Collagen type XVIII/endostatin is differentially expressed in primary and metastatic colorectal cancers and ovarian carcinomas

Collagen type XVIII (C18) is a nonfibrillar collagen of basement membranes. Its C-terminal fragment, endostatin, has been identified as an inhibitor of angiogenesis. C18 is predominantly expressed by hepatocytes of normal, cirrhotic and neoplastic liver. We compared the patterns of C18 RNA-expression in colonic adenocarcinoma metastases, which represent the most frequently occurring liver tumours, to normal colon mucosa, to primary colon cancers and to ovarian cancers which are often morphologically similar to colonic cancer or metastasis. Two C18-specific RNA-probes were generated to perform in situ hybridization combined with immunohistochemistry for cytokeratin, vimentin and the endothelial marker CD31, in order to characterize the C18-expressing cells. C18/endostatin protein was localized by immunohistology. In colorectal carcinomas and their liver metastases high levels of C18 transcripts were observed in endothelial cells and fibroblasts/myofibroblasts, whereas C18 RNA was virtually absent from carcinoma cells. Ovarian carcinomas displayed high C18 RNA expression both in carcinoma and stromal cells, indicating that induction of C18 transcription in tumour stromal cells is independent of the ability of carcinoma cells to express C18. While the role of tumour cell derived C18 in cancer growth regulation remains unknown, stimulation of proteolysis of the locally strongly expressed C18 to endostatin could offer an attractive approach for a targeted antineoplastic therapy. © 2001 Cancer Research Campaign   http://www.bjcancer.co

Measuring The Evolutionary Rate Of Cooling Of ZZ Ceti

We have finally measured the evolutionary rate of cooling of the pulsating hydrogen atmosphere (DA) white dwarf ZZ Ceti (Ross 548), as reflected by the drift rate of the 213.13260694 s period. Using 41 yr of time-series photometry from 1970 November to 2012 January, we determine the rate of change of this period with time to be dP/dt = (5.2 +/- 1.4) x 10(-15) s s(-1) employing the O - C method and (5.45 +/- 0.79) x 10(-15) s s(-1) using a direct nonlinear least squares fit to the entire lightcurve. We adopt the dP/dt obtained from the nonlinear least squares program as our final determination, but augment the corresponding uncertainty to a more realistic value, ultimately arriving at the measurement of dP/dt = (5.5 +/- 1.0) x 10(-15) s s(-1). After correcting for proper motion, the evolutionary rate of cooling of ZZ Ceti is computed to be (3.3 +/- 1.1) x 10(-15) s s(-1). This value is consistent within uncertainties with the measurement of (4.19 +/- 0.73) x 10(-15) s s(-1) for another similar pulsating DA white dwarf, G 117-B15A. Measuring the cooling rate of ZZ Ceti helps us refine our stellar structure and evolutionary models, as cooling depends mainly on the core composition and stellar mass. Calibrating white dwarf cooling curves with this measurement will reduce the theoretical uncertainties involved in white dwarf cosmochronometry. Should the 213.13 s period be trapped in the hydrogen envelope, then our determination of its drift rate compared to the expected evolutionary rate suggests an additional source of stellar cooling. Attributing the excess cooling to the emission of axions imposes a constraint on the mass of the hypothetical axion particle.NSF AST-1008734, AST-0909107Norman Hackerman Advanced Research Program 003658-0252-2009Astronom

Measuring The Evolutionary Rate Of Cooling Of ZZ Ceti

We have finally measured the evolutionary rate of cooling of the pulsating hydrogen atmosphere (DA) white dwarf ZZ Ceti (Ross 548), as reflected by the drift rate of the 213.13260694 s period. Using 41 yr of time-series photometry from 1970 November to 2012 January, we determine the rate of change of this period with time to be dP/dt = (5.2 +/- 1.4) x 10(-15) s s(-1) employing the O - C method and (5.45 +/- 0.79) x 10(-15) s s(-1) using a direct nonlinear least squares fit to the entire lightcurve. We adopt the dP/dt obtained from the nonlinear least squares program as our final determination, but augment the corresponding uncertainty to a more realistic value, ultimately arriving at the measurement of dP/dt = (5.5 +/- 1.0) x 10(-15) s s(-1). After correcting for proper motion, the evolutionary rate of cooling of ZZ Ceti is computed to be (3.3 +/- 1.1) x 10(-15) s s(-1). This value is consistent within uncertainties with the measurement of (4.19 +/- 0.73) x 10(-15) s s(-1) for another similar pulsating DA white dwarf, G 117-B15A. Measuring the cooling rate of ZZ Ceti helps us refine our stellar structure and evolutionary models, as cooling depends mainly on the core composition and stellar mass. Calibrating white dwarf cooling curves with this measurement will reduce the theoretical uncertainties involved in white dwarf cosmochronometry. Should the 213.13 s period be trapped in the hydrogen envelope, then our determination of its drift rate compared to the expected evolutionary rate suggests an additional source of stellar cooling. Attributing the excess cooling to the emission of axions imposes a constraint on the mass of the hypothetical axion particle.NSF AST-1008734, AST-0909107Norman Hackerman Advanced Research Program 003658-0252-2009Astronom

Integration of decision support systems to improve decision support performance

Decision support system (DSS) is a well-established research and development area. Traditional isolated, stand-alone DSS has been recently facing new challenges. In order to improve the performance of DSS to meet the challenges, research has been actively carried out to develop integrated decision support systems (IDSS). This paper reviews the current research efforts with regard to the development of IDSS. The focus of the paper is on the integration aspect for IDSS through multiple perspectives, and the technologies that support this integration. More than 100 papers and software systems are discussed. Current research efforts and the development status of IDSS are explained, compared and classified. In addition, future trends and challenges in integration are outlined. The paper concludes that by addressing integration, better support will be provided to decision makers, with the expectation of both better decisions and improved decision making processes

Repeated Assessments of Informed Consent Comprehension among HIV-Infected Participants of a Three-Year Clinical Trial in Botswana

Informed consent (IC) has been an international standard for decades for the ethical conduct of clinical trials. Yet frequently study participants have incomplete understanding of key issues, a problem exacerbated by language barriers or lack of familiarity with research concepts. Few investigators measure participant comprehension of IC, while even fewer conduct interim assessments once a trial is underway.We assessed comprehension of IC using a 20-question true/false quiz administered in 6-month intervals in the context of a placebo-controlled, randomized trial for the prevention of tuberculosis among HIV-infected adults in Botswana (2004-2009). Quizzes were offered in both Setswana and English. To enroll in the TB trial, participants were required to have ≥ 16/20 correct responses. We examined concepts understood and the degree to which understanding changed over three-years. We analyzed 5,555 quizzes from 1,835 participants. The participants' highest education levels were: 28% primary, 59% secondary, 9% tertiary and 7% no formal education. Eighty percent of participants passed the enrollment quiz (Quiz1) on their first attempt and the remainder passed on their second attempt. Those having higher than primary education and those who took the quiz in English were more likely to receive a passing score on their first attempt (adjusted odds ratios and 95% confidence intervals, 3.1 (2.4-4.0) and 1.5 (1.2, 1.9), respectively). The trial's purpose or procedures were understood by 90-100% of participants, while 44-77% understood randomization, placebos, or risks. Participants who failed Quiz1 on their initial attempt were more likely to fail quizzes later in the trial. Pass rates improved with quiz re-administration in subsequent years.Administration of a comprehension quiz at enrollment and during follow-up was feasible in a large, international collaboration and efficiently determined IC comprehension by trial participants. Strategies to improve understanding of concepts like placebos and randomization are needed. Comprehension assessments throughout a study may reinforce key concepts

FasL is more frequently expressed in liver metastases of colorectal cancer than in matched primary carcinomas

Colorectal carcinoma cells have recently been shown to express Fas ligand (FasL). This ligand could allow the tumour cells to evade activated tumour-infiltrating lymphocytes (TILs) by inducing their apoptosis and would thus promote tumour survival and possibly metastasis formation. To test this hypothesis in vivo we analysed the expression of FasL mRNA and protein in paired tissue samples of normal colonic mucosa (N), primary colorectal carcinomas (T) and their metastases (M) from a total of 21 patients by four different methods. Additionally, the presence and activation status of infiltrating lymphocytes, which might contribute to the total amount of FasL in the tissue, was determined by semiquantitative reverse transcription–polymerase chain reaction (RT–PCR) in the same samples. The frequency of FasL detection was 30–40% in T and was 60–100% in M, depending on the sensitivity of the method. Simultaneously, the amount of CD25 mRNA, used as a measure of the number of activated TILs, was in 90% of patients lower in M than in T. The increased frequency of FasL detection in liver metastases was therefore not due to the presence of activated TILs. We conclude that metastasizing subpopulations of colorectal tumour cells express FasL more frequently than the primary carcinomas and may be able to eliminate activated TILs in vivo via Fas/FasL-induced apoptosis or other hitherto unknown mechanisms. © 1999 Cancer Research Campaig

Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK

Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies