Differences in self-reported depression, anxiety, self-esteem, and coping were evaluated in two groups of pediatric oncology patients: newly diagnosed (less than six months post-diagnosis) (n=5) and patients on cancer treatment for seven months or longer (n=5). Participants (6 males, 4 females, ages 7-17 years) completed the Children's Depression Inventory (CDI), the State-Trait Anxiety Inventory for Children (STAIC), and the Culture-Free Self-Esteem Inventory (CFSEI-2); nine of the ten participants discussed in a semi-structured interview their personal experiences and feelings about having cancer. Although the newly diagnosed group had a higher mean score on the CDI than the 7 months or greater group, the difference was not significant (p = .054). The newly diagnosed group also had higher mean state and trait anxiety scores on the STAIC, indicating higher anxiety levels, and a slightly lower CFSEI-2 mean score, indicating slightly lower self-esteem than the 7 months or greater group, but differences were not at a statistically significant level (p>.05).

Cancer is a generic term for a large group of diseases where cells of the body lose their normal mechanisms for growth so that they grow in an uncontrolled way. One of the most common treatments of cancer is chemotherapy that aims to kill abnormal proliferating cells; however normal cells and other organs of the patients are also adversely affected. In practice, it's often difficult to maintain optimum chemotherapy doses that can maximise the abnormal cell killing as well as reducing side effects. The most chemotherapy drugs used in cancer treatment are toxic agents and usually have narrow therapeutic indices, dose levels in which these drugs significantly kill the cancerous cells are close to the levels which sometime cause harmful toxic side effects. To make the chemotherapeutic treatment effective, optimum drug scheduling is required to balance between the beneficial and toxic side effects of the cancer drugs. Conventional clinical methods very often fail to find drug doses that balance between these two due to their inherent conflicting nature. In this investigation, mathematical models for cancer chemotherapy are used to predict the number of tumour cells and control the tumour growth during treatment. A feedback control method is used so as to maintain certain level of drug concentrations at the tumour sites. Multi-objective Genetic Algorithm (MOGA) is then employed to find suitable solutions where drug resistances and drug concentrations are incorporated with cancer cell killing and toxic effects as design objectives. Several constraints and specific goal values were set for different design objectives in the optimisation process and a wide range of acceptable solutions were obtained trading off among different conflicting objectives. Abstract v In order to develop a multi-objective optimal control model, this study used proportional, integral and derivative (PID) and I-PD (modified PID with Integrator used as series) controllers based on Martin's growth model for optimum drug concentration to treat cancer. To the best of our knowledge, this is the first PID/I-PD based optimal chemotherapy control model used to investigate the cancer treatment. It has been observed that some solutions can reduce the cancer cells up to nearly 100% with much lower side effects and drug resistance during the whole period of treatment. The proposed strategy has been extended for more drugs and more design constraints and objectives.

Doctor of Philosophy / Department of Chemistry / Stefan H. Bossmann / Cancer is one of the leading causes of death in the world. Billions of dollars are spent to treat cancer every year. This clearly shows the need for developing improved treatment techniques that are affordable to every person. Early diagnosis and imaging of tumors is equally important for the battle against this disease. This dissertation will discuss new approaches for discovering and developing novel detection and treatment techniques for cancer using organic ligands, and Fe/Fe3O4 core/shell magnetic nanoparticles. A series of o-phenylenediamine derivatives with nitro-, methyl- and chloro- substituents were synthesized and studied their ability to act as anticancer agents by using steady-state, UV/Vis-, and fluorescence spectroscopy. In the absence of zinc(II), intercalation with DNA is the most probable mode of interaction. Upon addition of zinc(II), DNA-surface binding of the supramolecular aggregates was observed. The interaction of the supramolecular (-ligand-Zn2+-)n aggregates with MDA 231 breast cancer cells led to significant cell death in the presence of UVA at λ=313 nm displaying their potential as anticancer agents. Bimagnetic Fe/Fe3O4 core/shell nanoparticles (MNPs) were designed for cancer targeting after intratumoral or intravenous administration. Their inorganic center was protected by dopamine-oligoethylene glycol ligands. TCPP (4-tetracarboxyphenyl porphyrin), a fluorescent dye, was attached to the dopamine-oligoethylene glycol ligands. These modified nanoparticles have the ability to selectively accumulate within the cancerous cells. They are suitable candidates for local hyperthermia treatment. We have observed a temperature increase of 11 ºC in live mice when subcutaneously injecting the MNPs at the cancer site and applying an alternating magnetic field The system is also suitable for Magnetic Resonance Imaging (MRI), which is a diagnostic tool to obtain images of the tumors. Our superparamagnetic iron oxide nanoparticles have the ability to function as T1 weighted imaging agents or positive contrasting agents. We were able to image tumors in mice using MRI. Various proteases are over-expressed by numerous cancer cell lines and, therefore, of diagnostic value. Our diagnostic nanoplatforms, designed for the measurement of protease activities in various body fluids (blood, saliva, and urine), comprise Fe/Fe3O4 core/shell nanoparticles featuring consensus sequences, which are specific for the target protease. Linked to the consensus sequence is a fluorescent organic dye (e.g. TCPP). Cleavage of the sequence by the target protease can be detected as a significant increase in fluorescence occurring from TCPP. We were able to correlate our diagnostic results with cancer prognosis.

Ph.D. / Chapter 1 presents a brief overview on the development of platinum, ruthenium and gold anti-cancer complexes. The clinical success of cisplatin has been a tremendous impetus for the design of metal-based antitumor drugs. Its mechanism of action is therefore briefly discussed, as well as the toxic side effects of its clinical use and the cellular resistance to the drug. It is its side effects and drug resistance that have stimulated the development of cisplatin analogues and other metal based anti-cancer agents. Compounds showing most promise are ruthenium complexes which are structurally different but have the same stability and show similar modes of binding to DNA. The last part of the introduction deals with the development of gold(I) and gold(III) complexes, the main topics of the research described in this thesis. Chapter 2 reports on the attempted preparation of dppf and dippf gold(III) complexes. However, the reaction of these diphosphines with H[AuCl4] and Na[AuCl4] all led to isolation of gold(I) complexes (dppf)Au2X2 (X = Cl (1), Br (3)) and (dippf)Au2X2 (X = Cl (2), Br (4)). In an attempt to oxidize the gold(I) complexes, (dppf)Au2Br2 (3) and (dippf)Au2Br2 (4) were reacted with excess bromine yielding two new complexes (C5H4Br3)(PR2)AuBr (R = Ph, 5; R = i-Pr, 6). This bromination reaction could be extended to the ligands and bromination of the free diphosphinoferrocene ligands produced the expected brominated cyclopentenes (C5H4Br3)(PR2) (R = Ph, 7; R = i-Pr, 8) in good yields. However, these could not be complexed to gold due to reduced basicity of 7 and 8. When the bromination was performed under wet aerobic conditions the oxidized pseudo-centrosymmetric product, [doppf][FeBr4] (9) {doppf = 1,1’-bis(oxodiphenylphosphino)ferrocene, was obtained as the major product. Solid-state structures of 1, 2, 4, 6, and 9 were established by means of single-crystal X-ray crystallography. Chapter 3 reports on the use of chiral Josiphos and Walphos diphosphine ligands to form palladium, platinum and gold complexes. The platinum complexes were prepared by reacting the ligands with [PtCl2(cod)] while the palladium complexes were prepared from [PdCl2(NCMe)2]. The complexes obtained had the general formula [MCl2(P-P)], where M = Pd, Pt, and P-P = Josiphos or Walphos ligand, and were obtained in good yields. The X-ray structures of a palladium(II) and a platinum(II) complex of the same Josiphos ligand were determined. The Josiphos complexes 12 and 14 show good solubility in common solvents. Furthermore, the complexes remained soluble and stable in a 40:60 water:DMSO mixture. The Walphos complexes 13 and 15 rapidly precipitated under the same conditions. In line with this limited solubility 13 and 15 showed minimal cytotoxic effects when compared to their Josiphos counterparts 12 and 14 whose cytotoxic effects (in terms of IC50 values ) were six to seven times less than cisplatin. Reaction of the Walphos ligand and H[AuCl4] in a 1:1 ratio gave a dinuclear gold(I) complex 18 while the same reaction with Josiphos gave a mixture of intractable materials. However a 1:1 reaction of the Josiphos with AuCl(tht) gave a mononuclear three-coordinate gold(I) complex 16. A P^N chiral ligand comprising of a diphenylphosphine and a pyrazole moiety was also prepared and was complexed with AuCl(tht) to give a phosphine bound gold(I) complex 19. The structure of this complex was determined by X-ray studies. From the studies it became evident that apart from increasing the basicity of compound the pyrazolyl moiety remains dangling and the complex shows bond parameters similar to those observed with monophosphine ferrocenyl complexes. Chapter 4 reports on the bidentate and monodentate gold(III) complexes based on the (pyrazolylmethyl)pyridine ligands together with their platinum(II) complexes. The denticity of the complexes depended on the position of the pyrazolyl moiety relative to the pyridine nitrogen. When ortho-substituted ligands were reacted in a 1:1 ratio with H[AuCl4] in a mixture of water and ethanol at room temperature, bidentate cationic complexes of the general formula [AuCl2(PyCH2R2pz)][X], where R = Me (20), X = AuCl4-; R = Ph (21), X = Cl-; t-Bu (22), X= Cl- and p-tol (23), X = AuCl4-, were obtained. When para-substituted ligands were used under same reaction conditions, neutral monodentate complexes [AuCl3(PyCH2R2pz)], where R = Me (24) and R = Ph (25), were obtained. Platinum(II) complexes were obtained using K2[PtCl4] in a mixture of water and ethanol under reflux, and affords neutral complexes of the type [PtCl2(PyCH2R2pz)], where R = Me (27), Ph (28), t-Bu (29) and p-tol (30). When acetone was used instead of ethanol monoacetonylplatinum(II) complex (29a) was formed and on prolonged heating formation of the diacetonyl complex (28b) was observed. Both the platinum and the gold complexes were evaluated for their anti-cancer potency. The gold(III) complexes were devoid of any activity while the platinum complex 30 showed activity 8 times lower than cisplatin. The structures of 23, 25, 28, 29 and 29a were determined from single-crystal X-ray diffraction studies. In Chapter 5, tridentate complexes based on bis(pyrazolylethyl)amine are reported. These were prepared with the aim of improving water-solubility and cytotoxicity of the resulting complexes. New synthetic methods for preparation of the ligands NH(CH2CH2pz)2 (R = Me (L7), H (L8), t-Bu (L9)) under mild reaction conditions were developed albeit the yields obtained were generally low. The reaction of these ligands with H[AuCl4] gave corresponding tridentate dicationic gold(III) complexes [NH(CH2CH2pz)2][X]2 (R = Me (31), H (32), X = AuCl4 , and R = t-Bu (33), X = Cl-). Despite the ligands stabilizing the gold(III) ion, they showed no solubility in water. In an attempt to make the ligand system water soluble, a thiocarbamate analogue with pyrazolyl groups replaced by hydroxyl groups was prepared. However the resulting gold(III) complex [Au{CS2N(CH2CH2OH)2}2][AuCl2] (34) was found to be only soluble in DMSO.

RNA-Sequencing (RNA-Seq) has become one of the most widely used techniques to interrogate the transcriptome of an organism since the advent of next generation sequencing technologies [1]. A plethora of tools have been developed to analyze and visualize the transcriptome data from RNA-Seq experiments, solving the problem of mapping reads back to the host organism's genome [2] [3]. This allows for analysis of most reads produced by the experiments, but these tools typically discard reads that do not match well with the reference genome. This additional information could reveal important insight into the experiment and possible contributing factors to the condition under consideration. We introduce PARSES, a pipeline constructed from existing sequence analysis tools, which allows the user to interrogate RNA-Sequencing experiments for possible biological contamination or the presence of exogenous sequences that may shed light on other factors influencing an organism's condition.

M.Sc. / Heat shock (HS) proteins and HS transcription factors (HSFs) have been coined as the ‘Achilles Heel’ for cancer therapy, since they have been found to be overexpressed in cancer cells and are required for cell survival during tumour progression and metastasis. Hsp70 and other members of the Hsp family have been shown to inhibit apoptosis at several different stages, contributing to resistance to chemotherapy. NSAIDs, like salicylates and aspirin, are used for the treatment and prevention of cancers such as breast cancer. SA has been shown to enhance HSF-DNA binding and results in the increased expression of heat-induced Hsp70 which is antiapoptotic. We hypothesise that SA treatment can result in the potentiation of Hsp70 in MCF-7 cells further increasing their resistance to apoptosis and thus the aim of this study was to investigate the dose-responsive effects of salicylic acid (SA) in the presence and absence of heat shock on components of the pro and antiapoptotic components of the apoptotic pathway. MCF-7 cells, which naturally overexpress Hsp70, were treated with several doses of SA in the presence and absence of a mild heat shock, followed by analysis of Hsp70 and several pro and antiapoptotic members of intrinsic and extrinsic apoptotic pathways, including Bcl-2, Bax, caspase 6 and 8, JNK, AIF and APAF-1. Induced Hsp70 accumulation by the SA treatments in the presence and absence of heat shock enhanced apoptosis in cells exposed to SA whereas higher concentrations of SA combination with heat shock induced necrosis and a decrease in Hsp70 accumulation in MCF-7 cells. Identification of the effects which specific concentrations of SA in the presence and absence of heat shock had on the apoptotic pathway constituents helped highlight potential pathways by which cell death could occur in MCF-7 cells through the downregulation of Hsp70. It is most likely that MCF-7 cell death is occurring due to the release of reactive oxygen species (ROS) which in turn lead to necrosis or death may be achieved via a cathepsin-B-mediated cell death pathway where both of these possibilities need to be further investigated.

This dissertation presents an ethnographic account of a socially diverse, public breast cancer clinic in Johannesburg. The findings of this qualitative research radically challenge the unproblematised and overdetermined use of the categories of race and gender in existing literature concerning this disease. The growing breast cancer epidemic in South Africa affects all demographic categories of women including young women. Yet, previous research frames this as a racialised and gendered crisis. Black women have been depicted as ignorant “problem patients” who resist biomedical treatment, and all women are described as having a particular relationship to their breasted bodies and a deep fear of mastectomy. Departing from these stereotypes, this ethnography reveals unanticipated data showing, firstly, that race, class, age and level of education did not determine women’s relationship to breast cancer and biomedicine. Secondly, socially diverse women commonly experienced breast cancer as a life-threatening disease that evoked confrontation with existential concerns regarding suffering, death, family, and faith. Due to these commonalities, an intimate and powerful sociality existed amongst women at this clinic. Thirdly, within this sociality, women accepted mastectomy as a necessity in creating a healthy body. Breastlessness was normalised and women generally were reluctant of breast reconstruction, thus destabilising the conceptual relationship between breasts and gender. This dissertation’s deconstruction of the use of hegemonic social categories is a significant intervention in a context where these categories are often viewed as absolute determinants of social and health phenomena, and therefore prompts more nuanced approaches to understanding experiences of illness in post-apartheid South Africa.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of requirements for the degree of Master of Science. Johannesburg 2015. / Ovarian cancer is the most lethal gynaecological cancer. About 90% of ovarian cancers are epithelial (ovarian carcinomas), thought to arise from the ovarian surface epithelium. Diagnosed usually at clinically advanced stages, many patients show poor response to chemotherapy, with resistance and recurrent disease being prevalent. siRNA technology is currently being explored in clinical trials as a form of targeted therapeutic strategy in the disease. RBBP6 is a 250kD protein that enhances MDM2-mediated ubiquitination of p53 and also plays a role in cell cycle regulation and cell differentiation. It is upregulated in numerous cancers such as lung, oesophageal, colorectal and cervical cancer. RBBP6 suppresses p53 binding to DNA thereby inhibiting p53-dependent gene transcription. RBBP6 was knocked down using 30 nM siRNA in RMG-1 cells for 48 hours, after which the cells were treated with 50 nM paclitaxel and 0.5μM camptothecin for 24 hours. xCELLigence real time cell analysis was used to evaluate cell proliferation. qPCR and western blot were used to evaluate both gene expression and protein expressions respectively, of Bax, Bcl-2, MDM2, p53 and p21. Flow cytometry was used to determine the mode of cell death elicited apoptosis and also analyse changes in cell cycle progression. qPCR and Western blot analyses showed that RBBP6 expression reduced by approximately 57%. There was a significant upregulation of p53 and a significant downregulation of Bcl-2 in siRBBP6 transfected cells (p<0.05). Knockdown of RBBP6 resulted in a 37±5.8% cell death. There was a significant increase in cell death in paclitaxel and siRBBP6 co-treated cells (81.6±0.79%) as compared to cells treated with paclitaxel only (76.±1.14%). siRNA-mediated knock down of RBBP6 induces cell death in RMG-1 ovarian carcinoma cells. In addition, paclitaxel-induced cell death in RMG-1 cells is potentiated by RBBP6 siRNA transfection. A combination of chemotherapy with paclitaxel or camptothecin and RBBP6 siRNA could be a possible therapeutic strategy in combatting ovarian carcinomas.

Studies have shown that tumor cells are susceptible to pharmacological targeting of their altered glycolytic metabolism with a variety of compounds that result in apoptosis. One such compound, 3-bromopyruvate (3-BP), has been shown to eradicate cancer in an animal model. However, no studies have shown whether the apoptotic fragments resulting from 3-BP treatment have the capacity to elicit an immunogenic cell death that activates dendritic cells, the primary antigen presenting cell in the immune system. Immunogenic cell death is critical to eliciting an effective adaptive immune response that selectively kills additional target cells and generates immunological memory. We demonstrated that 3-bromopyruvate induced apoptosis in a number of different murine breast cancer cell lines, including the highly metastatic 4T1 line. The dying tumor cells stimulated immature dendritic cells (DCs) of the immortal JAWS II cell line to produce high levels of the pro-inflammatory cytokine IL-12, and increased their expression of key co-stimulatory molecules CD80 and CD86. The activated dendritic cells showed increased uptake of fragments from dying tumor cells that correlated with the increased levels of calreticulin on the surface and release of high group motility box 1 (HMGB1) of the latter following 3-BP treatment. Additionally, the anti-phagocytic signal CD47 present on breast cancer cells was reduced by treatment with 3-bromopyruvate when compared to the levels on untreated 4T1 cells. 3-BP treated breast cancer cells were able to activate dendritic cells through TLR4 signaling. Signaling was dependent on both the expression of surface calreticulin and on the extracellular release of high mobility group box 1 protein (HMGB1) during the process of immunogenic cell death. Killing by 3-BP was compared to mitoxantrone and doxorubicin, among the few chemotherapeutics that induce immunogenic cell death. 3-BP killing was likewise compared to camptothecin, a compound that fails to induce immunogenic cell death. Importantly, 3-BP did not markedly decrease the levels of the key peptide presenting molecule MHC I on DCs that were co-cultivated with dying tumor cells. Treatment of the highly aggressive triple negative BT-20 human breast cancer cell line with 3-BP also induced an immunogenic cell death, activating human dendritic cells in vitro. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection

Extracellular stimuli may influence the M1/M2 phenotypic polarization of macrophages. We examined M1/M2 biomarkers, phagocytic activity, and tumoricidal activity in RAW 264.7 mouse macrophages. Macrophages were treated with conditioned media (CM) from 4T1 breast cancer cells, curcumin, 22-oxacalcitriol, LPS, or a combination of the previously listed. Arginase activity, a M2 phenotypic biomarker, was upregulated by the treatment of macrophages with conditioned media. Curcumin, 22- oxacalcitriol, and LPS partially inhibited RAW 264.7 arginase activity in the presence of 4T1 breast cancer media. 22-oxacalcitriol increased the phagocytic ability of RAW 264.7 macrophages in the presence of M2 polarizing substances produced by the 4T1 breast cancer cells. Also, LPS increased RAW 264.7 phagocytic ability in the presence of 4T1 breast cancer CM. This study looked at the potential substances that would possibly reverse the M2 tumor promoting macrophage phenotype seen in the breast cancer tumor environment. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection