Narratives of pregnancy across 19 Countries: Analysis of a 1.5-billion-word news media database.

Pregnancy is a universal experience shaped by sociocultural contexts. News media presents a unique opportunity to analyze public narratives of pregnancy and how it differs across cultures. Our study aims to (1) identify the most prevalent overall themes in news media narratives of pregnancy across 19 English-speaking countries, and (2) compare pregnancy narratives across geographic regions. We used the largest English news media corpus that included over 30 million news articles from more than 7000 news websites across 19 countries, and extracted a one-year data subset (2019; 1.5 billion words). Of the primary search terms 'pregnant' and 'pregnancy', we collated 240,464 descriptors that met criteria of lexical proximity and semantic bonding. Thereafter, we used topic modelling to identify the five most prevalent pregnancy-related themes: (1) complications and risk, (2) crime, (3) celebration, (4) celebrity births, and (5) contraception. Although there were regional differences, themes of complications and risk were most common, comprising 39.6% of all pregnancy narratives in our big-data corpus. The second-most dominant theme was crime (20.8%). Narratives of contraception were more prevalent in Europe, North America, and Oceania (27.2-31.3%) compared to Africa and Asia (11.9-19.6%). Though the vast majority of pregnancies are healthy, themes of complications and risk dominated the news media discourse; unchecked, this may be an avenue for misinformation, stress, and anxiety. In addition, lower prevalence of contraception narratives in Africa and Asia may reflect a gap that requires the attention of policymakers in building culturally-adapted programs to promote family planning and encourage open discussions about sexual health. Results contribute to the academic repository of societal representations of pregnancy through a big-data lens, providing contextual information for future development, implementation and evaluation of localized pregnancy-related campaigns.

Evaluating the Diagnostic Performance of Large Language Models on Complex Multimodal Medical Cases.

Large language models showed interpretative reasoning in solving diagnostically challenging medical cases.

News media coverage of LGBT identities over 10 years in a 400-million-word corpus.

BACKGROUND: This study is the first to analyze LGBT portrayals in a news media dataset over a decade (2010-2020). We selected Singapore as a country of interest, emblematic of a nation grappling with state-encouraged heteronormativity and a remnant colonial law against homosexuality (377A), fraught with calls for its repeal that was only enacted in 2022. Our study is interested in this period bookended by challenge and change, particularly in newspaper portrayals of LGBT narratives. Newspapers are an important source of current information and have the power to shape societal perceptions. We lay the groundwork and provide a framework to analyze news media narratives of other Commonwealth nations with colonial pasts and inherited laws criminalizing LGBT communities. OBJECTIVES: This study analyzes LGBT portrayals in a 400-million-word news media dataset over a decade (2010-2020). First, we aimed to track the volume of LGBT media coverage over time and elucidate differences in coverage of different identity markers. Second, we aimed to track sentiments on LGBT portrayals. Third, we aimed to track salient narratives circulated about LGBT stories. METHODS: The study leveraged a 400-million-word corpus from news media in Singapore, identifying the following target keywords: LGBT, Lesbian, Gay, Bisexual, Transgender, Pink Dot (a local Pride event), 377A. First, coverage volume was tracked using annual changes in keyword mentions per million, elucidating differences in coverage of different sub-groups. Second, sentiment analysis on a valence scale was conducted on LGBT collocates. Third, we distilled salient narratives about LGBT identities using thematic labelling of top-frequency collocates. RESULTS: First, overall coverage of LGBT steadily increased over the decade, though Gay identities evidenced asymmetrical coverage-outstripping 'Bisexual' keywords by seven times, 'Lesbian' by four, 'Transgender' by two. Second, sentiment scores for Pink Dot (a local pride event) were most positive; Lesbian, Gay, LGBT, Transgender were neutral; Bisexual and 377A dipped slightly negative. Third, topics differed across the four identities: uniquely, 'Lesbian' collocates related to sensationalized cinema; 'Gay' about hate crimes; 'Bisexual' about population surveys; 'Transgender' about challenges (transitioning, alienation, suicide). CONCLUSIONS: Practically, we presented a decade-long barometer of LGBT sentiments and themes on a national level, providing a framework to analyze media for more effective communication strategies-applicable to Commonwealth countries with similar inherited colonial laws. Salient repetition through media association may unwittingly frame certain issues negatively; caution is prudent in representing each sub-group adequately, rather than portraying the LGBT identity as monolithic.

Powerful tool or too powerful? Early public discourse about ChatGPT across 4 million tweets.

BACKGROUND: This paper investigates initial exuberance and emotions surrounding ChatGPT's first three months of launch (1 December 2022-1 March 2023). The impetus for studying active discussions surrounding its implications, fears, and opinions is motivated by its nascent popularity and potential to disrupt existing professions; compounded by its significance as a crucial inflexion point in history. Capturing the public zeitgeist on new innovations-much like the advent of the printing press, radio, newspapers, or the internet-provides a retrospective overview of public sentiments, common themes, and issues. OBJECTIVES: Since launch, few big data studies delved into initial public discourse surrounding the chatbot. This report firstly identifies highest-engagement issues and themes that generated the most interaction; secondly, identifies the highest-engaged keywords on both sides of the sentiment valence scale (positive and negative) associated with ChatGPT. METHODS: We interrogate a large twitter corpus (n = 4,251,662) of all publicly available English-language tweets containing the ChatGPT keyword. Our first research aim utilizes a prominent peaks model (upper-quartile significance threshold of prominence>20,000). Our second research aim utilized sentiment analysis to identify, week-on-week, highest-frequency negative, and positive keywords and emojis. RESULTS: Six prominent peaks were identified with the following themes: 'hype and hesitance', 'utility and misuse in professional and academic settings', 'demographic bias', 'philosophical thought experiments on morality' and 'artificial intelligence as a mirror of human knowledge'. Of high-frequency valence, negativity included credibility concerns, implicit bias, environmental ethics, employment rights of data annotators and programmers, the ethicality of neural network datasets. Positivity included excitement over application, especially in coding, as a creative tool, education, and personal productivity. CONCLUSIONS: Overall, sentiments and themes were double-edged, expressing excitement over this powerful new tool and wariness toward its potential for misuse.

Independent study demonstrates amyloid probability score accurately indicates amyloid pathology.

BACKGROUND: The amyloid probability score (APS) is the model read-out of the analytically validated mass spectrometry-based PrecivityAD® blood test that incorporates the plasma Aß42/40 ratio, ApoE proteotype, and age to identify the likelihood of brain amyloid plaques among cognitively impaired individuals being evaluated for Alzheimer's disease. PURPOSE: This study aimed to provide additional independent evidence that the pre-established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals. METHODS: The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available. RESULTS: In a subset of the dataset aligned with the Intended Use population (patients aged 60 and older with CDR ≥0.5), the pre-established APS algorithm predicted amyloid PET with a sensitivity of 84.9% (CI: 72.9-92.1%) and specificity of 96% (CI: 80.5-99.3%), exclusive of 13 individuals for whom the test was inconclusive. INTERPRETATION: The study shows individuals with a high APS are more likely than those with a low APS to have abnormal amounts of amyloid plaques and be on an amyloid accumulation trajectory, a dynamic and evolving process characteristic of progressive AD pathology. Exploratory data suggest APS retains its diagnostic performance in healthy individuals, supporting further screening studies in the cognitively unimpaired.

A Topic Modeling Comparison Between LDA, NMF, Top2Vec, and BERTopic to Demystify Twitter Posts.

The richness of social media data has opened a new avenue for social science research to gain insights into human behaviors and experiences. In particular, emerging data-driven approaches relying on topic models provide entirely new perspectives on interpreting social phenomena. However, the short, text-heavy, and unstructured nature of social media content often leads to methodological challenges in both data collection and analysis. In order to bridge the developing field of computational science and empirical social research, this study aims to evaluate the performance of four topic modeling techniques; namely latent Dirichlet allocation (LDA), non-negative matrix factorization (NMF), Top2Vec, and BERTopic. In view of the interplay between human relations and digital media, this research takes Twitter posts as the reference point and assesses the performance of different algorithms concerning their strengths and weaknesses in a social science context. Based on certain details during the analytical procedures and on quality issues, this research sheds light on the efficacy of using BERTopic and NMF to analyze Twitter data.

The Impact of Aging Policy on Societal Age Stereotypes and Ageism.

BACKGROUND AND OBJECTIVES: While studies have researched ageism in public policy, few investigated the impact of aging policy on ageism-typically, an unintended consequence. Ageism is linked to $63 billion in health care costs, so its antecedents are of interest. We test the association between Aging Policy Agenda Setting and Societal Age Stereotypes and hypothesize a mediating pathway via Medicalization of Aging, moderated by demographics. RESEARCH DESIGN AND METHODS: Scholars identified Singapore's Pioneer Generation Policy (PGP) as one of the largest policy implementations in recent years, where the agenda was set by the Prime Minister at an equivalent State of the Union address in 2013, and US$7 billion allocated to fund outpatient health care costs for aged 65 years or older. More than 400,000 older adults received a PGP card and home visits by trained volunteers who co-devised a personalized utilization plan. We leveraged a 10-billion-word data set with more than 30 million newspaper and magazine articles to dynamically track Societal Age Stereotype scores over 8 years from pre- to postpolicy implementation. RESULTS: Societal Age Stereotypes followed a quadratic trend: Prior to the Aging Policy Agenda Setting from 2010 to 2014, stereotypes were trending positive; after 2014, it trended downward to become more negative. Medicalization of Aging mediated the relationship between Aging Policy Agenda Setting and Societal Age Stereotypes. Furthermore, Old-age Support Ratio moderated the mediational model, suggesting that the impact of policy on medicalization is stronger when a society is more aged. DISCUSSION AND IMPLICATIONS: We provided a framework for policymakers to ameliorate the unintended consequences of aging policies on societal ageism-if unaddressed, it will exert an insidious toll on older adults, even if initial policies are well-intentioned.

News media narratives of Covid-19 across 20 countries: Early global convergence and later regional divergence.

BACKGROUND: Seldom in history does one get a 'front row seat'-with large-scale dynamic data-on how online news media narratives shift with a global pandemic. News media narratives matter because they shape societal perceptions and influence the core tent poles of our society, from the economy to elections. Given its importance-and with the benefit of hindsight-we provide a systematic framework to analyze news narratives of Covid-19, laying the groundwork to evaluate policy and risk communications. OBJECTIVES: We leverage a 10-billion-word-database of online news, taken from over 7,000 English newspapers and magazines across 20 countries, culminating in 28 million articles. First, we track the volume of Covid-19 conversations across 20 countries from before to during the pandemic (Oct'19 to May'20). Second, we distill the phases of global pandemic narratives, and elucidate regional differences. METHODS: To track the volume of Covid-19 narratives, we identified 10 target terms-Coronavirus, Covid-19, Covid, nCoV, SARS-CoV-2, Wuhan Virus, Virus, Disease, Epidemic, Pandemic-and tracked their combined monthly prevalence across eight months from October 2019 through May 2020. Globally, across 20 countries, we identified 18,042,855 descriptors of the target terms. Further, these descriptors were analysed with natural language processing models to generate the top five topics of Covid-19 that were labelled by two independent researchers. This process was repeated across six continents to distil regional topics. RESULTS: Our model found four phases of online news media narratives: Pre-pandemic, Early, Peak and Recovery. Pre-pandemic narratives (Oct'19-Dec'19) were divergent across regions with Africa focused on monkeypox, Asia on dengue fever, and North America on Lyme disease and AIDS. Early (Jan-Feb'20) and Peak Pandemic (Mar-May'20) evidenced a global convergence, reflecting the omnipresence of Covid-19. The brief transition from early to peak pandemic narratives underscored the pandemic's rapid spread. Emerging from the embers of the pandemic's peak were nascent recovery words that are regionally divergent-Oceania focused on hope and an uncertain future while North America centered on re-opening the economy and tackling discrimination. CONCLUSIONS: Practically, we presented a media barometer of Covid-19, and provided a framework to analyse the pandemic's impact on societal perceptions-laying the important groundwork for policy makers to evaluate policy communications, and design risk communication strategies.

Neurocognitive outcomes following fetal exposure to chemotherapy for gestational breast cancer: A Canadian multi-center cohort study.

BACKGROUND: Limited knowledge exists on outcomes of children exposed prenatally to chemotherapy for breast cancer (BC). The purpose of this study was to compare long-term neurocognitive, behavioral, developmental, growth, and health outcomes of children exposed in-utero to chemotherapy for BC. METHODS: This is a multi-center matched cross-sectional cohort study involving seven cancer centers across the region of Southern Ontario (Canada), and the Hospital for Sick Children (Toronto, Ontario). Using standardized psychological and behavioral tests, we compared cognitive and behavioral outcomes in children exposed to chemotherapy during pregnancy for BC to age-matched pairs exposed to known non-teratogens. RESULTS: We recruited 17 parent-child pairs and their matched controls. There were more preterm deliveries in the chemotherapy-exposed group compared to controls (p < 0.05). Full Scale IQ of children in the chemotherapy group was significantly confounded by maternal IQ and prematurity. Exposed children born at term were not different in cognitive outcomes. Children from both groups were similar in their developmental milestones, pediatric anthropometric measurements and health problems. There were no cases of autoimmune cytopenia. CONCLUSIONS: This is the first Canadian prospective comparative study designed to assess pediatric cognition following prenatal exposure to chemotherapy for BC. Chemotherapy was not found to be neurotoxic in this cohort and did not affect pediatric health. The decision to plan a preterm birth for initiating or continuing chemotherapy treatment must be taken into consideration in context of pediatric implications. While these results may assist in such decision making, replication with a larger sample is needed for more conclusive findings.

Culture Linked to Increasing Ageism During COVID-19: Evidence From a 10-Billion-Word Corpus Across 20 Countries.

OBJECTIVES: Older adults experience higher risks of getting severely ill from coronavirus disease 2019 (COVID-19), resulting in widespread narratives of frailty and vulnerability. We test: (a) whether global aging narratives have become more negative from before to during the pandemic (October 2019 to May 2020) across 20 countries; (b) model pandemic (incidence and mortality), and cultural factors associated with the trajectory of aging narratives. METHODS: We leveraged a 10-billion-word online-media corpus, consisting of 28 million newspaper and magazine articles across 20 countries, to identify nine common synonyms of "older adults" and compiled their most frequently used descriptors (collocates) from October 2019 to May 2020-culminating in 11,504 collocates that were rated to create a Cumulative Aging Narrative Score per month. Widely used cultural dimension scores were taken from Hofstede, and pandemic variables, from the Oxford COVID-19 Government Response Tracker. RESULTS: Aging narratives became more negative as the pandemic worsened across 20 countries. Globally, scores were trending neutral from October 2019 to February 2020, and plummeted in March 2020, reflecting COVID-19's severity. Prepandemic (October 2019), the United Kingdom evidenced the most negative aging narratives; peak pandemic (May 2020), South Africa took on the dubious honor. Across the 8-month period, the Philippines experienced the steepest trend toward negativity in aging narratives. Ageism, during the pandemic, was, ironically, not predicted by COVID-19's incidence and mortality rates, but by cultural variables: Individualism, Masculinity, Uncertainty Avoidance, and Long-term Orientation. DISCUSSION: The strategy to reverse this trajectory lay in the same phenomenon that promoted it: a sustained global campaign-though, it should be culturally nuanced and customized to a country's context.

Aging Narratives Over 210 Years (1810-2019).

OBJECTIVES: The World Health Organization launched a recent global campaign to combat ageism, citing its ubiquity and insidious threat to health. The historical context that promoted this pernicious threat is understudied, and such studies lay the critical foundation for designing societal-level campaigns to combat it. We analyzed the trend and content of aging narratives over 210 years across multiple genres-newspaper, magazines, fiction, nonfiction books-and modeled the predictors of the observed trend. METHOD: A 600-million-word dataset was created from the Corpus of Historical American English and the Corpus of Contemporary American English to form the largest structured historical corpus with over 150,000 texts from multiple genres. Computational linguistics and statistical techniques were applied to study the trend, content, and predictors of aging narratives. RESULTS: Aging narratives have become more negative, in a linear fashion (p = .003), over 210 years. There are distinct shifts: From uplifting narratives of heroism and kinship in the 1800s to darker tones of illness, death, and burden in the 1900s across newspapers, magazines, and nonfiction books. Fiction defied this trend by portraying older adults positively through romantic courtship and war heroism. Significant predictors of ageism over 210 years are the medicalization of aging, loss of status, warmth, competence, and social ostracism. DISCUSSION: Though it is unrealistic to reverse the course of ageism, its declining trajectory can be ameliorated. Our unprecedented study lay the groundwork for a societal-level campaign to tackle ageism. The need to act is more pressing given the Covid-19 pandemic where older adults are constantly portrayed as vulnerable.

Clinical Outcomes and Cost-effectiveness of Primary Prophylaxis of Febrile Neutropenia During Adjuvant Docetaxel and Cyclophosphamide Chemotherapy for Breast Cancer.

Docetaxel and cyclophosphamide (TC) is a widely used breast cancer adjuvant regimen. We sought to compare the rates of febrile neutropenia (FN) between patients receiving no primary prophylaxis (PP) and those receiving PP with either granulocyte-colony stimulating factor (G-CSF) or antibiotics. We also analyzed cost-effectiveness of TC with and without either G-CSF or antibiotics. Charts were reviewed of all 340 patients who received adjuvant TC between January 2008 and December 2012 at two major cancer centers. Rates of FN in the three groups - no PP, PP with G-CSF and PP with antibiotics were compared. A Markov model was constructed comparing cost-effectiveness of PP with G-CSF, PP with antibiotics, and secondary prophylaxis (SP) with G-CSF after an episode of FN in a previous cycle. Costs were based on actual resource utilization and supplemented by the published literature, adjusted to 2012 Canadian dollars. Of the 73 (21%) patients who did not receive any PP, 23 (32%) of patients developed FN. Of the 192 (57%) patients receiving PP with G-CSF alone, only two (1%; p < 0.0001) developed FN; and of the 53 (16%) receiving PP with antibiotics alone, six (11%; p < 0.01) developed FN. From a cost-standpoint, PP with G-CSF was less cost-effective than PP with antibiotics. The rate of FN with TC chemotherapy exceeds 30%, and American Society of Clinical Oncology guidelines recommend PP with G-CSF in this situation. PP with antibiotics is more cost-effective, and is a reasonable option in resource-limited settings or for patients who decline or do not tolerate G-CSF.

Impact of new chemotherapeutic and targeted agents on survival in stage IV non-small cell lung cancer.

PURPOSE: Significant advances in the systemic management of metastatic non-small cell lung cancer (NSCLC) have occurred over the past decade, with options now including multiple lines of chemotherapy, epidermal growth factor receptor inhibitors, and antiangiogenic agents. Improvements in overall survival have been demonstrated in randomized controlled trials comparing these newer agents with best supportive care or standard therapy. This study examined uptake of these therapies in general practice and their impact on survival. METHODS: This retrospective cohort study compared demographic, treatment, and survival data among 987 patients diagnosed with stage IV NSCLC at two institutions in 1998, 2003, and 2008. Cohorts were selected based on intervals when doublet chemotherapy, second-line chemotherapy, and targeted agents were incorporated into the standard treatment regimen. RESULTS: The proportion of patients receiving systemic therapy increased over time (20% in 1998, 42% in 2008). Overall survival improved significantly across cohorts (p < .001), with 2-year survival rates of 0.3% in 1998, 4% in 2003, and 15% in 2008. In a multivariate survival analysis, the 2003 and 2008 cohorts were independently associated with longer survival, as was the use of one or more lines of systemic therapy. Elderly patients (aged ≥70 years) were also more likely to receive systemic therapy over time, with longer overall survival (p < .001). CONCLUSION: Over the past decade, there has been an increasing use of systemic therapy in stage IV NSCLC patients, including the elderly. This has been associated with significantly longer overall survival.

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1.

INTRODUCTION: Tissue factor (TF) is the key trigger of the coagulation cascade and the membrane signalling receptor for coagulation protease, factor VIIa. In cancer, TF has been implicated in tumor cell survival, growth, and angiogenesis, and is upregulated as a result of oncogenic transformation. MATERIALS AND METHODS: We assayed TF expression and tumourigenicity in mice in the case of human cancer cell lines expressing oncogenic receptor tyrosine kinases. These cells were also subjected to genetic modulation of the kinase suppressor of ras 1 (KSR1), and treated with oncoprotein inhibitors in vitro and in vivo. RESULTS: Here we show that herceptin, AG1478 and CI-1033, inhibitors of two different members of the ErbB family of oncogenes (HER-2 and EGFR), reduce TF levels in epithelial cancer cells. In EGFR-driven A431 cells, TF upregulation is diminished upon genetic targeting of KSR1, the scaffolding protein involved in EGFR signalling. Conversely, upregulation of KSR1 in A431 cells increases their TF expression and tumourigenicity in mice. The latter property remains dependent on EGFR, as pan-Erb (EGFR) inhibitor, CI-1033, blocks TF promoter activity and inhibits tumour formation by the parental and KSR1 overexpressing A431 cells. CONCLUSIONS: KSR1 emerges, as an important modulator of TF expression in EGFR-driven cancer cells, which also impacts their aggressiveness in vivo.

Role of the tissue factor pathway in the biology of tumor initiating cells.

Oncogenic transformation and aberrant cellular differentiation are regarded as key processes leading to malignancy. They produce heterogenous cellular populations including subsets of tumour initiating cells (TICs), also known as cancer stem cells (CSCs). Intracellular events involved in these changes profoundly impact the extracellular and systemic constituents of cancer progression, including those dependent on the vascular system. This includes angiogenesis, vasculogenesis, activation of the coagulation system and formation of CSC-related and premetastatic niches. Tissue factor (TF) is a unique cell-associated receptor for coagulation factor VIIa, initiator of blood coagulation, and mediator of cellular signalling, all of which influence vascular homeostasis. Our studies established a link between oncogenic events, angiogenesis and the elevated expression of TF in several types of cancer cells. The latter suggests that cancer coagulopathy and cellular events attributed to the coagulation system may have cancer-specific and genetic causes. Indeed, in human glioma cells, a transforming mutant of the epidermal growth factor receptor (EGFRvIII) triggers not only the expression of TF, but also of its ligand (factor VII) and protease activated receptors (PAR-1 and PAR-2). Consequently, tumour cells expressing EGFRvIII become hypersensitive to contact with blood borne proteases (VIIa, thrombin), which upregulate their production of angiogenic factors (VEGF and IL-8), and contribute to formation of the growth promoting microenvironment (niche). Moreover, TF overexpression accompanies features of cellular aggressiveness such as markers of CSCs (CD133), epithelial-to-mesenchymal transition (EMT) and expression of the angiogenic and prometastatic phenotype. Conversely, TF blocking antibodies inhibit tumour growth, angiogenesis, and especially tumour initiation upon injection of threshold numbers of tumourigenic cells. Likewise, TF depletion in the host compartment (e.g. in low-TF mice) perturbs tumour initiation. These observations suggest that both cancer cells and their adjacent host stroma contribute TF activity to the tumour microenvironment. We postulate that the TF pathway may play an important role in formation of the vascular niche for tumour initiating CSCs, through its procoagulant and signalling effects. Therapeutic blockade of these mechanisms could hamper tumour initiation processes, which are dependent on CSCs and participate in tumour onset, recurrence, drug resistance and metastasis.

The use of quantum dot nanocrystals in multicolor flow cytometry.

Because of their unique fluorescence properties, quantum dots (QDs) represent a promising new technology in the realm of multicolor flow cytometry. Although commercial reagents and applications for the technology are still in the early phases of their development, the strategies and considerations necessary for successful use are becoming known. This article discusses the value of QDs in multicolor flow cytometry, introduces strategies to successfully incorporate QDs into routine use, and highlights emerging applications of the technology.

Tissue factor in tumour progression.

The linkage between activation of the coagulation system and cancer is well established, as is deregulation of tissue factor (TF) by cancer cells, their vascular stroma and cancer-associated inflammatory cells. TF is no longer perceived as an 'alternative' coagulation factor, but rather as a central trigger of the coagulation cascade and an important cell-associated signalling receptor activated by factor VIIa, and interacting with several other regulatory entities, most notably protease-activated receptors (PAR-1 and PAR-2). Preclinical studies revealed the role of oncogenic transformation and tumour micro-environment as TF regulators in cancer, along with the impact of this receptor on gene expression, tumour growth, metastasis, angiogenesis and, possibly, formation of the cancer stem cell niche. Increasing interest surrounds the shedding of TF-containing microvesicles from cancer cells, their entry into the circulation and their role in the intercellular transfer of TF activity, cancer coagulopathy and other processes. Recent data also suggest differential roles of cell autonomous versus global effects of TF in various settings. Questions are raised regarding the consequences of TF expression by tumour cells themselves and by their associated host stroma. Progress in these areas may soon begin to impact on clinical practice and, as such, raises several important questions. Can TF be exploited as a therapeutic target in cancer? Where and when may this be safe and beneficial? Is expression of TF in various disease settings useful as a biomarker of cancer progression or the associated hypercoagulability? What clinical questions related to TF are especially worthy of further exploration, at present and in the near future? Some of these developments and questions will be discussed in this chapter.

Tissue factor regulation by epidermal growth factor receptor and epithelial-to-mesenchymal transitions: effect on tumor initiation and angiogenesis.

ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue factor (TF), the transmembrane protein responsible for initiating blood coagulation and signaling through interaction with coagulation factor VIIa. We show that A431 cancer cells in culture exhibit a uniform TF expression profile; however, these same cells in vivo exhibit a heterogeneous TF expression and show signs of E-cadherin inactivation, which is coupled with multilineage (epithelial and mesenchymal) differentiation. Blockade of E-cadherin in vitro, leads to the acquisition of spindle morphology and de novo expression of vimentin, features consistent with epithelial-to-mesenchymal transition. These changes were associated with an increase in EGFR-dependent TF expression, and with enhanced stimulation of vascular endothelial growth factor production, particularly following cancer cell treatment with coagulation factor VIIa. In vivo, cells undergoing epithelial-to-mesenchymal transition exhibited an increased metastatic potential. Furthermore, injections of the TF-blocking antibody (CNTO 859) delayed the initiation of A431 tumors in immunodeficient mice, and reduced tumor growth, vascularization, and vascular endothelial growth factor expression. Collectively, our data suggest that TF is regulated by both oncogenic and differentiation pathways, and that it functions in tumor initiation, tumor growth, angiogenesis, and metastasis. Thus, TF could serve as a therapeutic target in EGFR-dependent malignancies.

Vascular determinants of cancer stem cell dormancy--do age and coagulation system play a role?

The inability of tumour-initiating cancer stem cells (CSCs) to bring about a net increase in tumour mass could be described as a source of tumour dormancy. While CSCs may be intrinsically capable of driving malignant growth, to do so they require compatible surroundings of supportive cells, growth factors, adhesion molecules and energy sources (e.g. glucose and oxygen), all of which constitute what may be referred to as a 'permissive' CSC niche. However, in some circumstances, the configuration of these factors could be incompatible with CSC growth (a 'non-permissive' niche) and lead to their death or dormancy. CSCs and their niches may also differ between adult and paediatric cancers. In this regard the various facets of the tumour-vascular interface could serve as elements of the CSC niche. Indeed, transformed cells with an increased tumour-initiating capability may preferentially reside in specific zones adjacent to tumour blood vessels, or alternatively originate from poorly perfused and hypoxic areas, to which they have adapted. CSCs themselves may produce increased amounts of angiogenic factors, or rely for this on their progeny or activated host stromal cells. It is likely that 'vascular' properties of tumour-initiating cells and those of their niches may diversify and evolve with tumour progression. The emerging themes in this area include the role of vascular (and bone marrow) aging, vascular and metabolic comorbidities (e.g. atherosclerosis) and the effects of the coagulation system (both at the local and systemic levels), all of which could impact the functionality of CSCs and their niches and affect tumour growth, dormancy and formation of occult as well as overt metastases. In this article we will discuss some of the vascular properties of CSCs relevant to tumour dormancy and progression, including: (i) the role of CSCs in regulating tumour vascular supply, i.e the onset and maintenance of tumour angiogenesis; (ii) the consequences of changing vascular demand (vascular dependence) of CSC and their progeny; (iii) the interplay between CSCs and the vascular system during the process of metastasis, and especially (iv) the impact of the coagulation system on the properties of CSC and their niches. We will use the oncogene-driven expression of tissue factor (TF) in cancer cells as a paradigm in this regard, as TF represents a common denominator of several vascular processes that commonly occur in cancer, most notably coagulation and angiogenesis. In so doing we will explore the therapeutic implications of targeting TF and the coagulation system to modulate the dynamics of tumour growth and tumour dormancy.

Contribution of host-derived tissue factor to tumor neovascularization.

OBJECTIVE: The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study. METHODS AND RESULTS: We compared tumor growth, vascularity, and responses to cyclophosphamide (CTX) of tumors in wild-type (wt) mice, or in animals with TF levels reduced by 99% (low-TF mice). Global growth rate of 3 different types of transplantable tumors (LLC, B16F1, and ES teratoma) or metastasis were unchanged in low-TF mice. However, several unexpected tumor/context-specific alterations were observed in these mice, including: (1) reduced tumor blood vessel size in B16F1 tumors; (2) larger spleen size and greater tolerance to CTX toxicity in the LLC model; (3) aborted tumor growth after inoculation of TF-deficient tumor cells (ES TF(-/-)) in low-TF mice. TF-deficient tumor cells grew readily in mice with normal TF levels and attracted exclusively host-related blood vessels (without vasculogenic mimicry). We postulate that this complementarity may result from tumor-vascular transfer of TF-containing microvesicles, as we observed such transfer using human cancer cells (A431) and mouse endothelial cells, both in vitro and in vivo. CONCLUSIONS: Our study points to an important but context-dependent role of host TF in tumor formation, angiogenesis and therapy.