tbuckley/cabot-search huggingface dataset:
Maximum likelihood estimation of the heterogeneity of substitution rate among nucleotide sites.
Authors: X Gu, Y X Fu, W H Li
Journal: Molecular Biology and Evolution (1995)

This paper presents a maximum likelihood approach to estimating the variation of substitution rate among nucleotide sites. We assume that the rate varies among sites according to an invariant+gamma distribution, which has two parameters: the gamma parameter alpha and the proportion of invariable sites theta. Theoretical treatments on three, four, and five sequences have been conducted, and computer program have been developed. It is shown that rho = (1 + theta alpha)/(1 + alpha) is a good measure for the rate heterogeneity among sites. Extensive simulations show that (1) if the proportion of invariable sites is negligible, i.e., theta = 0, the gamma parameter alpha can be satisfactorily estimated, even with three sequences; (2) if the proportion of invariable sites is not negligible, the heterogeneity rho can still be suitably estimated with four or more sequences; and (3) the distances estimated by the proposed method are almost unbiased and are robust against violation of the assumption of the invariant + gamma distribution.
Treatment outcomes in older adolescent and young adult (AYA) patients with newly diagnosed AML.
Authors: J. A. Canner, T. A. Alonzo, J. Franklin, D. R. Freyer, A. S. Gamis, R. B. Gerbing, B. Lange, S. Meshinchi, W. G. Woods, J. P. Perentesis, J. Horan
Journal: Journal of Clinical Oncology (2011)

9506 Background: In the CCG 2961 trial for newly diagnosed AML, adolescent and young adult patients (aged 16-21 years, AYA) had inferior survival relative to younger patients. To more broadly define the impact of older age on outcomes in this setting and to identify factors responsible for its effect, we performed an analysis utilizing data from 4 COG trials. Methods: We compiled data from the CCG 2891, CCG 2941, CCG 2961 and AAML03P1 trials. For the 2891 trial, we utilized only the data from patients assigned to the intensively timed treatment arm. We compared the demographics, disease-related characteristics and outcomes of the AYA patients to those of younger patients. Results: The data set included 238 AYA patients (median age=17.2 years) and 1,602 younger patients (median age=6.9 years). There were no significant differences between the groups in race or gender. A greater proportion of the AYA patients were overweight (19.9% vs. 13.2%, p=0.009) and had a matched related donor available (29.0% vs. 21.7%, p=0.016). Using cytogenetics and molecular abnormalities (FLT3, CEBPA, NPM) to define poor, favorable and standard risk groups, a greater proportion of AYA patients had poor risk disease (16.6% vs. 10.4%, p=0.026) and a smaller proportion had standard risk disease (50.3% vs. 61.8%, p=0.006). At 5 years, AYA patients had marginally poorer overall survival from study entry (49 +/-7% (+/-2SE) vs. 54 +/-3%, p=0.058). AYA patients had a higher cumulative incidence of TRM from study entry (25+/-6% vs. 12+/-2%, p<0.001), but lower cumulative incidence of relapse from end of first course (30+/-7% vs. 41+/-3%, p=0.002). Infection accounted for most cases of TRM in both age groups. Multivariate analyses results will be presented. Conclusions: Our preliminary results suggest that AYA patients are more likely to die from treatment related causes but, despite being more apt to have poor risk disease, they are less likely to die from leukemic relapse than younger patients. As a result, survival rates in AYA and younger patients are similar. Our results also suggest that efforts to develop more effective strategies for preventing infection during AML therapy could reap great benefit for AYA patients.
Abstract 18558: Exploring Site Level Variation in Radiation Exposure in the VA: Insights From CART
Authors: Evan P Carey, Thomas T Tsai, Anna Baron, Gary Grunwald, Andrew Klein, Mladen Vidovich, Jeffrey Zimmet, Steven M Bradley, Thomas M Maddox, John S Rumsfeld, P M Ho
Journal: Circulation (2013)

Background: Prior studies have assessed variation in radiation use and fluoroscopy times for patients undergoing coronary angiography (CA) and percutaneous coronary intervention (PCI); however, the extent that this varies by cath labs is unknown. Methods: We analyzed data from the VA National CART Program of patients undergoing CA and PCI between 2010 and 2011 (n=28,513). Radiation exposure was measured using fluoroscopy time. We fit a mixed effects linear regression using log fluoroscopy time as outcome, a random effect for site, and adjusted for procedural and patient characteristics. Empirical Best Linear Unbiased Predictors for sites were used to estimate adjusted site level medians. The intra-class correlation (ICC) for site random effect was calculated to estimate the proportion of variance explained by site adjusting for patient and procedural characteristics. Marginal residuals were aggregated to site and examined at quarterly intervals for 2 years to establish stability of site medians over time. Results: Overall site median fluoroscopy time was 6 minutes (IQR: 3.5, 10.2) for CA and 16.5 (IQR: 10.3,26.1) minutes for PCI. After adjusting for procedural and patient characteristics, site median fluoroscopy times ranged from 43% below to 57% above the median for CAs and 66% below to 75% above for PCIs (Figure). Sites in the top quartile of fluoroscopy time were above the overall median in 96% for CA and 99% for PCI of time periods assessed. Cath lab site accounted for a significant amount of variance in fluoroscopy times (11.9% for CA and 21.5% for PCI). Conclusion: There is significant variation in fluoroscopy times across VA cath labs for coronary angiographies and PCIs. Even after adjustment for patient and procedures factors, there remains significant variability at the cath lab level suggesting that there may be opportunities for quality improvement interventions to reduce fluoroscopy times and radiation exposure for patients undergoing these procedures.
Sex Differences in Animal Models: Focus on Addiction
Authors: Jill B. Becker, George F. Koob
Journal: Pharmacological Reviews (2016)

The purpose of this review is to discuss ways to think about and study sex differences in preclinical animal models. We use the framework of addiction, in which animal models have excellent face and construct validity, to illustrate the importance of considering sex differences. There are four types of sex differences: qualitative, quantitative, population, and mechanistic. A better understanding of the ways males and females can differ will help scientists design experiments to characterize better the presence or absence of sex differences in new phenomena that they are investigating. We have outlined major quantitative, population, and mechanistic sex differences in the addiction domain using a heuristic framework of the three established stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Female rats, in general, acquire the self-administration of drugs and alcohol more rapidly, escalate their drug taking with extended access more rapidly, show more motivational withdrawal, and (where tested in animal models of "craving") show greater reinstatement. The one exception is that female rats show less motivational withdrawal to alcohol. The bases for these quantitative sex differences appear to be both organizational, in that estradiol-treated neonatal animals show the male phenotype, and activational, in that the female phenotype depends on the effects of gonadal hormones. In animals, differences within the estrous cycle can be observed but are relatively minor. Such hormonal effects seem to be most prevalent during the acquisition of drug taking and less influential once compulsive drug taking is established and are linked largely to progesterone and estradiol. This review emphasizes not only significant differences in the phenotypes of females and males in the domain of addiction but emphasizes the paucity of data to date in our understanding of those differences.
In vitro fertilisation for all
Authors: Alison P Murdoch
Journal: BMJ (2003)

Editor—Ashcroft in his editorial and the National Institute for Clinical Excellence in its consultation document avoid the question of how the value of in vitro fertilisation can be measured both in absolute terms and relative to other health spending priorities. 2 When we read and hear of children born as the result of in vitro fertilisation we should not think, “There’s another £15 000 gone.” But rather, “There’s another couple whose distress has been relieved and who have the opportunity to experience the love and fulfilment of children; there’s another human being who has been given the opportunity to live a life; and, there’s another person to pay the taxes for our healthcare and pensions when we retire.”
A phase I trial of bexarotene, a retinoid X receptor agonist, in non-M3 acute myeloid leukemia
Authors: D. E. Tsai, S. Luger, A. Kemner, C. Andreadis, A. Loren, D. Porter, E. Stadtmauer, C. Swider, A. Goradia, M. Carroll
Journal: Journal of Clinical Oncology (2007)

7061 Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with non-M3 AML and has completed enrollment. Methods: Bexarotene was administered daily until disease progression occurred. Dose escalation occurred in cohorts of 3–6 patients through 6 dose levels ranging from 100–400mg/m 2 . Results: 27 patients were enrolled: 19M/8F, median age 69 (range 51–82), 13 prior MDS, 12 primary refractory, median number of induction attempts 2, no prior chemotherapy 3, prior autologous stem cell transplant 5, 26 blood transfusion dependent, 18 platelet transfusion dependent, and 20 neutropenic. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade ≥3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea, pleural/pericardial effusions, and edema in the setting of a rising neutrophil count. This syndrome resolved with stopping bexarotene and initiating steroids. Evidence of activity was noted with bone marrow blasts decreasing to ≤5% in 4 patients. Seven patients showed evidence of neutrophil response (pretreatment median ANC 364/μL, range 28–1,242/μL, treatment ANC 3,540/μL, range 1,200–26,207/μL). Flow sorted peripheral blood neutrophils were collected from 3 of these patients and examined by FISH. Between 92–100% of neutrophils contained the patient's leukemic cytogenetic abnormality suggesting differentiation of the leukemic blasts. Eleven patients with platelet counts &lt;100,000/μL had increases in their platelet counts &gt;20,000/μL (peak range 40- 292x10 3 /μL). Five of these patients with platelet counts &lt;20,000/μL had improvement to 40–91,000/μL and became transfusion independent. Conclusions: Bexarotene is well tolerated at the dose levels studied. Evidence for clinical activity has been seen as exemplified by improvement in platelet counts, increased neutrophil counts and decreased bone marrow blasts. We postulate that bexarotene may induce leukemic blast differentiation in non-M3 AML and represent a novel non-cytotoxic treatment. No significant financial relationships to disclose.
Role of Regional and Distant Lymph Nodes in Rejection of Feline Sarcoma Virus-Induced Tumors in Sheep&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: G H Thellen, N C Pedersen, J Higgins
Journal: JNCI Journal of the National Cancer Institute (1979)

The immune response of regional and distant lymph nodes was compared relative to rejection of feline sarcoma virus (FeSV)-induced tumors in sheep. Following injection of FeSV-transformed allogeneic or autochthonous flbroblasts into the lower leg, small tumors developed at the site of inoculation and subsequently regressed. Efferent lymph from the regional popliteal nodes and distant nodes in the same host was collected for periods up to 40 days after tumor cell inoculation. The cell response in the efferent lymph of the stimulated node was the same regardless of whether inoculum consisted of autochthonous or allogeneic FeSV-transformed sheep cells. There was a rapid rise in total lymphocytes leaving the regional node, beginning at 3 days and peaking at 6–8 days post inoculation. On days 6–8 post inoculation, lymphoblasts appeared in regional lymph ranging from 25 to 40% of the total cell output. The cell population in lymph from distant (nonstimulated) nodes, however, remained morphologically normal throughout the response. Lymphocytes cytotoxic to the injected FeSV-transformed cells appeared in efferent lymph from the regional node within 5 days post inoculation and in lymph from distant nonstimulated nodes several days later. Cytotoxic lymphocytic cells had no “killing” effect against the corresponding nontransformed cells if the inoculum was autochthonous in origin; however, they did have such an effect when corresponding nontransformed cells were allogeneic. The cytotoxlcity of lymph cells varied according to the type of cells in the lymph. With the use of the growth inhibition assay, it was possible to demonstrate that lymph cell populations high In lymphoblasts “killed” all target cells in 24 hours, whereas populations of lymph cells comprised mainly of small lymphocytes took up to 2–3 days to “kill” the target cells. Complement-dependent antibody first appeared in lymph from the stimulated popliteal node at 8 days post inoculation and at 12 days post Inoculation in blood sera and lymph from distant nodes.
The predictive value of KRAS and BRAF mutations for outcome in second-line irinotecan monotherapy in metastatic colorectal cancer (mCRC).
Authors: K. G. Spindler, N. Pallisgaard, A. K. Jakobsen
Journal: Journal of Clinical Oncology (2010)

e14062 Background: Response to anti-EGFR monoclonal antibodies is confined to KRAS and BRAF wild type mutational status. The importance of the mutational status for outcome in chemotherapy-only regimes is presently discussed. The role of KRAS and BRAF mutations has not been investigated with regard to irinotecan monoterapy, which was the aim of the present study. Methods: The study included 111 patients with mCRC, treated with monotherapy irinotecan (350 mg/m2 q3w) in a single institution. KRAS and BRAF mutation was analysed on DNA from archival tumour tissue using a commercially available kit from DxS and an in house qPCR method, respectively. Clinical data were obtained from hospital charts, and response evaluated according to RECIST. The Kaplan Meyer method was used for survival analysis. Results: At time of analysis 5 patients were still on treatment, 77 (69%) patients had died and 34 were still alive, whereas 102 of the 111 patients had progressed and/or died. The median number of cycles was 6 (range 2–15). The overall response rate (RR) was 14%, and 65% achieved disease control (DC). The median observation time was 12.7 months (range 1.2–49.5). The median PFS was 4.9 months (95% CI 4.3-6.1), and the median OS was 16.1 months (95% 13.7-18.2). KRAS and BRAF mutational status was available for 98% and 97% with a total of 42 and 8 mutations, respectively, all mutually exclusive. There was no significant association between RR, DC rates and mutational status. The median OS and PFS was not significantly different in mutated and wildtype patients, all though a tendency for poor PFS was suggested in the group of 8 patients with BRAF mutations (p = 0.10). Conclusions: The present data do not indicate that response to irinotecan monotherapy is influenced by KRAS and/or BRAF mutational status in colorectal tumours. The predictive value of these markers should therefore be regarded as related to EGFR monoclonal antibodies therapy only, but there is an obvious need for verification by survival analysis of a larger sample size. No significant financial relationships to disclose.
15-Hydroxyprostaglandin dehydrogenase (PGDH) is an aberrant tumor suppressor in human breast cancer
Authors: I. Wolf, J. O’kelly, T. Rubinek, M. Tong, B. T. Lin, H. Tai, B. Y. Karlan, H. P. Koeffler
Journal: Journal of Clinical Oncology (2006)

10550 Background: Prostaglandin E2 plays a growth stimulatory role in breast cancer; and the rate-limiting enzyme in its synthesis, cyclooxygenase-2 (COX-2), is over-expressed in breast cancers. However, little is known about the expression pattern and activities of the key prostaglandin catabolic enzyme PGDH, in breast cancer pathogenesis. Methods: 5-aza-2’-deoxycytidine and suberoyl anilide bishydroxamide (SAHA) were used to unmask epigenetically silenced genes. DNA and RNA were extracted from tumors and cell lines using standard methods, and bisulfite sequencing was used for methylation analysis. Western blotting and real time PCR were used for expression analysis, and PGDH expression vector and PGDH-directed siRNA were used for overexpression and downregulation of PGDH, respectively. Athymic mice were utilized for xenograft models. Results: Using a pharmacologically based, genome-wide screen for epigenetically silenced genes, we found low levels of PGDH in MDA-MB-231 cells (estrogen receptor- (ER) and HER2-negative), but high levels in MCF-7 cells (ER-positive, HER2-negative), and observed upregulation of this enzyme following demethylation treatment. Methylation analysis revealed methylation of the PGDH promoter in one breast cancer cell line and in 3 of 10 primary tumors. Analysis of PGDH expression demonstrated low levels in 40% of primary breast tumors and identified a correlation between PGDH and ER expression. Upregulation of PGDH levels in MDA-MB-231 cells decreased their clonal growth and reduced their ability to form tumors in athymic mice. In contrast, silencing of PGDH in MCF-7 cells increased proliferation and enhanced in-vivo tumorigenicity. Further analysis revealed upregulation of aromatase following silencing of PGDH and inhibition of the ER pathway by forced expression of the enzyme. PGDH levels were downregulated by estrogen but upregulated by the tumor suppressor gene C/EBPα. Conclusions: Our results identify for the first time, that PGDH, the COX-2 antagonist, is aberrantly silenced in breast cancer. Activation of this enzyme, particularly in ER- and HER2-negative tumors, now becomes an interesting target for clinical studies. No significant financial relationships to disclose.
Abstract P442: Apparently Healthy Fit Asymptomatic Adults Are Not Immune To Sub-clinical Atherosclerosis
Authors: Robert Scales, Kathryn A Cornella, Mohan Vardhini, Cengiz Akalan, Qing Wu, Susan Halli, Robert T Hurst
Journal: Circulation (2014)

Evidence suggests that cardiovascular (CV) fitness below the 20 th percentile for age and gender is associated with increased cardiac death and all cause mortality. This study assessed the association between CV fitness and sub-clinical atherosclerosis (SCA) in a self-selected group of participants in a cardiology-based prevention program. The study involved a single visit observation of participants. 240 apparently healthy asymptomatic adults &lt;65 years (69% male) received a maximal graded exercise stress test and a carotid intima-media thickness (CIMT) evaluation with B-mode ultrasound. CV fitness was classified based on age-gender norms (very poor=1-19 th , poor=20-39 th , fair=40-59 th , good=60-79 th , excellent/superior=80-100 th percentile). CIMT was used to define CV health based on age-gender-race norms. SCA was considered present when there was non-occlusive carotid artery plaque (&gt;1.5mm and &gt;50% of the surrounding intima-media) or CIMT &gt;75 th percentile. Anyone with a prior history of clinically apparent atherosclerosis or diabetes was excluded from the study. The mean age of participants was 50 yrs (SD= 8.7). 113 participants (47%) had excellent/superior CV fitness. 41 (17%) were classified good, 36 (15%) fair, 20 (8%) poor and 30 (12%) very poor. 69 (61%) participants with excellent/superior CV fitness had advanced atherosclerosis (plaque=43%; n=49 or CIMT &gt;75 th percentile=l7%; n=20). In the good classification there were 26 (64%) with plaque (49%; n=20) or CIMT &gt;75 th percentile (15%; n=6). There were 23 (63%) in the fair classification with plaque (44%; n=16) or CIMT &gt;75 th percentile (19%; n=7), 11 (55%) in the poor classification with plaque (45%; n=9) or CIMT &gt;75 th percentile (10%; n=2) and 17 (56%) in the very poor classification with plaque (53%; n=16) or CIMT &gt;75 th percentile (3%; n=1). 58 (24%) of the total number of participants were classified with superior CV fitness (95-100 th percentile); of which 36 (62%) had SCA (plaque=45%; n=26 or CIMT &gt;75 th percentile=17%; n=10). In this self-selected population, CIMT testing detected evidence of SCA across all age-gender fitness classifications, which included very fit individuals. Further investigation is needed to identify other factors that may be associated with increased CV risk in apparently healthy fit asymptomatic adults.
Cognitive and Academic Functioning in Survivors of Pediatric Bone Marrow Transplantation
Authors: Sean Phipps, Maggi Dunavant, Deo K. Srivastava, Laura Bowman, Raymond K. Mulhern
Journal: Journal of Clinical Oncology (2000)

To evaluate cognitive and academic functioning in survivors of pediatric bone marrow transplants (BMTs) at 1 and 3 years after a BMT.In a prospective, longitudinal design, patients underwent a comprehensive battery of neurocognitive measures before admission for transplantation and at 1, 3, and 5 years after a BMT. This article describes a cohort of 102 survivors with follow-up data available for 1 year after a BMT, including 54 survivors with follow-up available for 3 years. This represents the largest cohort of pediatric BMT survivors yet reported in a prospective study.In the cohort as a whole, there were no significant changes on global measures of intelligence (intelligence quotient [IQ]) and academic achievement at either 1 or 3 years after a BMT, despite adequate power to detect an IQ change of three points or greater. Likewise, performance on specific tests of neuropsychologic function remained stable. No significant differences were observed between patients whose conditioning regimen included total-body irradiation (TBI) and those whose did not. The primary predictor of neurocognitive outcome was patient age, with younger patients more likely to show declines over time. The subset of patients who were less than 3 years of age at the time of transplantation seemed to be particularly vulnerable to cognitive sequelae.The use of BMTs with or without TBI entails minimal risk of late neurocognitive sequelae in patients who are 6 years of age or older at the time of transplantation. However, patients who are less than 6 years of age at the time of transplantation, and particularly those less than 3 years of age, seem to be at some risk of cognitive declines.