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Open Access Publications from the University of California

Scholarly Works (6 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2018)

Problem

Approximately 75% of the breast cancer biopsies performed after recommendations from diagnostic mammography are benign, making it clear that specificity for diagnostic mammography still needs significant improvements. A novel three-compartment breast (3CB) composition technique developed by Laidevant et al. seeks to improve the specificity of diagnostic digital mammography, but it is prone to estimate incorrect compositional estimates for patient lesions. The focus of this thesis was to further develop this three-compartment technique for clinical applications in dual-energy X-ray imaging modalities.

Methods

Three potential sources of error in the 3CB technique were studied: (1) attenuation coefficient differences in biological materials—for which 3CB is estimating compositional estimates—and their calibration equivalents, (2) nonuniformities in full-field digital mammography (FFDM) from X-ray source spectra, and (3) initial intensity I_0 differences between biological and calibration images. Initial developments for 3CB applications in digital breast tomosynthesis were also investigated, and these were in two areas: (1) dose measurements and estimates were made for high energy 3CB digital breast tomosynthesis (DBT) images and (2) derivation of potential variables of interest as predictors of breast thickness from raw DBT projections. Lastly, a novel technique for measuring body composition from 2D optical images to help monitor and maintain healthy body weight was investigated, which could potentially aid in monitoring adipose and muscular tissues to monitor and maintain a lean weight to reduce risk of cancer for postmenopausal women in low-resource settings.

Results

To reduce error in the attenuation coefficient differences between biological and calibration materials, linear mappings were created using bovine and chicken phantoms. This linear mapping corrected negative 3CB compositional estimates in a population study. To reduce error in nonuniformities in FFDM source spectra, polynomial flat-fielding models were created. These reduced nonuniformities to at or below imaging noise levels. To reduce I_0 differences between biological and calibration images, two I_0 correction models made it possible to obtain similar log-signal values between breast and calibration images.

To make the 3CB applicable to DBT, two areas were investigated. Firstly, dose measurements and estimates were made for HE 3CB DBT images. It was found that a copper filter of 0.4064 mm (16 mils) seems to be optimal in terms of meeting dose requirements, availability, and CNR. In addition, imaging at 71 mAs seems to optimize CNR while satisfying dose requirements. Secondly, investigations sought to derive potential variables of interest as predictors of breast thickness from raw DBT projections. It was found that variables derived from sinograms could be potentially useful in estimating breast thickness from raw DBT projections.

The last topic discussed in this thesis focused on developing a novel body composition technique from optical images. This proof-of-concept study showed that it may be possible to determine fat mass index, fat-free mass index, and percent-fat from 2D optical images.

Conclusion

Two of the three major works in this study advanced the 3CB imaging technique to become more clinically practical in dual-energy absorptiometry applications. The last focus of this thesis may make it easier to monitor body composition in low-resource settings.

    Cover page: Development of Three-Compartment Breast Imaging for Clinical Applications in Dual Energy X-ray Absorptiometry
    • Article
    • Peer Reviewed
    UC Santa Barbara Previously Published Works (2014)
    Consumption of cruciferous vegetables is associated with reduced risk of various types of cancer. Isothiocyanates including sulforaphane and erucin are believed to be responsible for this activity. Erucin [1-isothiocyanato-4-(methylthio)butane], which is metabolically and structurally related to sulforaphane, is present in large quantities in arugula (Eruca sativa, Mill.), kohlrabi and Chinese cabbage. However, its cancer preventive mechanisms remain poorly understood. We found that erucin inhibits proliferation of MCF7 breast cancer cells (IC50 = 28 µM) in parallel with cell cycle arrest at mitosis (IC50 = 13 µM) and apoptosis, by a mechanism consistent with impairment of microtubule dynamics. Concentrations of 5-15 µM erucin suppressed the dynamic instability of microtubules during interphase in the cells. Most dynamic instability parameters were inhibited, including the rates and extents of growing and shortening, the switching frequencies between growing and shortening, and the overall dynamicity. Much higher erucin concentrations were required to reduce the microtubule polymer mass. In addition, erucin suppressed dynamic instability of microtubules reassembled from purified tubulin in similar fashion. The effects of erucin on microtubule dynamics, like those of sulforaphane, are similar qualitatively to those of much more powerful clinically-used microtubule-targeting anticancer drugs, including taxanes and the vinca alkaloids. The results suggest that suppression of microtubule dynamics by erucin and the resulting impairment of critically important microtubule-dependent cell functions such as mitosis, cell migration and microtubule-based transport may be important in its cancer preventive activities.
      Cover page: Erucin, the Major Isothiocyanate in Arugula (Eruca sativa), Inhibits Proliferation of MCF7 Tumor Cells by Suppressing Microtubule Dynamics
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2018)
      This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-β1 - 42 (Aβ) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients' macrophages in the brain's clearance of Aβ. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.
        Cover page: Immunotherapy of Mild Cognitive Impairment by ω-3 Supplementation: Why Are Amyloid-β Antibodies and ω-3 Not Working in Clinical Trials?
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2019)
        Purpose To investigate the combination of mammography radiomics and quantitative three-compartment breast (3CB) image analysis of dual-energy mammography to limit unnecessary benign breast biopsies. Materials and Methods For this prospective study, dual-energy craniocaudal and mediolateral oblique mammograms were obtained immediately before biopsy in 109 women (mean age, 51 years; range, 31-85 years) with Breast Imaging Reporting and Data System category 4 or 5 breast masses (35 invasive cancers, 74 benign) from 2013 through 2017. The three quantitative compartments of water, lipid, and protein thickness at each pixel were calculated from the attenuation at high and low energy by using a within-image phantom. Masses were automatically segmented and features were extracted from the low-energy mammograms and the quantitative compartment images. Tenfold cross-validations using a linear discriminant classifier with predefined feature signatures helped differentiate between malignant and benign masses by means of (a) water-lipid-protein composition images alone, (b) mammography radiomics alone, and (c) a combined image analysis of both. Positive predictive value of biopsy performed (PPV3) at maximum sensitivity was the primary performance metric, and results were compared with those for conventional diagnostic digital mammography. Results The PPV3 for conventional diagnostic digital mammography in our data set was 32.1% (35 of 109; 95% confidence interval [CI]: 23.9%, 41.3%), with a sensitivity of 100%. In comparison, combined mammography radiomics plus quantitative 3CB image analysis had PPV3 of 49% (34 of 70; 95% CI: 36.5%, 58.9%; P < .001), with a sensitivity of 97% (34 of 35; 95% CI: 90.3%, 100%; P < .001) and 35.8% (39 of 109) fewer total biopsies (P < .001). Conclusion Quantitative three-compartment breast image analysis of breast masses combined with mammography radiomics has the potential to reduce unnecessary breast biopsies. © RSNA, 2018 Online supplemental material is available for this article.
          Cover page: Combined Benefit of Quantitative Three-Compartment Breast Image Analysis and Mammography Radiomics in the Classification of Breast Masses in a Clinical Data Set.
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2019)
          Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders.
            Cover page: Adeno-associated viral vector serotype 9–based gene therapy for Niemann-Pick disease type A
            • Article
            • Peer Reviewed
            ICTS Publications (2013)
            The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.
              Cover page: DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease
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