Binary Population Synthesis: Methods, Normalization, and Surprises

In this paper we present a brief overview of population synthesis methods with a discussion of their main advantages and disadvantages. In the second part, we present some recent results from synthesis models of close binary compact objects with emphasis on the predicted rates, their uncertainties, and the model input parameters the rates are most sensitive to. We also report on a new evolutionary path leading to the formation of close double neutron stars (NS), with the unique characteristic that none of the two NS ever had the chance to be recycled by accretion. Their formation rates turn out to be comparable to or maybe even higher than those of recycled NS-NS binaries (like the ones observed), but their detection probability as binary pulsars is much smaller because of their short lifetimes. We discuss the implications of such a population for gravitational-wave detection of NS-NS inspiral events, and possibly for gamma-ray bursts and their host galaxies.Comment: 15 pages, 1 figure, to appear in the proceedings ``The influence of binaries on stellar population studies'', Brussels, August 2000 (Kluwer Academic Publishers), ed. D.Vanbevere

92-Gene Molecular Profiling in Identification of Cancer Origin: A Retrospective Study in Chinese Population and Performance within Different Subgroups

BACKGROUND: After cancer diagnosis, therapy for the patient is largely dependent on the tumor origin, especially when a metastatic tumor is being treated. However, cases such as untypical metastasis, poorly differentiated tumors or even a limited number of tumor cells may lead to challenges in identifying the origin. Moreover, approximately 3% to 5% of total solid tumor patients will not have to have their tumor origin identified in their lifetime. The THEROS CancerTYPE ID® is designed for identifying the tumor origin with an objective, rapid and standardized procedure. METHODOLOGY AND PRINCIPAL FINDINGS: This is a blinded retrospective study to evaluate performance of the THEROS CancerTYPE ID® in a Chinese population. In total, 184 formalin-fixed paraffin-embedded (FFPE) samples of 23 tumor origins were collected from the tissue bank of Fudan University Shanghai Cancer Center (FDUSCC). A standard tumor cell enrichment process was used, and the prediction results were compared with reference diagnosis, which was confirmed by two experienced pathologists at FDUSCC. All of the 184 samples were successfully analyzed, and no tumor specimens were excluded because of sample quality issues. In total, 151 samples were correctly predicted. The agreement rate was 82.1%. A Pearson Chi-square test shows that there is no difference between this study and the previous evaluation test performed by bioTheranostics Inc. No statistically significant decrease was observed in either the metastasis group or tumors with high grades. CONCLUSIONS: A comparable result with previous work was obtained. Specifically, specimens with a high probability score (>0.85) have a high chance (agreement rate = 95%) of being correctly predicted. No performance difference was observed between primary and metastatic specimens, and no difference was observed among three tumor grades. The use of laser capture micro-dissection (LCM) makes the THEROS CancerTYPE ID® accessible to almost all of the cancer patients with different tumor statuses

Adenosine Triphosphate Stimulates Aquifex aeolicus MutL Endonuclease Activity

BACKGROUND:Human PMS2 (hPMS2) homologues act to nick 5' and 3' to misincorporated nucleotides during mismatch repair in organisms that lack MutH. Mn(++) was previously found to stimulate the endonuclease activity of these homologues. ATP was required for the nicking activity of hPMS2 and yPMS1, but was reported to inhibit bacterial MutL proteins from Thermus thermophilus and Aquifex aeolicus that displayed homology to hPMS2. Mutational analysis has identified the DQHA(X)(2)E(X)(4)E motif present in the C-terminus of PMS2 homologues as important for endonuclease activity. METHODOLOGIES/PRINCIPAL FINDINGS:We examined the effect ATP had on the Mn(++) induced nicking of supercoiled pBR322 by full-length and mutant A. aeolicus MutL (Aae MutL) proteins. Assays were single time point, enzyme titration experiments or reaction time courses. The maximum velocity for MutL nicking was determined to be 1.6+/-0.08x10(-5) s(-1) and 4.2+/-0.3x10(-5) s(-1) in the absence and presence of ATP, respectively. AMPPNP stimulated the nicking activity to a similar extent as ATP. A truncated Aae MutL protein composed of only the C-terminal 123 amino acid residues was found to nick supercoiled DNA. Furthermore, mutations in the conserved C-terminal DQHA(X)(2)E(X)(4)E and CPHGRP motifs were shown to abolish Aae MutL endonuclease activity. CONCLUSIONS:ATP stimulated the Mn(++) induced endonuclease activity of Aae MutL. Experiments utilizing AMPPNP implied that the stimulation did not require ATP hydrolysis. A mutation in the DQHA(X)(2)E(X)(4)E motif of Aae MutL further supported the role of this region in endonclease activity. For the first time, to our knowledge, we demonstrate that changing the histidine residue in the conserved CPHGRP motif abolishes endonucleolytic activity of a hPMS2 homologue. Finally, the C-terminal 123 amino acid residues of Aae MutL were sufficient to display Mn(++) induced nicking activity

Sarcolemma-localized nNOS is required to maintain activity after mild exercise

Many neuromuscular conditions are characterized by an exaggerated exercise- induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients(1), and some patients experience severe fatigue without any demonstrable somatic disease(2). Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown(2). With no treatment available, this form of inactivity is a major determinant of disability(3). Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase ( nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS- null mice do not have muscle pathology and have no loss of muscle- specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction- induced signalling from sarcolemma- localized nNOS, which decreases cGMP- mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise- induced signalling.Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant ; University of Iowa Cardiovascular Interdisciplinary Research ; National Research Service Award ; National Institute of Arthritis and Musculoskeletal and Skin Diseases ; National Institutes of Health ; Senator Paul D. Wellstone Fellowship ; Muscular Dystrophy Association Development Grant ; Howard Hughes Medical InstituteWe thank M. Anderson and M. Henry for comments, and M. M. Kilburg, K. Uppal, B. J. Steinmann and S. Watkins and members of the Campbell laboratory for scientific contributions. This work was supported in part by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant. Y.M.K. was supported by grants from the University of Iowa Cardiovascular Interdisciplinary Research/ National Research Service Award (NRSA) Fellowship, from an individual NRSA Fellowship from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, from the National Institutes of Health (NIH), and from a Senator Paul D. Wellstone Fellowship. E.P.R. was supported by a Muscular Dystrophy Association Development Grant. R.M.W. was supported by the NIH. K.P.C. is an investigator of the Howard Hughes Medical Institute.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62850/1/nature07414.pd

Disease knowledge after an educational program in patients with GERD – a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Patient education has proved beneficial in several but not all chronic disease. Inconsistent findings may rely on varying educational effects of various programs and differential effects on subgroups of patients. Patients' increase in disease knowledge may serve as a feedback to the educator on how well the education program works – but may not be associated to relevant clinical outcomes like quality of life (QoL). This study aimed to investigate the effects of a group based education program for patients with gastroesophageal reflux disease (GERD) on disease knowledge and the association between knowledge and QoL.</p> <p>Methods</p> <p>Patients with GERD were randomly allocated to education (102 patients) or control (109 patients). The education program was designed as a structured dialogue conveying information about pathophysiology, pharmacological and non-pharmacological treatment of GERD, patients' rights and use of healthcare. Outcomes were a 24 item knowledge test on GERD (score 0 – 24) 2 and 12 months after the educational program and disease specific and general QoL (Digestive symptoms and disease impact, DSIQ, and General Health Questionnaire, GHQ).</p> <p>Results</p> <p>Patients allocated to education achieved higher knowledge test scores than controls at 2 months (17.0 vs. 13.1, p < 0.001) and at 12 months (17.1 vs. 14.0, p < 0.001) follow-up. Knowledge test score was positively associated with having completed advanced school and inversely related to psychiatric illness and poor QoL as perceived by the patients at the time of inclusion. Overall, changes in knowledge test score were not associated with change in QoL.</p> <p>Conclusion</p> <p>A group based education program for patients with GERD designed as a structured dialogue increased patients' disease knowledge, which was retained after 1 year. Changes in GERD-knowledge were not associated with change in QoL.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: NCT0061850</p

Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression

<p>Abstract</p> <p>Background</p> <p>Neuropilin-2 (Nrp2) is a receptor for vascular endothelial growth factor-C (VEGF-C), which is a well-known lymphangiogenic factor and plays an important role in lymph node metastasis of various human cancers, including breast cancer. Recently, Nrp2 was shown to play a role in cancer by promoting tumor cell metastasis. CXC chemokine receptor 4 (CXCR4) also promotes tumor metastasis. In the previous studies, we demonstrated that VEGF-C and cytoplasmic CXCR4 expressions were correlated with poorer patient prognosis (BMC Cancer 2008,8:340; Breast Cancer Res Treat 2005, 91:125–132).</p> <p>Methods</p> <p>The relationship between Nrp2 expression and lymph node metastasis, VEGF-C expression, CXCR4 expression, and other established clinicopathological variables (these data were cited in our previous papers), including prognosis, was analyzed in human breast cancer. Effects of neutralizing anti-Nrp2 antibody on CXCR4 expression and chemotaxis were assessed in MDA-MB-231 breast cancer cells.</p> <p>Results</p> <p>Nrp2 expression was observed in 53.1% (60 of 113) of the invasive breast carcinomas. Nrp2 expression was significantly correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival. In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival. Neutralizing anti-Nrp2 antibody blocks cytoplasmic CXCR4 expression and CXCR4-induced migration in MDA-MB-231 cells.</p> <p>Conclusion</p> <p>Nrp2 expression was correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer. Our data also showed a role for Nrp2 in regulating cytoplasmic CXCR4 expression <it>in vitro</it>.</p

Inequalities in colorectal cancer screening participation in the first round of the national screening programme in England

BACKGROUND: Introduction of organised, population-based, colorectal cancer screening in the United Kingdom using the faecal occult blood test (FOBT) has the potential to reduce overall colorectal cancer mortality. However, socio-economic variation in screening participation could exacerbate existing inequalities in mortality.METHODS: This study examined FOBT uptake rates in London, England in relation to area-level socio-economic deprivation over the first 30 months of the programme during which 401 197 individuals were sent an FOBT kit. Uptake was defined as return of a completed test kit within 3 months. Area-level deprivation in each postcode sector was indexed with the Townsend Material Deprivation Index. Analyses controlled for area-level household mobility, ethnic diversity and poor health, each of which was associated with lower return rates.RESULTS: The results showed a strong socio-economic gradient in FOBT uptake, which declined from 49% in the least deprived quintile of postcodes to 38% in the middle quintile and 32% in the most deprived quintile. Variation in socio-economic deprivation between sectors accounted for 62% of the variance in return rates, with little attenuation as a result of controlling for ethnic diversity, household mobility or health status.CONCLUSION: These results highlight the need to understand the causes of socio-economic gradients in screening participation and address barriers that could otherwise increase disparities in colorectal cancer survival