SACM - United States of America
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Item Restricted Sleep Quality in Women with Breast Cancer: A Longitudinal Analysis of Predictors for One-Year Post-Diagnosis(University at Buffalo, 2024-06-01) Alanazi, Nouf; Lorenz, RebeccaBreast cancer (BC) remains a significant public health concern worldwide, posing considerable challenges to individuals' health and well-being. Among the myriad of issues faced by breast cancer survivors (BCS), sleep disturbances emerge as a prevalent and often debilitating problem. Understanding the complex interplay of factors influencing sleep quality in BCS is crucial for developing targeted interventions to mitigate these disturbances and improve overall quality of life. The purpose of this dissertation is to generate comprehensive knowledge regarding sleep quality in women with BC, while also characterizing associated factors contributing to these disturbances. By delving into the multifaceted nature of sleep disturbances in BCS, this research aims to expand upon the existing body of knowledge surrounding the causes of sleep disruptions in this population. This dissertation follows the three-manuscript style dissertation that provides knowledge regarding sleep disturbances, while also characterizing associated factors in women with breast cancer from pre-diagnosis to 1- year post diagnosis. The first manuscript used existing data from the prospective Women’s Health after Breast Cancer Study (N=606) to examine sleep quality, quantity, and self-reported causes of sleep disturbance among female breast cancer patients at the time of diagnosis and one year after treatment. The second manuscript is an integrative review of current literature to describe the risk factors of poor sleep quality among BCS based on Spielman's three-factor model of insomnia (3 P's model). This theoretical basis for the review examines cancer-related factors that predispose, precipitate, and perpetuate insomnia. The third manuscript utilizes a secondary data analysis approach to assess the association between different types of breast cancer treatments, breast cancer symptoms, cancer characteristics and sleep quality using longitudinal data from the Women’s Health after Breast Cancer Study (N=715). Findings add to the existing body of knowledge on the causes of sleep disturbances in BCSs by exploring the influence of factors that affect sleep quality. Results provide a better understanding of the myriad of contributing factors that increase the potential for short- or long-term sleep disruptions among BCSs and the resulting outcomes on individuals' health and health-related QoL. Further, the results contribute to the existing literature on salient factors and conditions that aggravate sleeping problems in BCSs at diagnosis prior to treatment and at one-year post-diagnosis. Specifically, results from this study have significantly advanced our understanding of the predisposing and precipitating factors associated with sleep disturbances among BCS.18 0Item Restricted Optimizing Lipid Nanoparticles for mRNA Delivery to Tumor-associated Macrophages for Breast Cancer Immunotherapy(Virginia Commonwealth University, 2024-05-08) Alshehry, Yasir A.; da Rocha, Sandro; Sweet, Douglas; Wang, Xiang-YangBreast cancer remains the most prevalent cancer among women worldwide, with triple-negative breast cancer (TNBC) presenting distinct treatment hurdles due to its lack of hormone receptors and HER2 expression. In spite of recent advances including immune checkpoint inhibitors, there is still a significant unmet need in the treatment of TNBC. Innovative pharmacotherapies are crucial to support the treatment of TNBC. The tumor microenvironment (TME) is an important target for new therapies as it profoundly influences cancer progression and response to current treatments. Tumor-associated macrophages (TAMs) are the most abundant immune infiltrates in the TME and their phenotype correlates with treatment outcomes. While M1-like TAMs exhibit anti-tumor effects, M2-like TAMs promote tumor progression. Reprogramming M2-like TAMs into an M1-like phenotype thus represents a promising strategy. With recent developments and clinical translation of mRNA lipid nanoparticle (LNP) therapeutics (as in COVID-19 vaccines), there has been a significant focus on mRNA as an active pharmaceutical ingredient. However, efficient mRNA delivery to macrophages via LNP is hindered by challenges in cell uptake and intracellular delivery, thereby limiting cytosolic release and efficacy. Our study aims to optimize LNP formulations for enhanced mRNA delivery to macrophages, recognizing their essential role of TAMs in the TME, and the potential to improve treatment outcomes in TNBC. We initiated our study by optimizing the formulation method and subsequently systematically evaluated various clinically relevant lipids to determine the optimal LNP composition for mRNA delivery to macrophages. We investigated the effect of the chemistry of the ionizable and helper lipids, as well as the nitrogen to phosphorus (N:P) ratio and particle size, on mRNA LNP internalization and reporter protein expression in murine macrophages (RAW 264.7), bone marrow derived macrophages (mBMDMs) and human peripheral monocyte-derived macrophages (hMDMs). The screening process comprised three phases. In the first phase, after the identification of optimum LNP preparation conditions based on desirable quality target product profile (QTPP), including high encapsulation efficiency (EE%), we assessed the effect of different types of ionizable lipids both in vitro and in vivo. Subsequently, in the second phase, for optimized ionizable lipid chemistry, we evaluated various phospholipids, followed by an evaluation of the impact of changing sterol lipids and their molar ratios in the third phase. Following the identification of the optimal formulation, we proceeded to investigate and validate its efficacy by evaluating the translation of reporter proteins in different macrophage models, including RAW264.7, mBMDMs, and hMDMs, and also in vivo. Additionally, we assessed the ability of the optimal formulation to deliver mRNA into macrophages of various phenotypes, including M0-, M1-, and M2-like macrophages. At this point, we also introduced an M2-targeting ligand into the formulation and assessed the potential of our formulations to target tumor promoting (M2-like) macrophages, which is the final step before the evaluation of the ability of mRNA LNP to efficiently shift the phenotype of TAMs in the TME of TNBC. Our initial screenings across various ionizable lipids revealed that SM-102, CL1, and cKK-E12 showed superior efficiency in delivering the firefly luciferase (Fluc) reporter mRNA in macrophages in vitro, with SM-102 and ALC-0315 excelling in vivo translation of this reporter protein. Based on efficacy and cytotoxicity assessments, SM-102 was selected as the ionizable lipid for subsequent formulations. Further investigations into phospholipids indicated that DOPE-based LNPs enhanced the mRNA delivery in vitro, which is also supported by literature results. Additionally, exploring various sterols and their ratios pointed to β-sitosterol-based LNPs as the most effective sterol for this formulation and this type of cell (macrophage). Modifying the N:P ratio from 6 to 24 and increasing the LNP size significantly enhanced performance. The optimized formulation, containing SM-102, DOPE, β-sitosterol, and DMG-PEG2k (F6), outperformed Onpattro-like and Moderna-like LNPs in delivering reporter mRNA to primary and immortalized macrophages, which we tentatively attribute to an increased cellular uptake. However, the precise mechanisms, whether improved intracellular trafficking or endosomal escape also contributes to the enhanced efficacy of the designer formulation, remain to be clarified. Interestingly, LNPs with an N:P ratio of 24 did not exhibit increased cell uptake compared to those with a ratio of 6, suggesting the improvements may lie within intracellular processing pathways. Moreover, preliminary results indicated that targeting LNP composed of mannose modified F6 LNP enhanced eGFP expression in M2-like macrophages compared to those treated with non-targeting F6, suggesting its potential as a platform for targeting and repolarizing M2 towards M1-like macrophages. Finally, we also demonstrated that F6 facilitates mRNA translation within the tumor microenvironment in an in vivo TNBC model. Identification of expression in the various cell types in the TME will allow us to use such a model for further optimization of our formulation. This investigation underscores the significant impact of lipid chemistry and quality attributes of the LNP on mRNA delivery efficiency in macrophages, laying the groundwork for further optimization efforts. The optimized formulation, F6, notably enhances mRNA delivery to macrophages, opening avenues for future research into repolarizing M2-like to M1-like macrophages with mRNA LNPs, representing a promising immunotherapeutic strategy for remodeling the TME and enhancing anti-tumor immunity.19 0Item Restricted THE MEANINGS OF DAILY ACTIVITIES AND ATTITUDES OF OLDER BREAST CANCER SURVIVORS: A CASE STUDY RESEARCH(Saudi Digital Library, 2023-06-07) Alquraini, Wadha; Jacelon, CynthiaObjectives: The aim of the study was to explore how older breast cancer survivorsmade meaning from daily activities and their attitudes to life and behaviors in it. Method: Secondary data was analyzed from nine older women with breast cancer.Data on living women was used to elicit the influence of breast cancer on survivors' attitudes and behaviors. Results: Eight significant themes were identified that were related to breast cancer meanings, attitudes to it, and behaviors that impact participants' survivorship; breast cancer means death or being close to death, survivor-provider relationships, social support, the meaning of dignity or a good prognosis, grief attitudes, everyday work, and biographical work. Findings: The meaning of dignity and good prognosis could impact older breast cancer survivors' inner views and behaviors. However, throughout the survivorship years, the good prognosis could be interrupted by other influence factors that altered the inner views of the women. Implications: Healthcare systems must enhance their interventions to involve dignity in the care of older breast cancer survivors and offer accessible programs for them. In addition, future research must use a meaning framework to represent the making-meaning vii process and rethink the use of coexistence instead of the accept concept because the term coexistence describes deeply the adaptation state of anyone who has experienced a traumatic event such as breast cancer.20 0Item Restricted NOVEL IN SILICO-DESIGNED SMYD3 INHIBITORS ELIMINATE UNRESTRAINED PROLIFERATION OF BREAST CARCINOMA CELLS(Saudi Digital Library, 2023-10-03) Alshiraihi, Ilham Mohammed; Brown, MarkSMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. Elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation. In this study, we used in silico screening to identify potential small molecule inhibitors of SMYD3 and tested the ability of these inhibitors to reduce its methyltransferase activity in vitro. Using breast cancer cell lines that overexpress SMYD3 and normal breast epithelial cell lines, we have confirmed the ability of one of these inhibitors, Inhibitor-4, to reduce cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting normal cell behavior. Our results provide a proof of concept for the in silico design of small molecule enzyme inhibitors and for the use of such an inhibitor to target SMYD3 for the treatment of cancer.14 0