The burden of osteoporosis and low bone mass is unrelenting, affecting over 50% of the U.S. population over the age of 50. In a similar reach but different clinical realm, nearly 40% of all men and women will be diagnosed with cancer at some point during their lifetimes. The impact of both of these diseases is compounded by the limited knowledge of cellular mechanisms and the insufficiency of effective treatment options. At the microscopic level of the cell cytoskeleton, increasing evidence has led researchers to further explore microtubules (MTs) and MT-based structures, such as primary cilia, as potential keys to unlocking improved treatment options. However, the way in which microtubules regulate the processes giving rise to these diseases remains a critical gap in knowledge. The works outlined here aimed to elucidate mechanisms that may be used to combat diseases attacking the skeletal and immune systems. In order to characterize the influence of primary cilia with respect to osteoclast differentiation, we implemented a series of treatments to an immortalized macrophage cell line: cilia lengthening (using Fenoldopam) and mechanical stimulation (using oscillatory fluid flow). The results were analyzed by a combination of immunocytochemistry and quantitative PCR. Our first result showed definitively that while osteoclasts do not possess primary cilia, their macrophage precursors do. We also discovered that these macrophage primary cilia are dynamic and can be modulated; cells whose cilia had been lengthened showed a significant decrease in osteoclast formation, indicating that macrophage cilia resorption may be a necessary step for osteoclast differentiation to occur. Combined with findings from previous studies, there is increasing evidence that the primary cilium, as a therapeutic target for bone diseases, may offer a dual beneficial approach to both promote bone formation and downregulate osteoclast activity. We then explored the possibility of directional MT translocation during T-cell activation being linked to Rho GTPases, which regulate actin polymerization. WASp and WAVE2, known to have functional roles in T-cell activation, were identified as primary candidates. In order to investigate this relationship, we implemented a stepwise micropatterning procedure by which PDMS was used to transfer local areas of activation (presenting fluorescently-tagged antibodies against CD3 and CD28) which, upon T-cell receptor (TCR) triggering, could mimic immune synapse (IS) formation. We showed that, although there was no correlation between the spatial organization of MTs and WASp, MTs and WAVE2 location were highly correlated, providing strong evidence for a link between these two systems. In addition, MT disruption via nocodazole resulted in a significant decrease in T-cell activation and mechanosensing capabilities. Given the role of WAVE2 in promoting cell spreading and adhesion during IS formation, this result provides additional evidence that this cytoskeletal filament is in fact connected to proteins involved in actin nucleation and elongation. We anticipate the work in Aim 1 to help reveal a previously unexplored therapeutic target for osteoporosis, a disease that currently has no clinical manifestations prior to a fracture event. Further investigation has the potential to contribute to diagnosis and prevention techniques, as well as new treatments. Similarly, given the emergence of adoptive T-cell immunotherapy for immune-related disorders, the findings of Aim 2 will advance our understanding of both the biological and mechanical influence of the cytoskeleton and motivate microtubules as one component of a more comprehensive armamentarium of treatment approaches.

Polymeric nanoparticles were designed, synthesized, and loaded with metal ions to explore the therapeutic potential for transition metals other than platinum found in cisplatin. Nanoparticles were synthesized to show the potential for polymer based vectors. Metal loading and release were characterized via Inductively Coupled Plasma Mass Spectrometry (ICP MS), Energy Dispersive X-Ray Spectroscopy (EDX), X-Ray Photoelectron Spectroscopy (XPS), and Elemental Analysis. Targeting was attempted with the expectation of observed increased particle uptake by cancer cells with flow cytometry and fluorescence microscopy. Results demonstrated that a variety of metals could be loaded to the nano-sized carriers in an aqueous environment, and that the release was pH-dependent. Expected increased targeting was inconsistent. The toxicity of these particles was measured in cancer cells where significant toxicity was observed in vitro via dosing of high copper-loaded nanoparticles and slight toxicity was observed in ruthenium-loaded nanoparticles. No significant toxicity was observed in cells dosed with metal-free nanoparticles. Future research will focus on ruthenium loaded polymeric nanoparticles with different targeting ligands dosed to different cell lines for the aim of increased uptake and decreased cancer cell viability.

Hormone ablation therapy is a mainstay in the treatment of breast and prostate cancers. However, aromatase inhibitors (AIs) used in postmenopausal women with breast cancer and androgen-deprivation therapy (ADT) used in men with prostate cancer contribute to substantial bone loss, thereby increasing the risk of osteoporotic fractures. Evidence-based guidelines, therefore, urge oncology practices to screen these patients for bone loss and, if needed, provide treatment to maintain bone health. In addition to lifestyle modification and calcium or vitamin D supplementation, bone protection strategies include treatment with bisphosphonates and denosumab, a monoclonal antibody against RANK ligand. Identification of patients at greater risk for bone loss and fracture and proper interventions can reduce fracture rates. Oncology nurses can play an important role in screening these patients. The purpose of this article is to inform oncology nurses about the effects of cancer treatment on bone health, review current prevention and treatment options for cancer treatment-induced bone loss, and discuss recommendations for identifying high-risk individuals.

Nasopharyngeal Carcinoma (NPC) as a typical malignancy that occurs in high-incidence areas, e.g. southern China region, including Hong Kong, and it has aroused wide interests for local researchers to study. The Epstein-Barr virus (EBV) was reported as a vital herpes virus for the growth of NPC. Two significant proteins in EBV, namely Epstein-Barr Nuclear Antigen 1 (EBNA1) and latent infection membrane protein 1 (LMP1) are crucial for virus maintenance and EBV-infected cell development, and essential for cell proliferation and differentiation of EBV latent life cycle, respectively. Thus, inhibition of EBNA1 and LMP1 can be regarded as effective and potent therapy on EBV-associated cancers. In this thesis, the conjugation of core-shell structured upconversion nanoparticles (UCNPs) with distinct EBV-specific peptides including EBNA1 and LMP1 targeting peptides to achieve both impressive inhibition on EBV-positive cancers in vitro/in vivo and visualization on EBV-positive cells with responsive upconversion emission signals were investigated. Taking advantage of lanthanide-based UCNPs, their unique photophysical properties offer deep tissue penetration depth, negligible photobleaching and photocytotoxicity, and therefore provides a solid foundation for convincible theranostic studies. Furthermore, desired inhibitory performance was achieved, it was shown that ~50 mg/mL of nanoprobes can inhibit half of EBV-infected cell viability and only 0.25 mg/tumor of nanoprobes dosage via intravenous injection can prohibit 64.7% of growth inhibition of an EBV-positive tumor

Background: The number of cancer survivors across North America is increasing, with estimates indicating that this population will grow to nearly 19 million individuals by the end of 2020. This increase can be attributed, in part, due to improvements in cancer treatments, of which radiation therapy is most commonly used. Unfortunately, exposure to radiation also increases the risk of secondary cancer development long-term. Moreover, obesity and physical inactivity are prevalent, modifiable, risk factors among cancer survivors, with both factors being linked to decrements in quality of life, increased cancer risk, and greater mortality risk. To date, there has been promising epidemiological and clinical data highlighting the role of exercise as a way to mitigate cancer risk and improve survival; however, longitudinal studies are lacking and the effects of radiation in these studies have been largely ignored. Therefore, there is a major clinical need to directly evaluate the combinatory long-term effects of radiation, exercise, and/or obesity to reveal their implications on healthspan, cancer incidence, and survival. Recent pre-clinical work from our group has shown that after being exposed to radiation, endurance exercise prevented several negative alterations to hematopoietic stem cells and their niche caused by high-fat diet (HFD)-induced obesity. We also showed that leukemic blast viability in vitro was greater when cultured in bone marrow supernatant from mice with HFD-induced obesity compared to bone marrow supernatant from mice without HFD-induced obesity. It is unknown, however, whether these findings extend to alterations in cancer risk across the lifespan. As such, the purpose of this study was to evaluate the effects of lifelong exercise and diet-induced obesity on healthspan, cancer incidence, and survival in an established mouse model of radiation-induced cancer. Methods: Male CBA mice (n=80) were randomly divided into either a control diet (CTRL; n=40) of 45% high-fat diet (HFD; n=40) and then further divided into either a sedentary group (SED; n=20) or exercise-trained group (EX; n=20). At age 13 weeks, all mice were exposed to a cancer inducing dose of whole-body ionizing radiation (3 Gy). A healthspan index score and endpoint monitoring were conducted throughout the study by blinded investigators. Results: When normalized to CTRL/SED, the highest healthspan score was in the CTRL/EX (score = +2.5), followed by HFD/EX (score = +1) and lastly HFD/SED (score = -0.5). Cancer incidence was significantly higher in the HFD/SED group when compared to the CTRL/EX group (p<0.05) and a trend for higher cancer incidence for HFD/SED was observed when compared to the CTRL/SED group (p=0.079). There was no significant difference between the HFD/SED and HFD/EX group in cancer incidence (p>0.05). Overall survival was significantly higher in the HFD/SED group compared to CTRL/SED group (p<0.05); however, risk of cancer-related mortality was 1.6-times higher in the HFD/SED group compared to the CTRL/SED group (RR=1.60; 95% CI, 1.00-2.56; p=0.0495) and 1.68-times that of the CTRL/EX group (RR=1.68; 95% CI, 1.02-2.78; p=0.0415). Conclusion: Our findings show that lifelong exercise training resulted in higher healthspan index, lower cancer incidence, and lower risk of cancer-related mortality following radiation exposure, with these effects being largely reversed by HFD-induced obesity. This study provides the rationale for future studies to uncover cellular and molecular mechanisms that could be underlying these results. Moreover, this study presents a proof of concept for the consideration of clinical studies in cancer survivors examining exercise as an intervention to reduce the long-term effects of radiation.

Over the last two decades, the concept of precision medicine has remained more of a promise than a reality. While there has been significant advancement in the field in terms of scientific discovery, precision medicine has yet to truly permeate standard clinical practice. There are a few individual examples, such as the treatment of breast cancer, in which the precision medicine approach has been ubiquitously adopted, but for most applications it remains exploratory. This barrier can arguably be attributed to the lack of accessible technology. That is, highly laborious, costly, and time-consuming methods that inhibit the integration of precision medicine techniques into the current clinical paradigm. In this dissertation, we aim to develop new technology, for both therapeutics and diagnostics, that would enable access to precision medicine by considering factors such as scalability, manufacturability, cost, turnaround time and integration. In Aim 1, we developed a direct tissue engineering approach to increase endogenous brown fat for the treatment of obesity. This method capitalized on the use of brown adipose tissue (BAT), a highly metabolic tissue that expends energy via uncoupled respiration and has been shown to correlate with a lean phenotype and decreased risk of metabolic disease. Existing methods that seek to increase BAT mass include either the use of pharmacologic agents, which often exhibit detrimental off-target effects, or cold exposure, which is obviously unsustainable in practice. Cell therapies that involve the isolation of adipocyte progenitor cells have also been explored but are not easily scaled and are difficult to implement. Here, we developed a method to convert a patient’s own white adipose tissue (WAT) en masse to thermogenic BAT in a single ex vivo step, followed by reimplantation back into the patient. We demonstrated that this method, called exBAT, was able to convert full fragments of WAT to a BAT-like tissue, which sustained its phenotype up to 8-weeks after reimplantation in a mouse model. Further, allogeneic transplantation of exBAT in a diet-induced obesity mouse model exhibited a trend toward weight loss which should further be explored with additional dosing experiments. This method is highly scalable, patient-specific, and easily implemented with current clinical practice and has the potential to provide a precise method to combat the growing challenge of obesity. In Aim 2, we shifted our focus to the development of a point-of-care (POC) diagnostic device for precision oncology. Here, we developed a device capable of performing a POC liquid biopsy for the detection of resistance mutations in non-small cell lung cancer (NSCLC). While liquid biopsies, which seek to identify tumor fragments in a patient’s blood, hold significant promise and advantages over traditional tissue biopsies, there are still several challenges including long turnaround time, high cost, and challenges with sensitivity. We sought to build a fully integrated device that can reduce the turnaround time for liquid biopsies from 2 weeks to one hour, enabling much higher throughput for important genotyping tests in NSCLC patients, and thereby enabling faster access to treatment. We demonstrated the ability to isolate plasma from undiluted whole blood at the POC, purify and concentrate circulating nucleic acids, and perform detection of low variant allelic frequency (VAF) mutations down to 1% in a microfluidic chip using a low-cost thermocycler. The device was initially designed to identify the presence or absence of T790M mutations, an important gatekeeper mutation with a clear clinical use case that confers sensitivity toward specific tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. However, the device can be easily extrapolated toward any type of molecular profiling and has the potential to significantly increase access to precision oncology diagnostics and therapeutics. Finally, in Aim 3, we sought to develop a molecular diagnostic for detection of SARS-CoV-2 that would provide a qualitative result in less than 15 minutes at the POC. As the COVID-19 pandemic has continued to spread rapidly throughout the world, there is still an unmet need for high-throughput, ultrafast diagnostics that are sensitive, specific and accessible to all. To meet this challenge, we developed a molecular diagnostic that performs RT-PCR off of crude lysate from patient specimens in 15 minutes or less. To achieve this, we built upon previously demonstrated photothermal amplification techniques and extended its capabilities to perform ultrafast RT-PCR using a low-power infrared LED. We also sought to integrate sample preparation methods for both nasopharyngeal (NP) swabs and saliva samples to eliminate the need for labor-intensive RNA extraction and enable full automation for POC testing. Testing of our device using purified SARS-CoV-2 RNA showed high sensitivity and a limit of detection down to 500 copies/mL. We also demonstrated preliminary results showing the ability to detect SARS-CoV-2 RNA in unpurified saliva and further testing of clinical specimens in the POC device is ongoing. With a significantly faster and low-cost test that maintains gold-standard sensitivity and specificity, this device has the potential to drastically increase testing throughput and help contain the spread of COVID-19. Underlying this work is the development of accessible technology for precision medicine. Aim 1 focuses on a simple, patient-specific tissue engineering approach to treating obesity, which is significantly more scalable than other cell and tissue engineering methods. Aim 2 demonstrates the ability to perform a highly sensitive liquid biopsy at the POC down to 1% VAF. Aim 3 demonstrates a new POC diagnostic for SARS-CoV-2 that provides a result in less than 15 minutes. Both Aims 2 and 3 focus on the development of POC diagnostics and were designed to be user-friendly, scalable, and easily integrated into current clinical paradigms. In Appendix I, we expand the discussion of POC diagnostics and present a design framework based on cost and budget constraints that was used for the development of these POC devices. Overall, the sum of this work illustrates examples of thoughtful engineering for the development of impactful new technologies for precision therapeutics and diagnostics.

By conducting interviews, prototyping and user tests this thesis aims to explore the question how not-thought-trough interaction design can be improved by implementing thoughtful interaction design. To explore this is a cancer therapy software presented and investigated with the intention to improve the current interface and user experience. The study presents findings based on the methods used that highlights the importance of interaction aesthetics and thoughtful interaction design when designing cancer therapy software. This is followed by the designer implementing improvements based on the feedback from the test subjects. The final results show that interaction aesthetics and thoughtful interaction design is of high importance in designing cancer therapy software.

Bakgrund: Cancer drabbar cirka 250-300 barn varje år. Föräldrar har fått en alltmer betydelsefull roll i omvårdnaden av sitt barn på sjukhus. Enligt tidigare forskning har föräldrars upplevelser av vården varit beroende av sjuksköterskors bemötande, deras intresse för barnet och tillgänglighet. Familjefokuserad omvårdnad inriktar sig på hela familjen och deras behov. Syfte: Att belysa föräldrars upplevelser av att ha ett barn som drabbats av cancer. Metod: En litteraturstudie där tio kvalitativa studier granskades varav en var mixed-method. Resultat: Två teman med sex subkategorier presenterar resultatet. Det första temat beskriver hur föräldrarna påverkas den första tiden av sina barns cancer gällande känslor, information och maktlöshet kring behandling. Det andra temat beskriver föräldrarnas försök att uppnå ett meningsfullt liv igen, vikten av att finnas där för sina barn och föräldrarnas strategier att hantera känslor och återfå kontroll igen. Slutsats: Sjuksköterskor behöver se till hela familjens behov och finnas där som stöd. Föräldrar kan inte bearbeta sina känslor förrän barnets behandling visar framsteg. I takt med att föräldrar börjar konfrontera verkligheten och tro på att barnet kommer bli friskt, hjälper det familjen att sträva efter en ny mening med livet. Klinisk betydelse: Att ge sjuksköterskor insikt om hur komplext det kan vara att bemöta föräldrar till barn som har drabbats av cancer. Att öka förståelsen för föräldrars upplevelser i de olika faserna av behandlingen kan bidra till att sjuksköterskor kan ge ett individanpassat stöd. / Background: Cancer affects about 250-300 children each year. Parents have got an even more important role in nursing care of their child at hospital. According to prior research parents experiences of care has been dependent on nurses‟ treatment, their interest and availability. Family focused care focuses on the whole family and their needs. Aim: To illuminate parents‟ experiences of having a child that is affected by cancer. Method: A literature study where ten studies were reviewed whereof one was a mixed method study. Results: Two themes with six subcategories represent the results. The first theme describes how parents‟ get affected the first period during their child‟s cancer and concerns feelings, information and powerlessness regarding the treatment. The second theme describes the parents‟ attempt to accomplish a meaningful life again, the importance of being there for their children and the parent‟s strategies to handle feelings and regain control again. Conclusion: Nurses have to ensure the whole family‟s needs and to be there as support. Parents can‟t process their own feelings until the treatment of their child shows progress. As the parents start to confront the reality and believe that their child will be cured, it helps the family to strive after a new meaning with life. Clinical implications: To give nurses an insight of how complex it can be to encounter parents‟ of children who is affected by cancer. To increase the understanding for parents‟ experiences in the different phases of the treatment can contribute so nurses can give an individualized support.

Breast cancer affects over three million women in the United States, but this disease burden is not shared equally across all races. Black women, in particular, are diagnosed with more advanced cancer at a younger age and experience a disproportionately high mortality rate compared to white women. Factors that contribute to such disparity include socioeconomic status, tumor biology, age, insurance status, comorbidities, obesity, patients’ reproductive history and barriers to quality care. These factors alone, however, do not account for all the racial differences in mortality and outcomes experienced by black women. There is a growing body of literature that indicates black women are not receiving the same treatment and care as white women. Black women are less likely to receive surgery, radiation therapy, hormone therapy and targeted therapy than white women. Black women are also more likely to experience delays in the initiation of treatment, early discontinuation of treatment and overall guideline non-concordant care. The current literature has presented widespread racial disparities in the treatment of black women with breast cancer. Future research needs to focus on tangible interventions such as physician bias training and patient navigators to mitigate the inequity of care in the treatment of breast cancer.

March 2011. "Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Occupational Therapy Department, College of Allied Health and Nursing, Nova Southeastern University." This phenomenological study was designed to understand the lived experience of adolescents being treating for cancer and the impact of their lived experience on engagement in occupations and social participation. Participants in this study included four young adolescents 17-19 years of ages attending school on a part-time basis. They were on active treatment protocols for cancer and enjoyed participating in sports or other activities with friends. In-depth structured interviews with questions to illuminate the impact of cancer treatment on social participation were completed and audio recorded. Data analysis was completed utilizing a phenomenological reduction method to determine emerging themes and significant statements. A description of the experience and its meaning were then developed from themes emerging from the perspective of the participants. The four major themes and sub themes resulting from this study were: 1. Change of Lifestyle a) Physical & Emotional Pain of Living b) School Re-entry--A Saving Grace; 2. Exploring New Occupations a) Adapting Occupations b) Awakening or Confirming Beliefs; 3. Reconnecting with Family a) Importance of Support b) A Kid Again. 4. Living with Cancer Isn't Easy a) Isolation b) Hidden Disability. The findings revealed lifestyle changes, which these adolescents needed to deal with in order to maintain a sense of routine and engagement in occupation. Changes in appearance, physical strength, and overall endurance impacted the participants' ability to engage in occupation(s) which often led to isolation among their peers. In spite of this, participants discovered new occupations that were less physically demanding but still fostered social participation with peers. The study of social participation for adolescents with cancer has implications for and can assist in developing client-centered interventions and simultaneously increase occupational therapy's understanding of these individuals during a transitional period of their lives.