The CTSA mandate: are we there yet? Sampselle, Carolyn M; Pienta, Kenneth J; Markel, Dorene S
Research and theory for nursing practice,
01/2010, Volume:
24, Issue:
1
Journal Article
Peer reviewed
The ultimate aim of the National Institutes of Health Clinical and Translational Science Award (CTSA) initiative is to accelerate the movement of discoveries that can benefit human health into ...widespread public use. To accomplish this translational mandate, the contributions of multiple disciplines, such as dentistry, nursing, pharmacy, public health, biostatistics, epidemiology, and bioengineering, are required in addition to medicine. The research community is also mandated to establish new partnerships with organized patient communities and front line health care providers to assure the bidirectional flow of information in order that health priorities experienced by the community inform the research agenda. This article summarizes current clinical research directives, the experience of the University of Michigan faculty during the first 2 years of CTSA support, and recommendations to enhance the effectiveness of future CTSA as well as other interdisciplinary initiatives. While the manuscript focuses most closely on the CTSA Community Engagement mission, the challenges to interdisciplinarity and bidirectionality extend beyond the focus of community engagement.
We define cell morphodynamics as the cell’s time dependent morphology. It could be called the cell’s shape shifting ability. To measure it we use a biomarker free, dynamic histology method, which is ...based on multiplexed Cell Magneto-Rotation and Machine Learning. We note that standard studies looking at cells immobilized on microscope slides cannot reveal their shape shifting, no more than pinned butterfly collections can reveal their flight patterns. Using cell magnetorotation, with the aid of cell embedded magnetic nanoparticles, our method allows each cell to move freely in 3 dimensions, with a rapid following of cell deformations in all 3-dimensions, so as to identify and classify a cell by its dynamic morphology. Using object recognition and machine learning algorithms, we continuously measure the real-time shape dynamics of each cell, where from we successfully resolve the inherent broad heterogeneity of the morphological phenotypes found in a given cancer cell population. In three illustrative experiments we have achieved clustering, differentiation, and identification of cells from (A) two distinct cell lines, (B) cells having gone through the epithelial-to-mesenchymal transition, and (C) cells differing only by their motility. This microfluidic method may enable a fast screening and identification of invasive cells, e.g., metastatic cancer cells, even in the absence of biomarkers, thus providing a rapid diagnostics and assessment protocol for effective personalized cancer therapy.
Abstract
In recent years, the emergence of prostate-specific membrane antigen (PSMA)-targeted positron-emission tomography (PET) imaging has brought about a paradigm shift in the way that prostate ...cancer (PCa) is imaged in many parts of the world. Although PSMA-targeted PET imaging has been demonstrated to be a highly sensitive and specific imaging modality for the identification of sites of PCa, its clinical utility hinges on the ability of imaging specialists and their clinical colleagues to recognize potential false-positive sources of uptake and to tailor therapy based on that recognition. In this manuscript, we report the case of a 74-year-old male with a history of recurrent PCa who was referred for a restaging PSMA-targeted
18
F-DCFPyL PET/computed tomography (PET/CT). PET images demonstrated low level but focal and definitive uptake in the left femoral head. This uptake corresponded to sclerotic changes on CT whose morphology was most compatible with avascular necrosis without femoral head collapse. In the presented case, the integrated assessment of the CT imaging together with the PET findings was fundamental to avoid misinterpretation of the left femur finding as metastatic disease, which would have ultimately altered the clinical management of the patient.
In recent years, the emergence of prostate-specific membrane antigen (PSMA)-targeted positron-emission tomography (PET) imaging has brought about a paradigm shift in the way that prostate cancer ...(PCa) is imaged in many parts of the world. Although PSMA-targeted PET imaging has been demonstrated to be a highly sensitive and specific imaging modality for the identification of sites of PCa, its clinical utility hinges on the ability of imaging specialists and their clinical colleagues to recognize potential false-positive sources of uptake and to tailor therapy based on that recognition. In this manuscript, we report the case of a 74-year-old male with a history of recurrent PCa who was referred for a restaging PSMA-targeted
F-DCFPyL PET/computed tomography (PET/CT). PET images demonstrated low level but focal and definitive uptake in the left femoral head. This uptake corresponded to sclerotic changes on CT whose morphology was most compatible with avascular necrosis without femoral head collapse. In the presented case, the integrated assessment of the CT imaging together with the PET findings was fundamental to avoid misinterpretation of the left femur finding as metastatic disease, which would have ultimately altered the clinical management of the patient.
Cancer metastasis is a multistep process associated with the induction of an epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Although significant progress has been made in ...understanding the molecular mechanisms regulating EMT and the CSC phenotype, little is known of how these processes are regulated by epigenetics. Here we demonstrate that reduced expression of DNA methyltransferase 1 (DNMT1) plays an important role in the induction of EMT and the CSC phenotype by prostate cancer (PCa) cells, with enhanced tumorigenesis and metastasis. First, we observed that reduction of DNMT1 by 5-azacitidine (5-Aza) promotes EMT induction as well as CSCs and sphere formation
in vitro
. Reduced expression of DNMT1 significantly increased PCa migratory potential. We showed that the increase of EMT and CSC activities by reduction of DNMT1 is associated with the increase of protein kinase C. Furthermore, we confirmed that silencing DNMT1 is correlated with enhancement of the induction of EMT and the CSC phenotype in PCa cells. Additionally, chromatin immunoprecipitation assay reveals that reduction of DNMT1 promotes the suppression of H3K9me3 and H3K27me3 on the Zeb2 and KLF4 promoter region in PCa cells. Critically, we found in an animal model that significant tumor growth and more disseminated tumor cells in most osseous tissues were observed following injection of 5-Aza pretreated–PCa cells compared with vehicle-pretreated PCa cells. Our results suggest that epigenetic alteration of histone demethylation regulated by reduction of DNMT1 may control induction of EMT and the CSC phenotype, which facilitates tumorigenesis in PCa cells and has important therapeutic implications in targeting epigenetic regulation.
PDF
