Why does breast cancer receive so much more federal funding and fundraising efforts than other types of cancers, particularly lung cancer – the leading cause of cancer related deaths? This question is critical to public relations practitioners, in order to replicate or build on the success of breast cancer campaigns. This study was conducted in two parts. First, an Internet survey was distributed as a pilot study to examine public perceptions of cancer related issues. Next, depth interviews were conducted with 25 experts in the cancer field from across the nation. A comparison of pilot study results with actual statistics shows that breast cancer advocates are making a significant difference in people’s perceptions. Breast cancer advocacy campaigns are so pervasive, people don’t understand the significant numbers of other cancers that are diagnosed each year, as opposed to breast cancer. Interviews revealed that breast cancer awareness and funding have benefited from a perfect storm. According to interview participants, breast cancer advocacy may be attributed to: the feminist movement, the HIV/AIDS campaign, celebrity endorsers, and a passionate advocate named Nancy Brinker, who had just lost her sister, Susan G. Komen, to breast cancer. Screening and surgical technology also advanced at the right time, allowing breast cancer research funding and awareness to benefit from the perfect storm. It’s clear that Komen and other breast cancer advocates have made a huge impact on public perceptions of the disease and its research funding. Will other advocates be able to replicate it with the same degree of success, or will it take another perfect storm? / Department of Journalism

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The intestinal epithelium represents one of the most actively renewing tissues in the body, and is widely used as a model system to study epithelial cell biology. ASPP2, a member of the ASPP (apoptosis stimulating protein of p53) protein family, has been shown to act as a regulator of epithelial cell polarity and tumour suppressor. This study investigated whether the dual function of ASPP2 is involved in the regulation of intestinal homeostasis and tumourigenesis, with a particular interest in the distinction between epithelial cell autonomous and non-autonomous mechanisms. Germline and intestinal epithelial cell-specific ASPP2 conditional knockout mice were employed in this study. Deficiency of ASPP2 in the intestinal epithelium resulted in delayed recovery from dextran sulfate sodium (DSS)-induced acute colitis, concurrent with a reduction in the expression of proinflammatory cytokines such as interleukin (IL)-1β and IL-6. Moreover, ASPP2-deficient mice showed increased susceptibility to Azoxymethane/DSS-induced colorectal tumourigenesis. While wild-type and ASPP2-deficient crypts showed similar incidence of tumour formation, the local immune microenvironment of ASPP2-deficient mice favoured tumour progression. The intestinal organoid culture was established to supplement in vivo experiments. The feasibility of the system was demonstrated with small intestinal organoids, in the context of proliferation, differentiation, and cell death. Using the established workflow, a colonic organoid-based tissue regeneration model was developed. The intrinsic susceptibility of organoids to DSS-induced cell death was not affected by the loss of ASPP2. However, ASPP2-deficient colonic organoids were less responsive to the pro-proliferative effects of IL-6, but were more sensitive to tumour necrosis factor-α-induced cell death in the presence of IL-22. In conclusion, this project undertook parallel examinations of animal models and organoids, demonstrating that a deficiency of ASPP2 in the intestinal epithelium results in dysregulated epithelial-immune cell interactions. This may partially explain the pathological conditions observed in ASPP2-deficient mice. Importantly, this study highlights the possibility of using organoids to investigate epithelial cell non-autonomous factors implicated in intestinal pathogenesis.

Somatic mutations are the main triggers that initiate the formation of cancer. Large sequencing data sets in recent years revealed a substantial number of mutational processes, many of which are poorly understood or of completely unknown aetiology. These mutational processes leave characteristic sequence patterns, often called "signatures", in the DNA. Characterisation of the mutational patterns observed in cancer patients with respect to different genomic features and processes can help to unravel the aetiology and mechanisms of mutagenesis. Here, we explored the effects of DNA modifications and DNA replication on mutagenesis. The most common mutation type, C>T mutations in a CpG context, is thought to result from spontaneous deamination of 5-methylcytosine (5mC), the major DNA modification. Much less is known about the mutational properties of the second most frequent modification, 5-hydroxymethylcytosine (5hmC). Integrating multiple genomic data sets, we demonstrate a twofold lower mutagenicity of 5hmC compared to 5mC, present across multiple tissues. Subsequently, we show how DNA modifications may modulate various mutational processes. In addition to spontaneous deamination of 5mC, our analysis suggests a key role of replication in CpG > TpG mutagenesis in patients deficient in post-replicative proofreading or repair, and possibly also in other cancer patients. Together with an analysis of mutation patterns observed in cancers exposed to UV light, tobacco smoke, or editing by APOBEC enzymes, the results show that the role of DNA modifications goes beyond the well-known spontaneous deamination of 5mC. Finally, we explored which of the known mutational processes might be modulated by DNA replication. We developed a novel method to quantify the magnitude of strand asymmetry of different mutational signatures in individual patients followed by evaluation of these exposures in early and late replicating regions. More than 75 % of mutational signatures exhibited a significant replication strand asymmetry or correlation with replication timing. The analysis gives new insights into mechanisms of mutagenicity in multiple signatures, particularly the so far enigmatic signature 17, where we suggest an involvement of oxidative damage in its aetiology. In conclusion, our results suggest that DNA replication or replication-associated DNA repair interacts with most mutagenic processes.

A description of two techniques used extensively in this study namely cell counting with a "cell counting plate" and argentation TLC for the separation of ω -6 -fatty acids is given. Zn supplementation into GM of two malignant (BL-6 and Hep- 350) and a non-malignant (LLC-MK) cell line/s resulted in an increased uptake of Zn by the cells and progressively suppressed proliferation of particularly the malignant cells. Zn chelation by EDTA suppressed in vitro proliferation of all 3 cell line, this effect being more pronounced in the malignant cells. A dietary Zn deficiency resulted in alopecia in mice and both a dietary Zn deficiency and Zn excess reduced growth of BL-6 tumours implanted subcutaneously in mice. Zn supplementation into GM progressively increased the uptake of [1-¹⁴C]-LA by BL-6 and LLC-MK cells but had a very slight though irregular effect on this parameter in the Hep- 350 cells. Zn supplementation also stimulated desaturase activity in the BL-6 cells. These results suggested that there are select cell lines whose Δ⁶-desaturase activity responds positively to Zn supplementation (e.g. the BL-6 cells). Delta-6-desaturase activity was also assayed in microsome preparations from different tissues. No enzyme activity was detected in the microsomes prepared from the BL-6 tumours. There was no significant effect with the addition of Zn or EDTA, on Δ⁶-desaturase activity of the regenerating liver microsomes. In the resting liver microsomes this enzyme activity was reduced only when EDTA and Zn were added together and when EDTA was added to the reaction medium as well as to the microsome preparations 2 hr before the enzyme activity assay was initiated. The results of these experiments suggested that the Δ⁶-desaturase enzyme in the microsome preparations may have had an adequate amount of Zn with further additions having no stimulatory effect on the enzyme. Two independent mechanisms of control of cell proliferation by low and high Zn are suggested to operate.

There is a growing attention in the synthesis of fructo-oligosaccharides (FOS) due to their excellent bio-functional and health-promoting properties. The current production processes are limited to chemical hydrolysis reactions of plant extracts, which are often associated with several drawbacks. In this study, fructosyltransferase (FTase) and polygalacturonase (PGase) activities, present in a commercial enzyme preparation (Pectinex® Ultra SP-L) sourced from Aspergillus aculeatus, have been separated and fully purified by anion-exchange and sizeexclusion chromatography. The FTase possesses fructosyl transfer activity for FOS synthesis and the PGase has pectin hydrolytic activity. Fructosyltransferase is a single-band protein with a molecular weight of 85 kDa, whereas PGase is a distinct protein of 40 kDa. The temperature and pH optima of FTase were 60 ºC and 6.0, with a half-life of 8 h; while that for PGase were 40 ºC and 6.0, respectively. FTase was slightly inhibited in the presence of Ni²⁺, Mg²⁺ and urea; but PGase was more susceptible to divalent ions such as Ca²⁺, Mg²⁺ and Mn²⁺. The kinetic parameters (Km and Vmax) of FTase for the hydrolysis of β-(2→1) linkages from sucrose were 752.3 mM and 120.5 μmol.min⁻¹.mL⁻¹, respectively; whereas the same parameters for pectin hydrolysis by PGase were 13.0 mg.mL⁻¹ and 263 μmol.min-1.mL⁻¹, respectively. The purified FTase was able to transfer fructosyl residues from sucrose, synthesizing the corresponding chains of FOS. PGase was relatively stable at 40 ºC (t½ > 3 h), depolymerizing the pectin backbone while releasing the inulins from within the chicory roots. Analysis of various mixtures of FOS by mass spectrometry, HPLC and ¹H-NMR was undertaken. Results indicated that MS with electrospray ionization and ¹H-NMR are capable of providing relative quantitative data of the FOS present in the mixtures. The pharmaceutical effects of various sc-FOS (0.5%, v/v) and SCFA (0.3%, v/v) on certain bacterial enzymes (β-glucuronidase, urease and β-glucosidase) associated with the formation of carcinogens were also studied. These enzyme activities were not directly influenced by the sc-FOS, but were found to be remarkably decreased by SCFA, pointing toward the prebiotic effect of FOS in intestinal microflora modulation.

Glioblastoma multiforme (Glioma) is an extremely aggressive tumor that arises from intrinsic glial cells in the central nervous system (CNS)5. It is the most common primary brain tumor in humans and has a typical survival time of 15-16 months5. Current treatments for gliomas include surgery, radiation, and treatment with temozolomide (TMZ). While these treatments tend to add 2-3 months to a patient’s survival, none have been capable of altering the course of the disease1. One of the shortcomings of novel therapeutics for glioma, is the inability to evaluate in real time how therapeutics are affecting the patient. There is also the problem of the blood brain barrier (BBB), which can be overcome by administering drugs through an intracranial catheter (delivered via CED). The primary obstacle that’s been observed in intracranial drug delivery is the inadequacy of the delivery. This inadequacy is an inability of the drug to diffuse homogenously throughout the tumor. CED also creates a possibility for toxicity due to highly concentrated volumes of drugs delivered; we believe the novel delivery method we are trying to develop, will make this possibility null. The purpose of this study was initially to demonstrate the problem of delivering drugs via diffusion while simultaneously collecting biomarkers to interpret efficacy of the drugs, due to differing molecular weights. The other objective of this study was to demonstrate that it is possible to manipulate both the direction of bulk flow and the rate of diffusion of drugs delivered through a catheter using a gel phantom as a representative of brain tissue. What we found is that by utilizing a two-catheter method with convection and retro-convection enhanced delivery, we could in fact manipulate these parameters and achieve a more even distribution of drug (represented by fluorophores in our experiments). Using these two catheter methods, we will also be able to collect fluids from the tumor to monitor the effect of any treatment in real time.

Groundwater contamination is a concern due to the large number of people that can become exposed to the contaminant. The chemicals benzene and phenol are known groundwater contaminants. The main health problem caused by benzene or phenol is bone marrow toxicity. Benzene and phenol are also immunotoxins reported to cause decreased thymic weights, altered lymphocyte mitogenic responses, and lower antibody production. Cytokines are key signaling molecules produced by the cells of the immune system to activate other cells in the immune system, produce antibodies, and recruit other cells to sites of inflammation. The purpose of this study was to determine if exposure to benzene or phenol in drinking water for 30 days could lead to alterations in IL-l, IL-6, and TNFa production in in vitro activated murine macrophages, or in IL-2, IL-3, and IFNy production in in vitro activated murine lymphocytes. Cytokine mRNA and protein production were evaluated to determine if any alteration occurred. Benzene and phenol exposure resulted in significantly decreased thymus weights. Interleukin-2 mRNA production was increased at the medium dose (200 mg/L) but the IL-2 protein secreted from the lymphocytes of benzene-treated mice was unchanged. The macrophages from benzene-treated mice showed a decrease at all dosage levels in both TNFa mRNA and protein production. These macrophages also produced increased JLIa mRNA at the medium benzene concentration, although this increase did not mean an increase of IL-Ia protein secreted. Mice given phenol at the medium (20 mg/L) and high (100 mg/L) dosages had decreased 30-day body weights. The production ofiL-3 mRNA was decreased in the lymphocytes of mice receiving both low and high concentrations of phenol. Lowered TNFa mRNA values were observed in the macrophages from phenoltreated mice. Interleukin-la mRNA production was increased in the macrophages of mice given the low (5 mg/L) dose of phenol. The TNFa cytokine protein was decreased at the low and medium doses, and the IL-l a protein level was decreased at the medium and high doses. The results indicate that benzene and phenol in groundwater should continue to be a concern for public and regulatory agencies.

Urologists, researchers and statisticians work with a centralized database in Stockholm containing more than two million prostate cancer patient records. In order to expedite the analytical process, an interactive visualization system was developed through the collaboration of Janssen and KTH. The usability of the system was measured in terms of efficiency and satisfaction. The efficiency of the system was evaluated by measuring task-time and the number of errors per task, and the satisfaction of the user was evaluated using well-established questionnaires. Through this usability evaluation, the system was evaluated as easy to use and understand. / Urologer, forskare och statistiker arbetar med en centraliserad databas i Stockholm som består av mer än två miljoner vårdjournaler för prostata cancer patienter. För att påskynda denna process har ett interaktivt visualiserings system utvecklats genom ett samarbete mellan Janssen och KTH. Användarvänligheten av system mättes genom hur effektivt och tillfredställande det var att använda. Effektiviteten av systemet utvärderades genom att mäta hur lång tid användarna tog på sig att utföra en uppgift, samt hur många misstag de begick medan de utförde uppgiften. Tillfredsställelsen och användarvänligheten av systemet utvärderades genom väl etablerade frågeformulär. Systemet evaluerades till lätt att använda och förstå.

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