Studying the origins of primary tumours and residual disease in breast cancer

Breast cancer is the leading cause of death in women worldwide and these deaths are mostly attributed to metastasis and tumour recurrence following initially successful therapy. Metastasis refers to the development of invasive disease, wherein malignant cells dissociate from primary tumours, infiltrating other organs and tissues to give rise to secondary outgrowths. Previously, metastasis was thought to be initiated in advanced tumours, but breast cancer cellsh with metastatic potential have now been shown to disseminate very early from the primary site via largely unknown mechanisms. These early interactions of tumour cells with their cellular micro-environment and normal neighbours also results in early tumour cell heterogeneity and must therefore be elucidated such that we can prevent metastatic spread in the patient situation and better treat the resulting heterogenous tumours. However, studying tumour initiation is not possible in patients because it happens on a cellular level not detectable by current technology. Tumour recurrence is another major cause of breast cancer related death and is believed to be caused by residual disease cells that survive initial therapy. These are a reservoir of refractory cells that can lay dormant for many years (sometimes decades) before resulting in relapse tumours. They are also difficult to obtain from human patients, since they are very few and cannot be detected easily, and thus their molecular mechanisms have not been fully explored. In addition to the unavailability of human tissue, mouse models of breast cancer also fall short in helping us study early cancer initiation, because they allow oncogenic expression in all cells of the tissue instead of initiating cancer like in the human situation|one neoplastic transformed cell proliferating unchecked in a normal epithelium. To address this issue, we used primary organoids from an inducible mouse model of breast cancer and lentivirally transduced single cells within these organoids to express oncogenes. We further optimized parameters for long term imaging using light sheet microscopy and developed big data analysis pipelines that lead us to discern that single transformed cells had a lower chance at establishing tumorigenic foci, when compared to clusters of cells. Thus, we postulate a proximity-controlled signalling that is imperative to tumour initiation within epithelial tissues using the first ever in vitro stochastic breast tumorigenesis model system. This new stochastic tumorigenesis system can be further used to identify the molecular interactions in the early breast cancer cells. Our group has already revealed distinct characteristics, such as dysregulated lipid metabolism, of the residual disease correlate obtained from an inducible mouse model. As survival mechanisms invoked by residual cells remain largely unknown, we analysed the dynamic transcriptome of regressing tumours at important timepoints during the establishment of residual disease. Key molecular players upregulated during regression {like c-Jun and BCL6 { were identified and the inflammatory arm of the Nf-kB cascade was found to be dysregulated among others. Further validation of these molecular targets as potentially synthetic lethal interactors remains to be performed so that they can be used to limit the residual disease reservoir and eventually tumour recurrence

A randomised controlled trial evaluating the use of polyglactin mesh, polydioxanone and polyglactin sutures for pelvic organ prolapse surgery

To compare the effectiveness of polyglactin mesh, and polydioxanone or polyglactin sutures in women having pelvic organ prolapse surgery. Randomised controlled trial with a factorial 2(2 design of polyglactin mesh or not, and polydioxanone or polyglactin suture. Outcomes were assessed using questionnaires at baseline and on the third day and at 6 months after surgery. Women were also examined clinically 3 months after surgery. The primary outcome was the subjective improvement in prolapse symptoms and quality of life scores from baseline to 6 months. There was a subjective improvement in the prolapse symptom score from baseline to 6 months after surgery (mean difference of 9.2 (95% CI for difference 7.2-11.2, p < 0.001) and an improvement in the mean quality of life score over the same period with a reduction of 3.4 (95% CI for difference 2.4-4.3, p < 0.001). However, there were no significant differences in the mean difference in prolapse symptoms and quality of life (QoL) scores according to the randomised groups. The majority (86%) of women were satisfied with their surgery. Our study demonstrated that at short-term follow-up, there was no significant difference in the mean differences in prolapse symptoms and QoL scores after surgery using polyglactin mesh or not, polyglactin or polyglactin sutures, but the numbers were too small for a definitive conclusion. Longer-term follow-up and/or a larger trial are required

Oxide Memristive Devices

Resistive switching in metal oxide materials has recently renewed the interest of many researchers due to the many application in non-volatile memory and neuromorphic computing. A memristor or a memristive device in general, is a device behaving as nonlinear resistor with memory which depends on the amount of charges that passes through it. A novel idea of combining the physical resistive switching phenomenon and the circuit-theoretic formalism of memristors was proposed in 2008. The physical mechanism on how resistive switching occurs is still under debate. A physical understanding of the switching phenomenon is of much importance in order to tailor specific properties for memory applications. To investigate the resistive switching in oxide materials, memristive devices were fabricated starting from materials processing: low-pressure chemical vapor deposition of ZnO nanowires (NWs), low-temperature atomic layer deposition (ALD) of TiO2 thin films and micro-pulse ALD of Fe2O3 thin films. The distinct geometry of ZnO NWs makes it possible to investigate the effect of the electrode material, surface states and compliance to the memristive properties. A simpler method of fabricating TiO2-based devices was explored using low-temperature atomic layer deposition. This approach is very promising for device application using photoresist and polymeric substrates without thermal degradation during and after device fabrication. ALD of pure phase Fe2O3 thin films was demonstrated using cyclic micro-pulses. Based on the performance of the fabricated devices, the oxide materials under this study have promising properties for the next-generation memory devices

Social dysfunction in chronic schizophrenia: nature, treatment and generalization

The present research explores the impact of neurocognitive status on generalization of social skills training and how these difficulties are further compounded by the difficulty of inadequate matching of problems to treatments. The generalization problem is addressed in two phases. In the first phase, a suggestion that a subgroup of chronic schizophrenia patients may have normal abstract problem solving was investigated by comparing paranoid and non-paranoid chronic schizophrenic in-patients (n= 11 per group) with assessed social dysfunction. Only the paranoid group had profiles comparable to matched normal controls. The non-paranoid group had neuropsychological deficits (executive dysfunction) on the Wisconsin Card Sorting Test (WCST).In the second phase, a longitudinal study compared the differential efficacy of behavioural versus cognitive-behavioural social skills training (SST), and monitored the effects on maintenance and generalization, focusing on social anxiety. Concurrently, the treatment validity of a multidimensional assessment of social problem solving was assessed using an alternating treatments design with a multiple baseline across participants from three groups: skill deficits (n=3), cognitive blocks (n=3) and a control group (n=3) with both problems. All participants received four randomized sessions each of Behavioural SST and Cognitive-Behavioural SST. The group SST used a 'whisper in the ear' game format and included self-instructional training and social problem solving to facilitate generalization. The findings demonstrated the treatment validity of the multidimensional assessment and offered preliminary evidence for the differential efficacy, maintenance and generalization of Behavioural and Cognitive-Behavioural SST which occurred for untrained behaviours and was maintained at the 3- and 9-month follow-ups but only for those not impaired on the WCST.It is concluded that it is more productive for assessmentto focus on social anxiety and the practice of mixing schizophrenia patients in SST, without taking a neurocogitive baseline, may be responsible for confounding generalization efforts. A limitation of the research is that gender differences were not testable as there were insufficient numbers

The joint impact of brand value and advertising on corporate financial performance and on stock return: A case study of the computer industry

Firm\u27s advertising and marketing expenditures do not always translate to measurable financial returns. Understanding brand value appropriation and financial consequences of advertising is important for more focused investments in branding and marketing. This quantitative study sought to understand the joint effects of advertising expenditure and brand value (BV) on firms return on assets (ROA) and on stock return (SR) in the computer industry. The theoretical framework of the study was the resource-based view theory that proposes that the intangible assets of a corporation have a direct relationship to its ability to sustain its competitive advantage. The key research question involved the joint and positive effect of a firm\u27s advertising expenditure and brand value on return on assets and on stock return. The research design was a non randomized cross sectional study. The data consisted of advertising expenditures and brand value of 17 firms listed on the Interbrand annual global brand list from 2000 to 2007, ROA and SR extracted from each firms 10K and Morningstar financial report. The study used panel data modeling and time series of cross section analysis. Results showed positive correlation between ROA and BV, and between AER and BV. The association between brand value and ROA, even after accounting for the effect of advertising expenditure and the interaction effect between brand value and advertising expenditure, was statistically significant. Further research is needed to confirm the findings. Effective marketing increases firms\u27 profitability. Profitable firms contribute more to causes that drive social changes in the areas of education, healthcare and food sustainability

56 Days of Solitude

Man is a social animal. He needs community for support and for the success of his life. Yet, throughout history, man has withdrawn from community to retreat into the wilderness. The journey takes him from the world, into solitude, and then back to the world again with the fruits of his experience. This thesis participates in the tradition of solitude. It begins nearly five years ago with a sketch in a notebook of a trailer in the forest. Below the drawing, a question from Henry David Thoreau’s Walden: “What sort of space is that which separates a man from his fellows and makes him solitary?”[1] Over the next three-and-a-half years, the idea for solitude is cultivated and develops before I transform a 1970’s Grand Air Travel Trailer into my own solitary space. Then, on May 24, 2015, with the trailer as my shelter, I withdrew to the shores of the Spanish River in Northern Ontario, learning solitude for fifty-six days. When I returned from my retreat, for the next four months, I lived out of the trailer in the driveway of my childhood home, producing this book by assembling entries and illustrations from various journals and notebooks I kept during my isolation. The final leg of my journey struggles to find answers in my retreat, and to Thoreau’s questions. In solitude, the relationship between man and his space is the mechanism which separates him from the world, and at the same time, the stage on which the drama of his self-discovery is played out.This thesis explores architecture as the backdrop of solitude, and my relationship to the vessel that makes me solitary

Importance of Phenotype-Genotype correlation for Next Generation Sequencing Data to diagnose Pediatric Neurological Disorders

Background:Pediatric neurological disorders can be mainly categorized into four areas such as movement disorders, epilepsy associated disorders, neuro-peripheral disorders and neuropsychiatric disorders. They can be identified from in-utero to 18 years. The interpretation of sequencing results based on phenotype-genotype correlation are important for the clinicians, patients and the family for further treatment and&nbsp; management.Materials &amp; Methods: Sixteen patients were referred to the department of Genetics of a tertiary care hospital for post-test counselling along with clinical exome reports. In cases where there was no reported variants, reanalysis of raw data was performed using a freeware by Illumina. Variants identified were assessed for genotype-phenotype correlations and evaluated by segregation analysis wherever required to arrive at a molecular diagnosis.Results:Six patients had a report with a pathogenic sequence variant correlating with the phenotype,&nbsp;&nbsp; four patients were reported with a Variant of Unknown Significance, while the sequence data of remaining six patients was reanalyzed to establish diagnosis.Conclusion:Results indicate the important role that a genetic counselor plays in establishing the genotype-phenotype correlation and providing appropriate post-test genetic counselling to help pediatric neurologists to manage patients and assist patients to take informed reproductive/predictive/pre-natal decisions. Keywords: neurological,patients,genetics,hospita

Properties of Mortar Incorporating Spent Garnet as Fine Aggregates Replacement

The rapid growth in the construction industry has increase in the consumption of fine aggregates whereby it depletes the natural resources. Also, garnet is a materials that can be reused for several times in the ship cleaning process. However, when this garnet can no longer be used, it is then are disposed in landfill, oceans and rivers, thus increase the volume of landfill waste and causing environmental problems. Therefore this research is aimed to study the effect of spent garnet as a fine aggregates replacement in terms of physical, fresh and hardened properties of mortar. In this study, several specimens are prepared by using different percentage of spent garnet range from 0%, 25%, 50%, 75% and 100% as a fine aggregates replacement in mortar. The specimens are casted using 50 mm x 50 mm x 50 mm mould and the materials used in preparing the mortar sample are cement, fine aggregates, water and spent garnet. The samples is then cured in the water before it is tested at the age of 7, 14, and 28 days. The characteristic of the materials and fresh and hardened properties of mortar were investigated. It was found that the workability of mortar increases with the increasing amount of spent garnet. Overall, it is found out that the spent garnet can be used as fine aggregates replacement in mortar up to 50% since it has a comparable strength (40 MPa at 28 days) with a conventional mortar with 16% improvement in water absorption test. In addition, the environmental impact can also be reduced through the use of spent abrasive waste by preserving the use of natural resources

Metabolic memory underlying minimal residual disease in breast cancer.

Funder: European Molecular Biology LaboratoryFunder: European Molecular Biology Laboratory (EMBL)Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer-related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi-omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small-molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence

Advertising in Medical Journals: Should Current Practices Change?

Fugh-Berman and colleagues surveyed medical journals' policies and practices on advertising. Pharmaceutical products, they say, dominate journals' advertising pages, creating conflicts of interests