are being re-consented for this and data sharing through FITBIR.