Metastatic Breast Cancer: Biomolecular Characterization and Targeted Therapy

Metastasis is a complex process that remains a major challenge in the clinical management of cancer, because most cancer-related deaths are attributed to disseminated disease rather than the primary tumor. Despite the significant advances in the prediction of prognosis, and therapeutic management of primary breast cancers, coupled with the substantial improvement in our understanding of the molecular determinants of metastasis, breast cancer relapse and death rates remain unacceptably high. The aim of the research presented in this thesis was to characterize the biomolecular heterogeneity of breast cancer across tumor progression stages and to identify novel biomarkers and therapeutic strategies which may improve prognostication and personalization of therapy for women diagnosed with metastatic breast cancer. By analysis of tumor biopsies collected at different stages of disease progression, we showed that, in general, the phenotype of the primary tumor is typically conserved during tumor progression. However, in a clinically relevant number of cases, a phenotypic drift in biomarkers and tumor molecular subtypes occurs longitudinally with disease progression, with a change to a more aggressive phenotype being associated with an inferior clinical outcome. We also uncovered that breast cancer liver metastases are transcriptionally different from metastases in other anatomical sites and identified candidate liver metastasis-selective genes with the potential to specifically predict liver metastatic relapse and more generally, the time to any recurrence in early stage breast cancer. Furthermore, we demonstrated that co-targeting of PARP1 and PI3K may represent an improved and specific treatment strategy for BRCA1 deficient breast cancers. The results we present continue to emphasize the clinical significance of breast cancer heterogeneity and highlight possible ways to improve the accuracy of predicting prognosis and effectively treating patients with metastatic disease, a step towards achieving the promise of personalized cancer management and overcoming the clinical burden of metastatic breast cancer

Measuring the Effects of Interpretive Journalism on Trust and Credibility Perceptions in the Context of Political News Coverage

This study examines the effects of interpretive journalism on trust and credibility perceptions. Specifically, this study investigates interpretive journalism in the context of political news coverage and also examines the relationship between political ideology and the aforementioned variables. This study uses a 2 (interpretive journalism; fact-based journalism) x 2 (political ideology: conservative leaning; liberal leaning) between-subjects online experiment to test the proposed hypotheses. Findings illustrate the predictive value of credibility to trust within the context of political news coverage. Additionally, this study shows that individuals exhibit higher perceptions of trust and credibility towards fact-based political coverage as opposed to interpretive political coverage. Preliminary findings also indicate that conservatives exhibit lower perceptions of trust and credibility towards interpretive political news coverage than their liberal counterpart

Discovery of the Principal Cystic Fibrosis Mutation (F508del) in Ancient DNA from Iron Age Europeans

The most common, life-threatening autosomal recessive disease of Europeans and Euro-Americans, cystic fibrosis (CF), occurs predominately in patients with the F508del mutation.1 Although F508del is currently detectable as a single allele in 1/30-1/40 Europeans2-4 and Euro-Americans,5 it has not been determined what heterozygote selective advantage(s) might account for its relatively high prevalence. Indirect evidence6 suggests that this mutation was present in Brittany at least 3000 years ago, but no direct analyses of ancient DNA have been reported to identify F508del and clarify its frequency in prehistoric inhabitants of Europe. Here we show that F508del was present in 3 of 32 Iron Age inhabitants of Austria from whom DNA could be recovered from molar teeth using procedures that fulfill authenticity criteria.7 Because these individuals, who were buried in cemeteries along the Danube river, were shown by radiocarbon dating of isolated bone collagen to have lived there during 544-255 BC, this indicates that the F508del mutation is definitely more than 2000 years old and that CF (the disease) was present among them. More generally, the apparent enrichment of this Iron Age population in F508del suggests an evolutionary advantage in their environment that can be investigated by interdisciplinary strategies of paleoepidemiology

On Expectation Correlate System and Chaotic Dynamics in Time-Series

ABSTRACT This paper suggests a new system of time-series called Expectation Correlate System (ECS) that are good at detecting the behavior of dynamical systems (both deterministic and stochastic systems) and the dependence on initial values. A new measure on sensitivity to initial values can be monitored by the newly defined Lyaponov Correlate, so ECS can be a signal to chaotic property. In a stochastic systems, small shifts in some initial value can lead to error in prediction, this property and

Claudin-2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences.

Predicting any future metastatic site of early-stage breast cancer is important as it significantly influences the prognosis of advanced disease. This study aimed at investigating the potential of claudin-2, over-expressed in breast cancer liver metastases, as a biomarker for predicting liver metastatic propensity in primary breast cancer

Chemotherapeutic wafers for High Grade Glioma

addresses: Clinical Neurosciences, Bramwell Dott Building, Western General Hospital, Crewe Road, Edinburgh, Midlothian, UK, EH4 2XU. [email protected]: Journal Article; Meta-Analysis; ReviewThis review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 2008, Issue 3. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.Standard treatment for high grade glioma (HGG) usually entails biopsy or surgical resection where possible followed by radiotherapy. Systemic chemotherapy is usually only given in selected cases and its use is often limited by side effects. Implanting wafers impregnated with chemotherapy agents into the resection cavity represents a novel means of delivering drugs to the central nervous system (CNS) with fewer side effects. It is not clear how effective this modality is or whether it should be recommended as part of standard care for HGG

Tomotherapy as a tool in image-guided radiation therapy (IGRT): current clinical experience and outcomes

Modern radiotherapy is characterised by a better target definition through medical imaging accompanied by significantly improved radiation delivery methods, most notably Intensity-Modulate Radiation Therapy (IMRT). However, the treatment can only be as accurate as the positioning of patients for their daily radiotherapy fraction. It is in this context that a number of imaging modalities - ranging from ultrasound to on-board kilovoltage imaging and computed tomography (CT) - have found their way into the treatment room where they verify accurate patient positioning prior to or even during delivery of radiation. Helical tomotherapy (HT) combines IMRT delivery with in-built image guidance using megavoltage CT scanning. This paper discusses the initial experience of different centres with IGRT using HT illustrated by a number of clinical examples from the installation in London in Ontario, Canada, one of the world’s first HT sites. We found that HT allows the delivery of highly conformal radiation dose distributions combined with adequate daily image acquisition. An important feature of this unit is its seamless integration, which also includes a customised inverse treatment planning system and a quality assurance module for individual patients

Transcriptional profiling of breast cancer metastases identifies liver metastasis-selective genes associated with adverse outcome in luminal A primary breast cancer.

The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis

Improving the Clinical Treatment of Vulnerable Populations in Radiation Oncology

The increasing role of radiation oncology in optimal cancer care treatment brings to mind the adage that power is never a gift, but a responsibility. A significant part of the responsibility we in radiation oncology bear is how to ensure optimal access to our services. This article summarizes the discussion initiated at the 2019 American Society for Radiation Oncology Annual Meeting educational panel entitled "Improving the Clinical Treatment of Vulnerable Populations in Radiation Oncology: Latin, African American, Native American, and Gender/Sexual Minority Communities." By bringing the discussion to the printed page, we hope to continue the conversation with a broader audience to better define the level of responsibility our field bears in optimizing cancer care to the most vulnerable patient populations within the United States

Methoxyflurane: a review with emphasis on its role in dental practice

Methoxyflurane was developed as an anaesthetic agent and introduced into clinical practice in 1960. It soon became evident that it possessed analgesic properties that other drugs did not. Due to toxicity concerns, it lost favour in general anaesthesia and had been largely abandoned by the late 1970's. The manufacturer withdrew it in 1999, and the Food and Drug Administration in the United States did not renew its license in 2005. It has also been withdrawn by the European Union. However, it continues to be used in Australasia, primarily as an inhaled self-administered analgesic by emergency services immediately following trauma. It has become attractive for use in dental practice, likely due to its effectiveness as an analgesic and its additional sedative qualities. Its acceptance is controversial as its use in dentistry is largely elective. Despite its good safety record in analgesic doses, adverse reactions have been recorded. Practitioners should be well aware of risks associated with its use before considering administration, and carefully assess whether or not there are equally good alternative options that do not the carry the same risks. Methoxyflurane is reviewed below with an emphasis on its use in dental practice.Angus Kingon, Tami Yap, Carmelo Bonanno, Paul Sambrook, and Michael McCulloug