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Title: THE INFLUENCE OF 3D POROUS CHITOSAN-ALGINATE BIOMATERIAL SCAFFOLD PROPERTIES ON THE BEHAVIOR OF BREAST CANCER CELLS.
Creator: Le, Minh-Chau N., Steward, Robert L., Florczyk, Stephen J., University of Central Florida
Abstract / Description: The tumor microenvironment plays an important role in regulating cancer cell behavior. The tumor microenvironment describes the cancer cells, and the surrounding endothelial cells, fibroblasts, and mesenchymal stem cells, along with the extracellular matrix (ECM). The tumor microenvironment stiffens as cancer undergoes malignant progression, providing biophysical cues that promote invasive, metastatic cellular behaviors. This project investigated the influence of three dimensional (3D)...
Show moreThe tumor microenvironment plays an important role in regulating cancer cell behavior. The tumor microenvironment describes the cancer cells, and the surrounding endothelial cells, fibroblasts, and mesenchymal stem cells, along with the extracellular matrix (ECM). The tumor microenvironment stiffens as cancer undergoes malignant progression, providing biophysical cues that promote invasive, metastatic cellular behaviors. This project investigated the influence of three dimensional (3D) chitosan-alginate (CA) scaffold stiffness on the morphology, growth, and migration of green fluorescent protein (GFP) � transfected MDA-MB-231 (231-GFP) breast cancer (BCa) cells. The CA scaffolds were produced by the freeze casting method at three concentrations, 2 wt%, 4 wt%, and 6 wt% to provide different stiffness culture substrates. The CA scaffold material properties were characterized using scanning electron microscopy imaging for pore structure and compression testing for Young's Modulus. The BCa cell cultures were characterized at day 1, 3, and 7 timepoints using Alamar Blue assay for cell number, fluorescence imaging for cell morphology, and single-cell tracking for cell migration. Pore size calculations using SEM imaging yielded pore sizes of 253.29 +/- 52.45 [micro]m, 209.55 +/- 21.46 [micro]m, and 216.83 +/- 32.63 [micro]m for 2 wt%, 4 wt%, and 6 wt%, respectively. Compression testing of the CA scaffolds yielded Young's Modulus values of 0.064 +/- 0.008 kPa, 2.365 +/- 0.32 kPa and 3.30 +/- 0.415 kPa for 2 wt%, 4 wt%, and 6 wt% CA scaffolds, respectively. The results showed no significant difference in cell number among the 3D CA scaffold groups. However, the 231-GFP cells cultured in 2 wt% CA scaffolds possessed greater cellular size, area, perimeter, and lower cellular circularity compared to those in 4 wt% and 6 wt% CA scaffolds, suggesting a more prominent presence of cell clusters in softer substrates compared to stiffer substrates. The results also showed cells in 6 wt% CA having a higher average cell migration speed compared to those in 2 wt% and 4 wt% CA scaffolds, indicating a positive relationship between substrate stiffness and cell migration velocity. Findings from this experiment may contribute to the development of enhanced in vitro 3D breast tumor models for basic cancer research using 3D porous biomaterial scaffolds.
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Date Issued: 2019
Identifier: CFH2000492, ucf:45626
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH2000492

Title: INTERVENTIONS FOR TREATMENT RELATED SIDE EFFECTS IN OLDER WOMEN WITH BREAST CANCER.
Creator: Suarez, Stephanie, Loerzel, Victoria, University of Central Florida
Abstract / Description: Over half (57%) of the women diagnosed with breast cancer are age 65 and older. Treatment for breast cancer may exacerbate current chronic illnesses and/or cause multiple treatment related side effects such as insomnia, fatigue, decreased physical functioning, alterations in body image, poorer quality of life, and changes in psychosocial health. While many women with breast cancer experience these changes, research suggests that older women have different needs than younger women and may not...
Show moreOver half (57%) of the women diagnosed with breast cancer are age 65 and older. Treatment for breast cancer may exacerbate current chronic illnesses and/or cause multiple treatment related side effects such as insomnia, fatigue, decreased physical functioning, alterations in body image, poorer quality of life, and changes in psychosocial health. While many women with breast cancer experience these changes, research suggests that older women have different needs than younger women and may not always benefit from interventions. The purpose of this integrative review of literature was to evaluate interventions designed to improve treatment related side effects in female breast cancer survivors age 65 years and older. This review of literature was conducted using CINAHL, PsycINFO, and MEDLINE databases using various key terms. Inclusion criteria consisted of peer reviewed research articles, women who have experience breast cancer, interventions directed at decreasing side effects, and research articles written in the English language.While using these search criteria, no interventions were found therefore, the age group was lowered to include women 50 and older. Eleven studies met the inclusion criteria. Interventions addressed a variety of treatment related side effects and were delivered in multiple formats. The findings indicate that interventions resulted in a significant improvement in sleep and fatigue, physical function, perception of body image, psychosocial health, and quality of life for older women with breast cancer. While these findings are positive, the literature did not break down results based on developmental stage or "older" age groups. Currently, there is limited literature that examines interventions in women age 65 and older, this may limit nurses' ability to suggest successful interventions to some of our oldest cancer survivors.
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Date Issued: 2013
Identifier: CFH0004393, ucf:44990
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH0004393

Title: The CT20 peptide as an agent for cancer treatment.
Creator: Bassiouni, Rania, Khaled, Annette, Altomare, Deborah, Zhao, Jihe, Estevez, Alvaro, University of Central Florida
Abstract / Description: Due to cancer recurrence and the development of drug resistance, metastatic breast cancer is a leading cause of death in women. In the search for a new therapeutic to treat metastatic disease, we discovered CT20p, an amphipathic peptide based on the C-terminus of Bax. Due to inherent properties of its sequence and similarity to antimicrobial peptides, CT20p is a promising cytotoxic agent whose activity is distinct from the parent protein (e.g. does not cause apoptosis). CT20p is not membrane...
Show moreDue to cancer recurrence and the development of drug resistance, metastatic breast cancer is a leading cause of death in women. In the search for a new therapeutic to treat metastatic disease, we discovered CT20p, an amphipathic peptide based on the C-terminus of Bax. Due to inherent properties of its sequence and similarity to antimicrobial peptides, CT20p is a promising cytotoxic agent whose activity is distinct from the parent protein (e.g. does not cause apoptosis). CT20p is not membrane permeable but can be introduced to cells using polymeric nanoparticles, a method that promotes efficient delivery of the peptide into the intracellular environment.We demonstrated that CT20p was cytotoxic using triple negative breast cancer (TNBC) cell lines, primary breast tumor tissue, and breast tumor murine xenografts. Importantly, normal breast epithelial cells and normal primary breast cells were resistant to the lethal effects of the peptide. Examination of multiple cellular processes showed that CT20p causes cell death by promoting cytoskeletal disruption, cell detachment, and loss of substrate-mediated survival signals.In order to identify the intracellular target of CT20p, we performed pull-down experiments using a biotinylated peptide and found that CT20p binds directly to a type II chaperonin called chaperonin containing T-complex (CCT), which is essential for the folding of actin and tubulin into their native forms. The resulting effect of CT20p upon the cytoskeleton of cancer cells is disruption of vital cellular processes such as migration and adhesion. CCT gene expression and protein levels were examined across several breast cancer cell lines, and we found that susceptibility to CT20p correlated with higher CCT levels. Using human cancer tissue microarrays, we determined that CCT was present in significantly higher amounts in tumor tissues compared to normal tissues and that expression often increased with advanced cancer stage. These results indicate that CCT is a promising therapeutic target for the treatment of metastatic breast cancer and suggest that the use of cancer-targeted nanoparticles loaded with CT20p is a novel and effective therapeutic strategy for cancers, such as TNBC, that recur and are refractory to current treatments.
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Date Issued: 2015
Identifier: CFE0006207, ucf:51095
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006207

Title: QUALITY OF LIFE IN OLDER BREAST CANCER SURVIVORS.
Creator: Loerzel, Victoria, Meneses, Karen, University of Central Florida
Abstract / Description: Quality of life (QoL) in cancer survivors is an important area of research. While data are available about QoL and breast cancer, there is a paucity of research regarding older breast cancer survivors. The purpose of this research was to examine QoL in older women with early stage breast cancer, within the first year of post-treatment survivorship. The specific aims of this study were to: 1) Describe the changes in overall QoL and the four QoL domains of Physical, Psychological, Social, and...
Show moreQuality of life (QoL) in cancer survivors is an important area of research. While data are available about QoL and breast cancer, there is a paucity of research regarding older breast cancer survivors. The purpose of this research was to examine QoL in older women with early stage breast cancer, within the first year of post-treatment survivorship. The specific aims of this study were to: 1) Describe the changes in overall QoL and the four QoL domains of Physical, Psychological, Social, and Spiritual well-being; 2) Examine the effects of a psychoeducational support intervention on QoL outcomes in older women; and 3) Describe nurses' perceptions of their interactions with older breast cancer survivors. A descriptive, longitudinal design was used to answer the research questions. Data for this study were drawn from the Breast Cancer Education Intervention (BCEI), a longitudinal psychoeducational support intervention for women with early stage breast cancer. Fifty women from the BCEI who were 65 years of age and older were included in this sample, of whom 24 were assigned to the Experimental (EX) Group and 26 were assigned to the Wait Control (WC) Group. Data were collected at three time points: baseline, three months, and six months after study entry. Measurement tools included the BCEI Demographics Form, the Quality of Life-Breast Cancer Survey (QoL-BC), and field notes of the BCEI Research Nurses. The QoL-BC survey is a 50-item scale that measures QoL in women with breast cancer. Descriptive statistics, Generalized Estimating Equation (GEE) methods and t-tests were used to answer research questions #1 and #2. Content analysis was used to answer research question #3. Subjects reported good overall QoL at baseline, but QoL declined over six months. Physical and Psychological well-being declined from baseline to six months later. Social well-being initially improved from baseline to three months but declined at six months. Spiritual well-being initially declined at three months and improved at six months. There was insufficient power to detect a difference in the effects of the BCEI Intervention between the two groups. However, the decline in overall QoL was less in the EX Group. Field notes focusing on nurses' perception of their interactions with older women revealed four themes. These themes include: continuing breast-related health, personal health issues, family health issues, and potential stressors. Results from this study suggest that: 1) changes in overall QoL and within the four QoL domains occur over time; 2) decline in overall QoL was lessened by the BCEI Intervention; and 3) concerns after treatment are both breast cancer and non-breast cancer related. Study findings can direct future research in the following areas: 1) identification of specific concerns within each QoL domain that could lead to an increase or decrease in well-being in older breast cancer survivors; 2) interventions tailored to the needs of older breast cancer survivors to maintain, improve, or lessen decline in QoL after treatment; and 3) reconceptualizing QoL in older breast cancer survivors to include non-cancer related factors.
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Date Issued: 2007
Identifier: CFE0001720, ucf:47298
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0001720

Title: YOGA'S EFFECT ON QUALITY OF LIFE IN BREAST CANCER SURVIVORS.
Creator: Licata, Nicole M, Loerzel, Victorial, University of Central Florida
Abstract / Description: Background: Breast cancer is the most common cancer in the world with approximately 1.7 million new cases diagnosed in 2012. While women with breast cancer are treated with a multitude of different therapies, these treatments can lead to long-term effects that impact quality of life (i.e. fatigue, pain, lymphedema, anxiety, depression, osteoporosis). With more people looking into complementary and alternative medicine (CAM), research on yoga�s effect on quality of life in breast cancer...
Show moreBackground: Breast cancer is the most common cancer in the world with approximately 1.7 million new cases diagnosed in 2012. While women with breast cancer are treated with a multitude of different therapies, these treatments can lead to long-term effects that impact quality of life (i.e. fatigue, pain, lymphedema, anxiety, depression, osteoporosis). With more people looking into complementary and alternative medicine (CAM), research on yoga�s effect on quality of life in breast cancer survivors is vital. Methods: This literature synthesis used PsychINFO, MEDLINE, and CINAHL explore current research on yoga's effects on quality of life in breast cancer survivors. Search terms included: breast cancer, survivor, quality of life, lifestyle, wellbeing, clinical trial, and controlled trial. Literature was excluded if it included men, women under cancer treatment and if yoga was included in a mindfulness intervention. Results: Eleven articles met the inclusion criteria. Yoga was shown to have a positive impact on fatigue, pain, anxiety, depression, and breast cancer survivors' quality of life. A majority of the studies measured quality of life using the FACT-B and FACT-G scale. Others used similar measurement tools and qualitative journal entries. Specific studies indicated improvements in aromatase-inhibitor associated arthralgia, diurnal salivary cortisol levels, and menopausal symptoms. Conclusions: Yoga appears to be beneficial in improving breast cancer survivor's quality of life. More research is needed. However, nurses can use this information to educate clients about the benefit of yoga in survivorship. This research may promote further utilization of CAM in improving quality of life.
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Date Issued: 2016
Identifier: CFH2000036, ucf:45593
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH2000036

Title: Role of KLF8-CXCR4 signaling in Breast Cancer Metastasis.
Creator: Mukherjee, Debarati, Zhao, Jihe, Khaled, Annette, Altomare, Deborah, Siddiqi, Shadab, University of Central Florida
Abstract / Description: Kr(&)#252;ppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. In this study we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of...
Show moreKr(&)#252;ppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. In this study we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Furthermore, CXCR4-CXCL12 engagement downstream of KLF8 leads to the feed-forward activation of FAK. Interestingly, KLF8 expression, through CXCR4 engagement, triggered the formation of filopodium-like protrusions (FLP) and thereby enhanced the proliferation rate of breast cancer cells in 3D Matrigel-on-Top culture, under prolonged treatment with CXCL12. This indicates that KLF8 plays a major role in promoting aggressive colonization of tumor cells in a CXCL12-enriched foreign tissue microenvironment, thereby aiding in secondary macrometastasis formation. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. Apart from lung, KLF8 overexpression also induced spontaneous secondary metastasis to other CXCL12-rich organs through CXCR4 signaling. These results collectively suggest a critical role for KLF8 and the CXCR4-CXCL12 pathway in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies.
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Date Issued: 2016
Identifier: CFE0006149, ucf:51127
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006149

Title: IDENTIFICATION OF EPITHELIAL STROMAL INTERACTION 1 AND EPIDERMAL GROWTH FACTOR RECEPTOR AS NOVEL KR(&)#220;PPEL-LIKE FACTOR 8 TARGETS IN PROMOTING BREAST CANCER PROGRESSION.
Creator: Li, Tianshu, Zhao, Jihe, Khaled, Annette, Altomare, Deborah, Lambert, Stephen, University of Central Florida
Abstract / Description: Breast cancer is the major cause of cancer death among women worldwide. Understanding the mechanisms underlying breast cancer progression remains urgent for developing effective treatment strategies to eliminate breast cancer mortality. Our recent studies have demonstrated that Kr(&)#252;ppel-like transcriptional factor 8 (KLF8) plays a critical role for breast cancer progression. Other studies have shown that Epithelial stromal interaction 1 (EPSTI1), a recently identified stromal fibroblast...
Show moreBreast cancer is the major cause of cancer death among women worldwide. Understanding the mechanisms underlying breast cancer progression remains urgent for developing effective treatment strategies to eliminate breast cancer mortality. Our recent studies have demonstrated that Kr(&)#252;ppel-like transcriptional factor 8 (KLF8) plays a critical role for breast cancer progression. Other studies have shown that Epithelial stromal interaction 1 (EPSTI1), a recently identified stromal fibroblast-induced gene in non-invasive breast cancer cells and epidermal growth factor receptor (EGFR) are highly overexpressed in aggressively invasive breast carcinomas including triple negative breast cancers. In this thesis project, we demonstrate high co-overexpression of KLF8 with EPSTI1 as well as EGFR in invasive breast cancer cells and patient tumors. We also show that KLF8 upregulates the expression of EPSTI1 by directly binding and activating the EPSTI1 gene promoter, and KLF8 upregulates the expression of EGFR not only by directly activating the EGFR gene promoter but also by preventing EGFR translation from microRNA141-dependent inhibition. Genetic, signaling and animal cancer model analyses indicate that downstream of KLF8, EPSTI1 promotes the tumor invasion and metastasis by activating NF-?B through binding valosin containing protein (VCP) and subsequent degradation of I?B?, whereas EGFR promotes tumor growth and metastasis via activation of ERK. Taken together, these data identify EPSTI1 and EGFR as novel KLF8 targets in breast cancer and suggest that KLF8 may be targeted for new effective treatment of breast cancer.
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Date Issued: 2013
Identifier: CFE0005366, ucf:50474
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0005366

Title: Chaperonin Containing TCP1 (CCT) as a Target for Cancer Therapy.
Creator: Carr, Ana, Khaled, Annette, Altomare, Deborah, Tigno-Aranjuez, Justine, Fernandez-Valle, Cristina, University of Central Florida
Abstract / Description: Treatments for aggressive cancers like triple negative breast cancer (TNBC) and small-cell lung cancer (SCLC) have not improved and remain associated with debilitating side effects. There is an unmet medical need for better, druggable targets and improved therapeutics. To this end, we investigated the role of Chaperonin-Containing TCP1 (CCT), an evolutionarily conserved protein-folding complex composed of eight subunits (CCT1-8), in oncogenesis. Our laboratory was the first to report that the...
Show moreTreatments for aggressive cancers like triple negative breast cancer (TNBC) and small-cell lung cancer (SCLC) have not improved and remain associated with debilitating side effects. There is an unmet medical need for better, druggable targets and improved therapeutics. To this end, we investigated the role of Chaperonin-Containing TCP1 (CCT), an evolutionarily conserved protein-folding complex composed of eight subunits (CCT1-8), in oncogenesis. Our laboratory was the first to report that the CCT2 subunit is highly expressed in breast cancer and could be therapeutically targeted. To determine whether CCT is a marker of disease progression in other cancers, we analyzed CCT2 gene expression in liver, prostate and lung cancer, using publicly available genetic databases, and confirmed findings by assessing CCT2 and client proteins, like STAT3, in tumor tissues by immunohistochemistry. We found that CCT2 was high in all cancers, especially SCLC, and correlated with decreased patient survival. We tested CT20p, the peptide therapeutic developed by our laboratory to inhibit CCT, on SCLC and primary lung cells, finding that CT20p was only cytotoxic to SCLC cells. Since SCLC currently lacks targeted therapeutics, our work yielded a new targeted agent that could improve lung cancer mortality. To establish a mechanism of action for CT20p, we partially knocked out CCT2 in TNBC cells, which decreased tumorigenicity in mice and reduced levels of essential proteins like STAT3. To confirm, we overexpressed CCT2 in non-tumorigenic cells and conferred tumor-like characteristics such as increased migration and elevated STAT3. These studies positioned us to develop and validate a strategy for discovery of new small molecule inhibitors of CCT. We thus advanced the field of cancer research by demonstrating that CCT could have diagnostic potential for cancers, such as SCLC and TNBC, that are a significant cause of human death and showed that targeting CCT is a promising therapeutic approach.
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Date Issued: 2017
Identifier: CFE0007280, ucf:52191
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0007280

Title: USE OF CERIUM OXIDE NANOPARTICLES FOR PROTECTION AGAINSTRADIATION-INDUCED CELL DEATH.
Creator: Colon, Jimmie, Kolattukudy, Pappachan, University of Central Florida
Abstract / Description: The ability of engineered cerium oxide nanoparticles to confer radioprotection was examined. Rat astrocytes were treated with cerium oxide nanoparticles to a final concentration of 10 nanomolar, irradiated with a single 10 Gy dose of ionizing radiation and cell death was evaluated by propidium iodine uptake at 24 and 48 hours after radiation insult. Treatment of rat astrocytes with nanoceria resulted in an approximate 3-fold decrease in radiation induced death. These results suggest that the...
Show moreThe ability of engineered cerium oxide nanoparticles to confer radioprotection was examined. Rat astrocytes were treated with cerium oxide nanoparticles to a final concentration of 10 nanomolar, irradiated with a single 10 Gy dose of ionizing radiation and cell death was evaluated by propidium iodine uptake at 24 and 48 hours after radiation insult. Treatment of rat astrocytes with nanoceria resulted in an approximate 3-fold decrease in radiation induced death. These results suggest that the nanoceria are conferring protection from radiation induced cell death. Further experiments with human cells were conducted. Human normal and tumor cells (MCF-7 and CRL8798) were treated with the same dosage of cerium oxide nanoparticles, irradiated and evaluated for cell survival. Treatment of normal cells (MCF-7) conferred nearly 99% protection from radiation-induced cell death while the same concentration of nanoceria showed almost no protection in tumor cells (CRL8798). TUNEL analysis results of similarly treated cells demonstrated that nanoceria reduced radiation-induced cell death by 3-fold in normal breast cells but not in MCF-7 tumor cell lines when cultured under the same conditions. We concluded that cerium oxide nanoparticles confer radioprotection in a normal human breast line (CRL 8798) but not in a human breast tumor line (MCF-7). It is hoped that the outcome of this study will guide future endeavors toward a better elucidation of the molecular pathways involved in the protection of cells with nanoceria against radiation-induced cell death, as well as the minimization of the bystander effect in radiation therapy.
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Date Issued: 2006
Identifier: CFE0001048, ucf:46823
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0001048

Title: DISCOVERY AND OPTIMIZATION OF NOVEL SMALL-MOLECULAR INHIBITORS SUPPRESSING STAT3-DEPENDENT TUMOR PROCESS.
Creator: Zhang, Xiaolei, Turkson, James, University of Central Florida
Abstract / Description: With the critical role of aberrantly active Signal Transducer and Activator of Transcription (Stat) 3 protein in many human cancers, selective small-molecule inhibitors targeting the dimerization event which is required for stat3 activation, would be valuable as therapeutic agents. And the inhibitors will be useful chemical probes to clarify the complex biological functions of Stat3. By computational and structural analyses of the interaction between Stat3 and the lead dimerization disruptor,...
Show moreWith the critical role of aberrantly active Signal Transducer and Activator of Transcription (Stat) 3 protein in many human cancers, selective small-molecule inhibitors targeting the dimerization event which is required for stat3 activation, would be valuable as therapeutic agents. And the inhibitors will be useful chemical probes to clarify the complex biological functions of Stat3. By computational and structural analyses of the interaction between Stat3 and the lead dimerization disruptor, S3I-201, we have designed a diverse set of analogs. One of the most active analogs, S3I-201.1066 is derived to contain a cyclo-hexyl benzyl moiety on the amide nitrogen, which increases the binding to the Stat3 SH2 domain. Evidence is presented from in vitro biochemical and biophysical studies that S3I-201.1066 directly interacts with Stat3 or the SH2 domain, with an affinity (KD) of 2.74 [micro]M, and disrupts the binding of Stat3 to the cognate pTyr-peptide, GpYLPQTV-NH2, with an IC50 of 23 [micro]M. Moreover, S3I-201.1066 selectively blocks the association of Stat3 with the epidermal growth factor receptor (EGFR), and inhibits Stat3 tyrosine phosphorylation and nuclear translocation in EGF-stimulated mouse fibroblasts. In cancer cells that harbor aberrant Stat3 activity, S3I-201.1066 inhibits constitutive Stat3 DNA-binding and transcriptional activities. By contrast, S3I-201.1066 has no effect on Src activation or the EGFR-mediated activation of the Erk1/2MAPK pathway. S3I-201.1066 selectively suppresses the viability, survival, and malignant transformation of the human breast and pancreatic cancer lines and the v-Src-transformed mouse fibroblasts harboring persistently active Stat3. Treatment with S3I-201.1066 on malignant cells harboring aberrantly active Stat3 down regulated the expression of c-Myc, Bcl-xL, Survivin, matrix metalloproteinase 9, and VEGF, which are known Stat3-regulated genes important in diverse tumor processes. The in vivo administration of S3I-201.1066 induced significant anti-tumor response in mouse models of human breast cancer, which correlates with the inhibition of constitutively active Stat3 and the suppression of known Stat3-regulated genes. Further computer-aided lead optimization derives higher-affinity (KD, 504 nM), orally bioavailable Stat3 SH2 domain-binding ligand, BP-1-102 as a structural analog of S3I-201.1066. The most significant modification is the pentafluorobenzene sulfonamide component of BP-1-102, which permits accessibility of a third sub-pocket of the Stat3 SH2 domain surface. BP-1-102-mediated inhibition of aberrantly-active Stat3 in human pancreatic cancer, Panc-1, breast cancer, MDA-MB-231, and prostate (DU145) cancer cells and in the mouse transformed fibroblasts harboring aberrantly-active Stat3. It also disrupts Stat3-NFkB cross-talk and suppresses the release of granulocyte colony-stimulating factor, soluble intercellular adhesion molecule-1, macrophage-migration-inhibitory factor/glycosylation-inhibiting factor, interleukin-1 receptor antagonist and the serine protease inhibitor (serpin) protein 1, and the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, and vascular endothelial growth factor expression in vitro and in vivo. Inhibition of tumor cell-associated constitutively-active Stat3 further suppresses focal adhesion kinase and paxillin induction, enhances E-cadherin expression, and down-regulates Kruppel-like factor 8 (KLF8)expression. Consequently, BP-1-102 selectively suppresses anchorage-dependent and independent growth, survival, migration and invasion of Stat3-dependent tumor cells in vitro. Intravenous or oral gavage delivery of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of mouse xenografts of human breast and lung tumors. Computer-aided lead optimization has therefore derived a more suitable small-molecule inhibitor as a drug candidate. Our studies of the Stat3 SH2 protein surface and of the interactions between lead agents and the SH2 domain provided significant data to facilitate the structural optimization. From S2I-201 to S3I-201.1066 and to BP-1-102, we note the substantial gain in potency and efficacy, and the pharmacokinetic improvements. The oral bioavailability of BP-1-102 represents a substantial advancement in the discovery of small-molecule Stat3 inhibitors as novel anticancer agents.
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Date Issued: 2011
Identifier: CFE0003976, ucf:48669
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0003976

Title: Evaluation of a Mind-Body Website by Women with Breast Cancer.
Creator: Beck, Laura, Loerzel, Victoria, Sole, Mary, Morrison, Kimberly, University of Central Florida
Abstract / Description: Despite having access to volumes of information, women newly diagnosed with breast cancer report a moderate level of distress related to their diagnosis, treatment, life expectancy, threat to current roles, and life-changing surgery and treatment choices. Web sites designed to teach people strategies to reduce distress are readily available online. The online format may be useful and practical for women who can access the site at their convenience, learn the components of the interventions at...
Show moreDespite having access to volumes of information, women newly diagnosed with breast cancer report a moderate level of distress related to their diagnosis, treatment, life expectancy, threat to current roles, and life-changing surgery and treatment choices. Web sites designed to teach people strategies to reduce distress are readily available online. The online format may be useful and practical for women who can access the site at their convenience, learn the components of the interventions at their own pace, and practice the strategies in the comfort of their home. The purpose of this study was to evaluate an online Mind-Body web site (http://www.www.preparingforyoursurgery.com) designed to reduce distress related to surgery for its usability, practicality, and appropriateness for women newly diagnosed with breast cancer. Results of this study will be used to either adopt use of the web site into standard of care at our cancer center or explore development of a similar web site to meet the needs of women newly diagnosed with breast cancer. Women recently diagnosed with breast cancer, who had breast cancer surgery in the past 60 days, were asked to evaluate an online Mind-Body web site and then respond to an online questionnaire measuring the web site usability, practicality, and appropriateness. Thirty-one women evaluated the web site and completed the online survey. The majority of women agreed the web site is useful, practical, appropriate, and would recommend to others. There was no significant relationship between age, income, level of education, frequency of Internet use, or experience with Mind-Body techniques and women who agreed the web site is useful, appropriate, or practical compared to women who were neutral or disagreed the web siteis useful, appropriate, or practical. The results of this study suggest the web site could be introduced to women newly diagnosed with breast cancer at our cancer center regardless of age, income, education, frequency of Internet use, or experience with Mind-Body techniques.
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Date Issued: 2013
Identifier: CFE0005085, ucf:50752
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0005085

breast cancer (7)	+ -
Breast Cancer (2)	+ -
KLF8 (2)	+ -
BP-1-102 (1)	+ -
CT20p (1)	+ -

CXCL12 (1)	+ -
CXCR4 (1)	+ -
EGFR (1)	+ -
EPSTI1 (1)	+ -
Evaluation of web site (1)	+ -
Mind-Body web site (1)	+ -
Mixed Methods (1)	+ -
Nanoceria (1)	+ -
Older Women (1)	+ -
Practicality and Appropriateness (1)	+ -
Quality of Life (1)	+ -
S3I-201.1066 (1)	+ -
Stat3 inhibitor (1)	+ -
Targeted cancer therapy (1)	+ -
Website Usability (1)	+ -
antitumor (1)	+ -
biomaterials (1)	+ -
breast cancer survivors (1)	+ -
cerium oxide nanoparticles (1)	+ -
chaperonin (1)	+ -
chaperonin containing TCP1 (1)	+ -
complementary therapy (1)	+ -
cytoskeleton (1)	+ -
interventions (1)	+ -
invasion (1)	+ -

ETD Collection (8)	+ -
Honors Collection (3)	+ -

University of Central Florida (11)	+ -
Altomare, Deborah (4)	+ -
Khaled, Annette (4)	+ -
Loerzel, Victoria (3)	+ -
Zhao, Jihe (3)	+ -

Bassiouni, Rania (1)	+ -
Beck, Laura (1)	+ -
Carr, Ana (1)	+ -
Colon, Jimmie (1)	+ -
Estevez, Alvaro (1)	+ -
Fernandez-Valle, Cristina (1)	+ -
Florczyk, Stephen J. (1)	+ -
Kolattukudy, Pappachan (1)	+ -
Lambert, Stephen (1)	+ -
Le, Minh-Chau N. (1)	+ -
Li, Tianshu (1)	+ -
Licata, Nicole M (1)	+ -
Loerzel, Victorial (1)	+ -
Meneses, Karen (1)	+ -
Morrison, Kimberly (1)	+ -
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