A Novel High-Throughput, High-Content Three-Dimensional Assay for Determination of Tumor Invasion and Dormancy

Metastasis accounts for most cancer deaths, while dormancy of tumor cells leads to unexpected cancer recurrence. These two aspects of cancer remain relatively untreatable in part because current two-dimensional (2D) methods of high-throughput drug screening cannot quantify outcomes related to these phenotypes. Three-dimensional (3D) in-vitro tumor models are a promising alternative because they better recreate the tumor microenvironment and relevant phenotypes. However, outcome measures for high-throughput screening of these systems are often limited to single measures such as metabolic activity using assays that are not standardized or optimized for 3D models. To address this gap, the objective of this work to develop an image-based assay to measure tumor cell health, proliferation, invasion, and dormancy for high-throughput drug screening. Drug dosing experiments were performed using a novel 3D pancreatic tumor metastasis model, followed by application of various dye combinations to assess viability, proliferation, metabolic activity, and invasion. We successfully demonstrated that high throughput imaging and analysis can be performed to quantify proliferation, metabolic activity, and invasion in a single multi-output assay. Proof-of-concept experiments also revealed that while gemcitabine does effectively inhibit cancer cell proliferation it does not kill all cells and may contribute to tumor dormancy. Overall, this work using a novel 3D tumor metastasis model coupled with a multi-output assay serves as a first step toward a drug screening platform that will enable researchers to better correlate in-vitro model results with clinical outcomes related to metastasis and dormancy

The Physical Properties and Effective Temperature Scale of O-type Stars as a Function of Metallicity. II. Analysis of 20 More Magellanic Cloud Stars, and Results from the Complete Sample

We analyze the optical and UV spectra of an additional sample of 20 Magellanic Cloud O stars, and draw conclusions from the complete sample of 40 stars. We find (1) The SMC O3-7 dwarfs are about 4000 K cooler than their Galactic counterparts; this is in the sense expected from the decreased signficiance of line-blanketing and wind-blanketing at lower metallicities. The difference decreases with later types, becoming negligible by B0 V. A similar difference is found for the supergiants. (2) The wind momentum of these stars scales with luminosity and metallicty in the ways predicted by radiatively-driven wind theory. (3) A comparison of the masses derived from spectroscopy with those derived from stellar evolutionary theory shows a significant discrepancy for stars hotter than 45000, although good agreement is found for cooler stars. (4) For the hottest O stars (O2-3.5) neither the NIII/NIV ratio, nor even the HeI/HeII ratio, does a good job of predicting the effective temperature by itself. Instead, a full analysis is needed to derive physical parameters. Thus there are O3.5V stars which are as hot or hotter than stars classified as O2V. (5) The two stars with the most discordant radial velocities in our sample happen to be O3 "field stars". This provides the first compelling observational evidence that the "field" O stars in the Magellanic Clouds may be runaway OB stars, ejected from their birth place.Comment: Accepted by the Astrophysical Journal. A version with higher-resolution figures may be found at ftp://ftp.lowell.edu/pub/massey/haw2final.pdf This replacement included a revised version of Fig 29a and the accompanying tex

Regenerative tissue filler for breast conserving surgery and other soft tissue restoration and reconstruction needs

Complete removal of cancerous tissue and preservation of breast cosmesis with a single breast conserving surgery (BCS) is essential for surgeons. New and better options would allow them to more consistently achieve this goal and expand the number of women that receive this preferred therapy, while minimizing the need for re-excision and revision procedures or more aggressive surgical approaches (i.e., mastectomy). We have developed and evaluated a regenerative tissue filler that is applied as a liquid to defects during BCS prior to transitioning to a fibrillar collagen scaffold with soft tissue consistency. Using a porcine simulated BCS model, the collagen filler was shown to induce a regenerative healing response, characterized by rapid cellularization, vascularization, and progressive breast tissue neogenesis, including adipose tissue and mammary glands and ducts. Unlike conventional biomaterials, no foreign body response or inflammatory-mediated “active” biodegradation was observed. The collagen filler also did not compromise simulated surgical re-excision, radiography, or ultrasonography procedures, features that are important for clinical translation. When post-BCS radiation was applied, the collagen filler and its associated tissue response were largely similar to non-irradiated conditions; however, as expected, healing was modestly slower. This in situ scaffold-forming collagen is easy to apply, conforms to patient-specific defects, and regenerates complex soft tissues in the absence of inflammation. It has significant translational potential as the first regenerative tissue filler for BCS as well as other soft tissue restoration and reconstruction needs

Cell–cell and cell–matrix dynamics in intraperitoneal cancer metastasis

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis

Engineering Novel 3D Tumor-Stroma Models to Bridge the Gap Between Preclinical Drug Development and Human Clinical Outcomes

While much progress has been made in the war on cancer, shortcomings in the drug development process have kept anti-cancer clinical trial success rates low. One of the many factors implicated in this is the lack of pathophysiologically relevant and predictive preclinical models. Specifically, traditional preclinical tumor models do not capture tumor microenvironment complexity and heterogeneity, while advanced three-dimensional (3D) models suffer from poor reproducibility, lack of relevant and standardized extracellular matrix (ECM), and inability to interface with automated, high-throughput systems. Because of this, it has been suggested that developing novel phenotypic tumor models which balance the need for complexity and relevance with the ability to scale-up and translate, may help reduce the high attrition rates of clinical trials. Toward this end, this work describes the development and validation of a novel preclinical tumor model striving to achieve this balance. Model development was specifically focused on metastasis, as it remains the main cause of cancer deaths and has few good preclinical models. Since one major shortcoming of 3D in-vitro models is a lack of standardized, relevant ECM, initial work focused on defining the role of ECM composition and biophysical properties in guiding invasive phenotypes. Using a customizable and standardized oligomeric type I collagen, we demonstrated that 3D collagen fibril architecture and model geometry were key determinants of phenotypic trends and important design considerations for future model development. This work was followed by the design and validation of a custom fabrication platform to enable the rapid, reproducible embedment of tunable tumor-tissue spheres within a customizable 3D ECM. It was validated that this model can distinguish various metastatic phenotypes, is compatible with low-passage, patient-derived cells, and is able to interface with automated imaging systems. Overall, this work represents the first steps of design, verification, and validation of a novel 3D metastasis model which can serve as a relevant and predictive tool for high-throughput, high-content preclinical drug development

Engineering Novel 3D Tumor-Stroma Models to Bridge the Gap Between Preclinical Drug Development Aand Human Clinical Outcomes

While much progress has been made in the war on cancer, shortcomings in the drug development process have kept anti-cancer clinical trial success rates low. One of the many factors implicated in this is the lack of pathophysiologically relevant and predictive preclinical models. Specifically, traditional preclinical tumor models do not capture tumor microenvironment complexity and heterogeneity, while advanced three-dimensional (3D) models suffer from poor reproducibility, lack of relevant and standardized extracellular matrix (ECM), and inability to interface with automated, high-throughput systems. Because of this, it has been suggested that developing novel phenotypic tumor models which balance the need for complexity and relevance with the ability to scale-up and translate, may help reduce the high attrition rates of clinical trials. Toward this end, this work describes the development and validation of a novel preclinical tumor model striving to achieve this balance. Model development was specifically focused on metastasis, as it remains the main cause of cancer deaths and has few good preclinical models. Since one major shortcoming of 3D in-vitro models is a lack of standardized, relevant ECM, initial work focused on defining the role of ECM composition and biophysical properties in guiding invasive phenotypes. Using a customizable and standardized oligomeric type I collagen, we demonstrated that 3D collagen fibril architecture and model geometry were key determinants of phenotypic trends and important design considerations for future model development. This work was followed by the design and validation of a custom fabrication platform to enable the rapid, reproducible embedment of tunable tumor-tissue spheres within a customizable 3D ECM. It was validated that this model can distinguish various metastatic phenotypes, is compatible with low-passage, patient-derived cells, and is able to interface with automated imaging systems. Overall, this work represents the first steps of design, verification, and validation of a novel 3D metastasis model which can serve as a relevant and predictive tool for high-throughput, high-content preclinical drug development

CSES Module 3 Full Release

The module was administered as a post-election interview. The resulting data are provided along with voting, demographic, district and macro variables in a single dataset. CSES Variable List The list of variables is being provided on the CSES Website to help in understanding what content is available from CSES, and to compare the content available in each module. Themes: MICRO-LEVEL DATA: Identification and study administration variables: weighting factors; election type; date of election 1st and 2nd round; study timing (post election study, pre-election and post-election study, between rounds of majoritarian election); mode of interview; gender of interviewer; date questionnaire administered; primary electoral district of respondent; number of days the interview was conducted after the election Demography: age; gender; education; marital status; union membership; union membership of others in household; business association membership, farmers´ association membership; professional association membership; current employment status; main occupation; socio economic status; employment type - public or private; industrial sector; current employment status, occupation, socio economic status, employment type - public or private, and industrial sector of spouse; household income; number of persons in household; number of children in household under the age of 18; attendance at religious services; religiosity; religious denomination; language usually spoken at home; race; ethnicity; region of residence; rural or urban residence Survey variables: most important issues of election; candidates competencies to deal with most important issues; difference who is in power and who people vote for; evaluation of governments performance; party and leader that represent respondent´s view best; sympathy scale for selected parties and political leaders; assessment of parties and political leaders on a left-right-scale; self-assessment on a left-right-scale; differences of choice options; campaign involvement; satisfaction with democracy; party identification; intensity of party identification; respondent cast a ballot at the current and the previous election; vote choice (presidential, lower house and upper house elections) at the current and the previous election; respondent cast candidate preference vote at the current and the previous election; political information items DISTRICT-LEVEL DATA: number of seats contested in electoral district; number of candidates; number of party lists; percent vote of different parties; official voter turnout in electoral district MACRO-LEVEL DATA: election outcomes by parties in current (lower house/upper house) legislative election; percent of seats in lower house received by parties in current lower house/upper house election; percent of seats in upper house received by parties in current lower house/upper house election; percent of votes received by presidential candidate of parties in current elections; electoral turnout; party of the president and the prime minister before and after the election; number of portfolios held by each party in cabinet, prior to and after the most recent election; size of the cabinet after the most recent election; number of parties participating in election; ideological families of parties; left-right position of parties assigned by experts and alternative dimensions; most salient factors in the election; fairness of the election; formal complaints against national level results; election irregularities reported; scheduled and held date of election; irregularities of election date; extent of election violence and post election violence; geographic concentration of violence; post-election protest; electoral alliances permitted during the election campaign; existing electoral alliances; requirements for joint party lists; possibility of apparentement and types of apparentement agreements; multi-party endorsements on ballot; votes cast; voting procedure; voting rounds; party lists close, open, or flexible; transferable votes; cumulated votes if more than one can be cast; compulsory voting; party threshold; unit for the threshold; freedom house rating; democracy-autocracy polity IV rating; age of the current regime; regime: type of executive; number of months since last lower house and last presidential election; electoral formula for presidential elections; electoral formula in all electoral tiers (majoritarian, proportional or mixed); for lower and upper houses was coded: number of electoral segments; linked electoral segments; dependent formulae in mixed systems; subtypes of mixed electoral systems; district magnitude (number of members elected from each district); number of secondary and tertiary electoral districts; fused vote; size of the lower house; GDP growth (annual percent); GDP per capita; inflation, GDP Deflator (annual percent); Human development index; total population; total unemployment; constitutional federal structure; number of legislative chambers; electoral results data available; effective number of electoral and parliamentary partie

CSES Module 1-3 Harmonized Trend File

Für weitere Informationen zur Variablenliste siehe die Dokumentation (Codebook) des CSES Module 1-3 Harmonized Trend File. Informationen zum Inhalt können den Studiennummern ZA5179 CSES Module 1 Full Release, ZA5180 CSES Module 2 Full Release, und ZA5181 CSES Module 3 Full Release entnommen werden