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.

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.

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.

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.

Quantum dot semiconductor nanocrystals for immunophenotyping by polychromatic flow cytometry.

Immune responses arise from a wide variety of cells expressing unique combinations of multiple cell-surface proteins. Detailed characterization is hampered, however, by limitations in available probes and instrumentation. Here, we use the unique spectral properties of semiconductor nanocrystals (quantum dots) to extend the capabilities of polychromatic flow cytometry to resolve 17 fluorescence emissions. We show the need for this power by analyzing, in detail, the phenotype of multiple antigen-specific T-cell populations, revealing variations within complex phenotypic patterns that would otherwise remain obscure. For example, T cells specific for distinct epitopes from one pathogen, and even those specific for the same epitope, can have markedly different phenotypes. The technology we describe, encompassing the detection of eight quantum dots in conjunction with conventional fluorophores, should expand the horizons of flow cytometry, as well as our ability to characterize the intricacies of both adaptive and innate cellular immune responses.

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 live-cell assay to detect antigen-specific CD4+ T cells with diverse cytokine profiles.

Recently activated, but not resting, CD4(+) T cells express CD154, providing costimulatory signals to B cells and antigen-presenting cells (APCs). Therefore, de novo CD154 expression after stimulation identifies antigen-specific CD4(+) T cells. Previous assays were limited by the transient nature of surface CD154 expression; we overcame this by including fluorescently conjugated CD154-specific antibody during stimulation. Our assay is fully compatible with intracellular cytokine staining, and can be used for stimulations as long as 24 h. Notably, it is nonlethal, providing a means to purify viable antigen-specific CD4(+) T cells for further analysis. Using this assay, we found that stimulated cells expressing tumor necrosis factor (TNF)-alpha, interleukin (IL)-2 or interferon (IFN)-gamma were predominantly CD154(+). Furthermore, some cells expressing none of these cytokines also expressed CD154, suggesting that CD154 marks cells with other effector functions. For vaccine- or pathogen-specific responses, we found substantial heterogeneity in expression of CD154 and cytokines, suggesting previously unrecognized diversity in abilities of responding cells to stimulate APCs through CD40.

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.

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.

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.

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.

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.

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.

Tissue factor in cancer.

PURPOSE OF REVIEW: Tissue factor is increasingly viewed as an integral part of the vicious circle that links the vascular system with cancer progression at multiple systemic, cellular and molecular levels. RECENT FINDINGS: The emerging tenet in this area is that oncogenic events/pathways driving the malignant process also stimulate the expression of tissue factor by cancer cells and promote the release of tissue factor-containing microvesicles into the circulation. The combined effects of these changes likely contribute to cancer coagulopathy, cessation of tumour dormancy, aggressive growth, angiogenesis and metastasis, notably through a combination of procoagulant and signalling effects set in motion by tissue factor. As certain tumour-associated host cell types (inflammatory cells, endothelium) may also express tissue factor their contribution is plausible, though poorly understood. Interestingly, tissue factor could be 'shared' between various subsets of cancer and host cells due to intercellular transfer of tissue factor-containing microvesicles. It has recently been proposed that tissue factor may influence the interactions between tumour initiating (stem) cells and their growth or prometastatic niches. SUMMARY: Whereas targeting tissue factor in cancer is appealing, the prospects in this regard will depend on the identification of disease specific indications, active agents and their safe regimens.

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.

Tris-2-(3-methylindolyl)phosphine as an anion receptor.

A C3-symmetric phosphine with indolyl substituents has been synthesized that demonstrates the capability to bind anions through the indole NH sites and coordinate metal centres through the phosphorus centre.

Oncogenes, trousseau syndrome, and cancer-related changes in the coagulome of mice and humans.

Cancer is often associated with venous thrombosis, a phenomenon that was first described by Trousseau in 1865 (Trousseau syndrome). Recent studies have begun to explain how oncogenic events may deregulate the hemostatic system. For instance, activated oncogenes (K-ras, EGFR, PML-RARalpha, and MET) or inactivated tumor suppressors (e.g., 53 or PTEN) may increase the risk of thrombosis by inducing the expression of tissue factor, a potent procoagulant molecule, and plasminogen activator inhibitor-1, a fibrinolysis inhibitor. In a more complex clinical reality, transforming genes may often act in concert with numerous epigenetic factors, including hypoxia, inflammation, anticancer therapy, contact between blood and metastatic cancer cells, and emission of procoagulant vesicles from tumors and their stroma into the circulation. To add to mechanistic insights gained from mouse models, which may not fully phenocopy human Trousseau syndrome, we suggest that valuable clues to progression and thrombosis risk may be obtained by monitoring multiple hemostatic variables in cancer patients ("coagulomics").

The role of tumor-and host-related tissue factor pools in oncogene-driven tumor progression.

Oncogenic events play an important role in cancer-related coagulopathy (Trousseau syndrome), angiogenesis and disease progression. This can, in part, be attributed to the up-regulation of tissue factor (TF) and release of TF-containing microvesicles into the pericellular milieu and the circulation. In addition, certain types of host cells (stromal cells, inflammatory cells, activated endothelium) may also express TF. At present, the relative contribution of host- vs tumor-related TF to tumor progression is not known. Our recent studies have indicated that the role of TF in tumor formation is complex and context-dependent. Genetic or pharmacological disruption of TF expression/activity in cancer cells leads to tumor growth inhibition in immunodeficient mice. This occurred even in the case of xenotransplants of human cancer cells, in which TF overexpression is driven by potent oncogenes (K-ras or EGFR). Interestingly, the expression of TF in vivo is not uniform and appears to be influenced by many factors, including the level of oncogenic transformation, tumor microenvironment, adhesion and the coexpression of markers of cancer stem cells (CSCs). Thus, minimally transformed, but tumorigenic embryonic stem (ES) cells were able to form malignant and angiogenic outgrowths in the absence of TF. However, these tumors were growth inhibited in hosts (mice) with dramatically reduced TF expression (low-TF mice). Depletion of host TF also resulted in changes affecting vascular patterning of some, but not all types of tumors. These observations suggest that TF may play different roles growth and angiogenesis of different tumors. Moreover, both tumor cell and host cell compartments may, in some circumstances, contribute to the functional TF pool. We postulate that activation of the coagulation system and TF signaling, may deliver growth-promoting stimuli (e.g. fibrin, thrombin, platelets) to dormant cancer stem cells (CSCs). Functionally, these influences may be tantamount to formation of a provisional (TF-dependent) cancer stem cell niche. As such these changes may contribute to the involvement of CSCs in tumor growth, angiogenesis and metastasis.