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Description
Despite significant advances in digital pathology and automation sciences, current diagnostic practice for cancer detection primarily relies on a qualitative manual inspection of tissue architecture and cell and nuclear morphology in stained biopsies using low-magnification, two-dimensional (2D) brightfield microscopy. The efficacy of this process is limited by inter-operator variations in

Despite significant advances in digital pathology and automation sciences, current diagnostic practice for cancer detection primarily relies on a qualitative manual inspection of tissue architecture and cell and nuclear morphology in stained biopsies using low-magnification, two-dimensional (2D) brightfield microscopy. The efficacy of this process is limited by inter-operator variations in sample preparation and imaging, and by inter-observer variability in assessment. Over the past few decades, the predictive value quantitative morphology measurements derived from computerized analysis of micrographs has been compromised by the inability of 2D microscopy to capture information in the third dimension, and by the anisotropic spatial resolution inherent to conventional microscopy techniques that generate volumetric images by stacking 2D optical sections to approximate 3D. To gain insight into the analytical 3D nature of cells, this dissertation explores the application of a new technology for single-cell optical computed tomography (optical cell CT) that is a promising 3D tomographic imaging technique which uses visible light absorption to image stained cells individually with sub-micron, isotropic spatial resolution. This dissertation provides a scalable analytical framework to perform fully-automated 3D morphological analysis from transmission-mode optical cell CT images of hematoxylin-stained cells. The developed framework performs rapid and accurate quantification of 3D cell and nuclear morphology, facilitates assessment of morphological heterogeneity, and generates shape- and texture-based biosignatures predictive of the cell state. Custom 3D image segmentation methods were developed to precisely delineate volumes of interest (VOIs) from reconstructed cell images. Comparison with user-defined ground truth assessments yielded an average agreement (DICE coefficient) of 94% for the cell and its nucleus. Seventy nine biologically relevant morphological descriptors (features) were computed from the segmented VOIs, and statistical classification methods were implemented to determine the subset of features that best predicted cell health. The efficacy of our proposed framework was demonstrated on an in vitro model of multistep carcinogenesis in human Barrett's esophagus (BE) and classifier performance using our 3D morphometric analysis was compared against computerized analysis of 2D image slices that reflected conventional cytological observation. Our results enable sensitive and specific nuclear grade classification for early cancer diagnosis and underline the value of the approach as an objective adjunctive tool to better understand morphological changes associated with malignant transformation.
ContributorsNandakumar, Vivek (Author) / Meldrum, Deirdre R (Thesis advisor) / Nelson, Alan C. (Committee member) / Karam, Lina J (Committee member) / Ye, Jieping (Committee member) / Johnson, Roger H (Committee member) / Bussey, Kimberly J (Committee member) / Arizona State University (Publisher)
Created2013
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Description
Background
Grading schemes for breast cancer diagnosis are predominantly based on pathologists' qualitative assessment of altered nuclear structure from 2D brightfield microscopy images. However, cells are three-dimensional (3D) objects with features that are inherently 3D and thus poorly characterized in 2D. Our goal is to quantitatively characterize nuclear structure in 3D,

Background
Grading schemes for breast cancer diagnosis are predominantly based on pathologists' qualitative assessment of altered nuclear structure from 2D brightfield microscopy images. However, cells are three-dimensional (3D) objects with features that are inherently 3D and thus poorly characterized in 2D. Our goal is to quantitatively characterize nuclear structure in 3D, assess its variation with malignancy, and investigate whether such variation correlates with standard nuclear grading criteria.
Methodology
We applied micro-optical computed tomographic imaging and automated 3D nuclear morphometry to quantify and compare morphological variations between human cell lines derived from normal, benign fibrocystic or malignant breast epithelium. To reproduce the appearance and contrast in clinical cytopathology images, we stained cells with hematoxylin and eosin and obtained 3D images of 150 individual stained cells of each cell type at sub-micron, isotropic resolution. Applying volumetric image analyses, we computed 42 3D morphological and textural descriptors of cellular and nuclear structure.
Principal Findings
We observed four distinct nuclear shape categories, the predominant being a mushroom cap shape. Cell and nuclear volumes increased from normal to fibrocystic to metastatic type, but there was little difference in the volume ratio of nucleus to cytoplasm (N/C ratio) between the lines. Abnormal cell nuclei had more nucleoli, markedly higher density and clumpier chromatin organization compared to normal. Nuclei of non-tumorigenic, fibrocystic cells exhibited larger textural variations than metastatic cell nuclei. At p<0.0025 by ANOVA and Kruskal-Wallis tests, 90% of our computed descriptors statistically differentiated control from abnormal cell populations, but only 69% of these features statistically differentiated the fibrocystic from the metastatic cell populations.
Conclusions
Our results provide a new perspective on nuclear structure variations associated with malignancy and point to the value of automated quantitative 3D nuclear morphometry as an objective tool to enable development of sensitive and specific nuclear grade classification in breast cancer diagnosis.
Created2012-01-05
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Breast cancer affects about 12% of women in the US. Arguably, it is one of the most advertised cancers. Mammography became a popular tool of breast cancer screening in the 1970s, and patient-geared guidelines came from the American Cancer Society (ACS) and the US Preventative Task Force (USPSTF). This research

Breast cancer affects about 12% of women in the US. Arguably, it is one of the most advertised cancers. Mammography became a popular tool of breast cancer screening in the 1970s, and patient-geared guidelines came from the American Cancer Society (ACS) and the US Preventative Task Force (USPSTF). This research focuses on ACS guidelines, as they were the earliest as well as the most changed guidelines. Mammography guidelines changed over time due to multiple factors. This research has tracked possible causes of those changes. Research began with an extensive literature search of clinical trials, the New York Times and the Washington Post archives, systematic reviews, ACS and USPSTF archives.

Created2021-02-16
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Science fiction works can reflect the relationship between science and society by telling stories that are set in the future of ethical implications or social consequences of scientific advancements. This thesis investigates how the concept of reproduction is depicted in popular science fiction works.

Created2021-02-10
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By questioning methods of sex selection since their early development, and often discovering that they are unreliable, scientists have increased the creative and technological capacity of the field of reproductive health. The presentation of these methods to the public, via published books on timing methods and company websites for sperm

By questioning methods of sex selection since their early development, and often discovering that they are unreliable, scientists have increased the creative and technological capacity of the field of reproductive health. The presentation of these methods to the public, via published books on timing methods and company websites for sperm sorting, increased interest in, and influence of, sex selection within the global society. The purpose of explaining the history, interest, development, and impact of various sex selection methods in the mid-twentieth century based on the information that is available on them today is to show couples which methods have failed and provide them with the knowledge necessary to make an informed decision on how they choose to go about utilizing methods of sex selection.

Created2021-02-26
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By demonstrating the struggle for sound standard of care for non-medical reproductive health care providers during the nineteenth and early twentieth century, this project emphasizes what the standards of reproductive health care for abortion and contraception might be like if the organizations that made them so readily available, like Planned

By demonstrating the struggle for sound standard of care for non-medical reproductive health care providers during the nineteenth and early twentieth century, this project emphasizes what the standards of reproductive health care for abortion and contraception might be like if the organizations that made them so readily available, like Planned Parenthood, were defunded or criminalized in our modern setting.

Created2021-02-23
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On 29 June 1988, in Bowen v. Kendrick, the US Supreme Court ruled in a five-to-four decision that the 1981 Adolescent Family Life Act, or AFLA, was constitutional. Under AFLA, the US government could distribute federal funding for abstinence-only sexual education programs, oftentimes given to groups with religious affiliations. As

On 29 June 1988, in Bowen v. Kendrick, the US Supreme Court ruled in a five-to-four decision that the 1981 Adolescent Family Life Act, or AFLA, was constitutional. Under AFLA, the US government could distribute federal funding for abstinence-only sexual education programs, oftentimes given to groups with religious affiliations. As a federal taxpayer, Chan Kendrick challenged the constitutionality of AFLA, claiming it violated the separation of church and state. The Supreme Court found that although AFLA funded programs that aligned with certain religious ideologies, it was constitutional because it did not encourage government involvement in religion, and it held a valid secular purpose in seeking to prevent adolescent pregnancy and premarital sexual relations. By upholding AFLA, Bowen v. Kendrick enabled the US government to continue funding abstinence-only education, which researchers have found to be ineffective.

Created2021-02-26
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In 1997, physicians and researchers Ambre Olsen, Virginia Smith, John Bergstrom, Joyce Colling, and Amanda Clark published, “Epidemiology of Surgically Managed Pelvic Organ Prolapse and Urinary Incontinence,” in the journal Obstetrics and Gynecology. In their article, the authors retrospectively analyzed data from patients who underwent surgery for pelvic organ prolapse

In 1997, physicians and researchers Ambre Olsen, Virginia Smith, John Bergstrom, Joyce Colling, and Amanda Clark published, “Epidemiology of Surgically Managed Pelvic Organ Prolapse and Urinary Incontinence,” in the journal Obstetrics and Gynecology. In their article, the authors retrospectively analyzed data from patients who underwent surgery for pelvic organ prolapse or urinary incontinence two years prior in 1995. Often due to a weakening of or damage to their pelvic muscles, women with pelvic organ prolapse can experience a descent of pelvic organs into the lower pelvis and vagina. People with urinary incontinence can experience bladder control issues and urinary leaks. According to the authors, an estimated fifty percent of women who have previously given birth have had a prolapse. In their article, Olsen and colleagues analyze factors such as race, age, and weight in women who had surgery to treat pelvic organ prolapse and ultimately advocate for a standard assessment for the severity of those conditions.

Created2021-02-23
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In 1996, a team of researchers associated with the International Continence Society published “The Standardization of Terminology of Female Pelvic Organ Prolapse and Pelvic Floor Dysfunction” in American Journal of Obstetrics and Gynecology. Pelvic organ prolapse is characterized by the descent of the pelvic organs into the lower portion of

In 1996, a team of researchers associated with the International Continence Society published “The Standardization of Terminology of Female Pelvic Organ Prolapse and Pelvic Floor Dysfunction” in American Journal of Obstetrics and Gynecology. Pelvic organ prolapse is characterized by the descent of the pelvic organs into the lower portion of the pelvis and is often caused by a weakening of the muscles and ligaments that normally hold the organs in place. The authors concluded that physicians and researchers needed to develop a system of standardized terms to use to describe the anatomical position of pelvic organ prolapse in women. They propose using terms that emphasize the location of the prolapse rather than just the involved organ. They also suggest that the system utilizes a series of examinations and imaging to uniformly describe and quantify pelvic organ prolapse. The article by Bump and colleagues was one of the first to call for a standardized system using specific terms to communicate findings about pelvic organ prolapse systematically across clinical and academic research settings.

Created2021-03-10
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In 2013, Cynthia Daniels and a team of researchers at Rutgers University in New Brunswick, New Jersey, founded the Informed Consent Project. Daniels and the researchers assessed the medical accuracy of information within state-authored informational materials for abortion. States give those materials to women who want an abortion, but using

In 2013, Cynthia Daniels and a team of researchers at Rutgers University in New Brunswick, New Jersey, founded the Informed Consent Project. Daniels and the researchers assessed the medical accuracy of information within state-authored informational materials for abortion. States give those materials to women who want an abortion, but using their research, the Informed Consent Project found some information from those materials to be inaccurate, misleading, and coercive. The Informed Consent Project gathered a panel of researchers and medical specialists to review the information about embryological and fetal development from twenty-three states’ informational materials. They found that approximately one-third of that information was inaccurate. The work of the Informed Consent Project challenges abortion-specific informed consent laws, highlighting medical inaccuracies in state-authored informational materials as evidence that women’s consent to abortion may be based on false or misleading statements.

Created2021-06-01