tbuckley/cabot-search huggingface dataset:
Abstract A24: Network-based inference of resistance mechanisms to estrogen inhibitors in ER+ breast cancer
Authors: Mariano Javier Alvarez, Yao Shen, Brygida Bisikirska, Ronald Realubit, Sergey Pampou, Charles Karan, Andrea Califano
Journal: Clinical Cancer Research (2015)

Abstract Anti-estrogen therapy is the standard of adjuvant care for luminal breast cancer. However, more than 30% of the cases either do not respond to the therapy or develop resistance and progress to metastatic disease. In this work we use a network-based approach to identify the regulatory motifs driving resistance to estrogen inhibitors and to predict small molecule compounds that can abrogate the activity of such regulatory modules, thus reverting the resistance phenotype. This is similar to what we have accomplished in glucocorticoid resistance in T-ALL (Piovan et.al (2013) Cancer Cell 24(6):766). To accomplish this goal, we established genome-wide expression signatures characteristic of the resistant phenotype (ER-GES) both from patients' data and cell lines. Then, we used the VIPER algorithm to interrogate a breast carcinoma-specific transcriptional network (BRCAnet) assembled from 844 TCGA tumor samples with these signatures, to infer master regulators of resistance. Finally we leveraged the connectivity map (CMAP) dataset, containing expression profiles from MCF7 cells exposed to 1,300 small molecule compounds, to identify the effectors of each profiled compounds. By comparing drug effectors with master regulators of ER-inhibitors chemoresistance, we identified small molecule compounds predicted to revert resistant cells to a sensitive state. We reasoned that a compound able to reverse such resistance should induce synergistic activity when combined with anti-estrogen agents, like tamoxifen. To validate our prediction in an unbiased way, we assessed the synergistic nature of the interaction between tamoxifen and 100 compounds (sensitizer set) selected to have the most orthogonal mechanism of action, using 4 x 4 dilutions assays, with cell viability as readout. Synergistic interactors were identified by combination index (CI &amp;lt; 0.9) and Excess over BLISS (EOB &amp;gt; 10%). Interestingly, compounds predicted to rescue sensitivity to ER inhibitors in cell lines were highly enriched in those that were experimentally validated to be synergistic with tamoxifen. Taken together, these results suggest that network-based analysis is effective in capturing drivers of chemoresistance to estrogen deprivation, as well as the specific compounds that can rescue sensitivity by inhibiting them. Citation Format: Mariano Javier Alvarez, Yao Shen, Brygida Bisikirska, Ronald Realubit, Sergey Pampou, Charles Karan, Andrea Califano. Network-based inference of resistance mechanisms to estrogen inhibitors in ER+ breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A24.
HbA1c-levels in patients with operable chronic thromboembolic pulmonary hypertension
Authors: Sarah Haase, Henning Tiede, Eckhard Mayer, Christoph Wiedenroth, Stefan Guth, Mohammed Zaatar, Ardeschir Ghofrani, Manuel Jonas Richter
Journal: European Respiratory Journal (2014)

Background: In pulmonary arterial hypertension increased HbA1c-levels reflect disease severity and have been identified as negative prognostic factors. HbA1c and their association with disease severity in operable chronic thromboembolic pulmonary hypertension (CTEPH) are unknown.  Methods: HbA1c, hemodynamic and exercise parameters were prospectively analyzed in CTEPH before pulmonary endarterectomy (PEA). Using published criteria (American Diabetes Association), a HbA1c (International Federation of Clinical Chemistry and Laboratory Medicine (IFCC))   48 mmol/mol as manifest diabetes mellitus. All values are means ± standard deviation.  Results: In 63 patients (BMI: 27.6 ± 5.6 kg/m2; age: 61 ± 12 years) with CTEPH (mean pulmonary arterial pressure :43.2 ± 11.2 mmHg, pulmonary vascular resistance: 662 ± 318 dyn*s/cm5, cardiac index (CI): 2.3 ± 0.6 l/min/m2, WHO Functional Class: 3.0 ± 0.6 and peak VO2: 12.1 ± 3.9 l/min/kg) the HbA1c-level was 40.5 ± 6.5 mmol/mol. Diabetes mellitus was observed in 9 patients (14 %) with a HbA1c-level of 53.6 ± 4.8 mmol/mol, whereas 22 patients (35 %) had glucose intolerance (HbA1c: 43.5 ± 1.9 mmol/mol). In univariate linear regression analysis elevated HbA1c-levels were associated with a reduced CI (r= -0.4, p= 0.001) and reduced peak VO 2  (r= -0.35, p= 0.005). Multivariate linear regression analysis including age, gender and BMI as covariates, confirmed HbA1c as independently correlated with CI (r= -0.4, p= 0.002) and peak VO 2  (r= -0.35, p= 0.02).  Conclusions: In operable CTEPH diabetes mellitus and glucose intolerance assessed via HbA1c are common and associated with disease severity.
Age of the common ancestor of human mitochondrial DNA.
Authors: M Nei
Journal: Molecular Biology and Evolution (1992)

Studying the evolutionary change of the control region of human (H) and chimpanzee (C) mitochondrial DNAs (mtDNAs), Vigilant et al. ( 199 1) concluded that the root of the phylogenetic tree for H mtDNAs is located at a sequence from African populations and that the age of the common H ancestral mtDNA is 166,000-249,000 years. Hedges et al. ( 1992) and Templeton ( 1992) challenged the first of these conclusions, showing that valid statistical tests do not support it. In this letter, I would like to show that Vigilant et al.? second conclusion is also questionable and that, if we consider statistical errors associated with the rate of nucleotide substitution, the range of the estimate of the age becomes much wider. In the control region, transitional nucleotide substitution is known to occur at a much higher rate than does transversional substitution, and the transitional differences between the H and C mtDNAs seem to have reached a saturation level at hypervariable sites of this region (Kocher and Wilson 199 1) . Vigilant et al. therefore used information on the transversional differences between H and C and the transition/ transversion ratio obtained from H data, to calibrate the rate of nucleotide substitution. Let n be the number of transversional differences between H and C, and let R be the ratio of transitional (s) and transversional (v) substitutions observed among H sequences. [ Hasegawa and Horai ( 199 1) suggested that R may be different between H and C, but K. Tamura’s (personal communication ) detailed analysis indicates that it is essentially the same for the two species. Here I consider only H data, following Vigilant et al.] The expected total number of nucleotide substitutions between H and C can then be estimated by n +nR. So, if the total number of nucleotides examined is m, then the total number of nucleotide substitutions, per site, between H and C is given by
AVIATION MEDICINE—A BRIEF HISTORY: THE PHYSICAL QUALIFICATIONS FOR FLYING; OXYGEN WANT AND THE USE OF SUPPLEMENTARY OXYGEN
Authors: Louis H. Bauer
Journal: Annals of Internal Medicine (1943)

Article1 January 1943AVIATION MEDICINE—A BRIEF HISTORY: THE PHYSICAL QUALIFICATIONS FOR FLYING; OXYGEN WANT AND THE USE OF SUPPLEMENTARY OXYGENLOUIS H. BAUER, M.D., F.A.C.P.LOUIS H. BAUER, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-18-1-15 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptOne of the newest specialties in medicine is that known as Aviation Medicine. It is a little different from other specialties in that it, to a large extent, comprises portions of other specialties all applied to aeronautics. It includes a certain amount of ophthalmology, otology, internal medicine, neuropsychiatry, psychology and a large amount of physiology. The whole purpose of the subject is largely preventive in nature. It involves the selection and care of the pilot and his protection against the physical forces acting upon him in the air, all with a view to preventing accidents from a physical cause.Aviation... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Hempstead, New York*Read at the St. Paul meeting of the American College of Physicians April 20, 1942. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byPersonality and Somatotype of Trainee PilotsPhysique and success in military flying 1 January 1943Volume 18, Issue 1Page: 15-20KeywordsOphthalmologyOtologyOxygenPsychology ePublished: 1 December 2008 Issue Published: 1 January 1943 PDF downloadLoading ...
Late-breaking abstract: Genapha/dbASM: Investigating allele-specific methylation (ASM) and associations to common complex diseases
Authors: Denise Daley, Bi Ling Chen, Kevin Ushey, George Ellis
Journal: European Respiratory Journal (2014)

As interest in studying allele-specific methylation (ASM) grows, there is a need for a resource that stores and catalogs SNPs and regions that demonstrate allele specific methylation, analogous to dbSNP. We have created a new web resource called dbASM, hosted on the Genapha web server (www.genapha.ca),in order to help fulfill this need. The aim of dbASM is twofold: 1. Curate from the literature a publicly-accessible database of known sites of ASM. 2. Provide a web-based platform of tools for exploring ASM and determining regions of interest. These regions of interest can then be assayed for methylation status using small, custom arrays that are currently cheaper than using whole-genome approaches such as the Illumina 450K or bisulphite sequencing. We present the dbASM resource including details on the underlying database construction and datasets, in addition to the web tools and example workflows. The web tools that are currently available are: GWAS Catalog SNP Search, ASM SNP Search, SNP Counter, Methylation Plots Generation, and Sequence Viewer. GWAS Catalog SNP Search allows browsing through NHGRI9s Catalog of Published Genome-Wide Association Studies by phenotype and filtering SNPs based on their relation to suspected sites of ASM. ASM SNP Search supports finding SNPs based on: ASM status or interrogability; location compared to genes, a chromosomal region, or other SNP9s; and filtering by population minor allele frequencies and sample size. Methylation Plots Generation calculates SNP correlation stratifying by genotype with CpG site methlyation patterns from the HapMap population. These tools are all freely available for use at: http://genapha.icapture.ubc.ca/asm/.
PSYCHIC DETERMINISM : AN OUTMODED CONCEPT?
Authors: Lawrence Friedman
Journal: American Journal of Psychiatry (1960)

1. It is not yet clear what conclusions we may draw from the Indeterminacy Principle of physics in regard to causality or determinism. 2. We must explain why many thinkers hang on to the concepts of causality and determinism by factors of sufficient weight to account for the tenacity with which they hold on. 3. Determinism, as it is commonly thought of, has not as yet been expressed in non-causal terms, and causality or its proxies still appear to be essential concepts in scientific thought. 4. Attempts to make the question of determinism an empirical one have not been successful.
Abstract 2100: Curative Ablation for Atrial Fibrillation: Is There a Late Attrition Rate?
Authors: Arti Shah, Tina C Sichrovsky, Sripal Bangalore, Delia Cotiga, Khashayar Hematopour, Howard Levitt, Jonathan S Steinberg
Journal: Circulation (2006)

Background Large population of pts who undergo pulmonary vein isolation (PVI) for atrial fibrillation (AF) have a complete response (CR), become AF-free (AFF) and require no antiarrhythmic drug (AA...
Impact of Preoperative Weight Loss on Postoperative Morbidity
Authors: C S Higgens, M R B Keighley, R N Allan
Journal: Journal of the Royal Society of Medicine (1981)

Clinical observations in developing countries and experimental studies in animals suggest that preoperative weight loss adversely affects postoperative morbidity. Since it is not clear whether these findings can be applied to surgical series in European countries, we have studied 106 surgically-treated patients with inflammatory bowel disease. Patients were divided into three groups according to the degree of preoperative weight loss. The groups were well matched in all other respects. Postoperative morbidity was monitored independently. The outcome in all three groups was similar so that in these patients, at least, preoperative weight loss did not adversely affect the postoperative outcome.
Attempts to Find Human Adenovirus Type-12 Tumor Antigens in Human Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: K. J. McCormick, G. L. van Hoosier, J. J. Trentin
Journal: JNCI Journal of the National Cancer Institute (1968)

Journal Article Attempts to Find Human Adenovirus Type-12 Tumor Antigens in Human Tumors Get access K. J. McCormick, K. J. McCormick Division of Experimental Biology, Baylor University College of Medicine, Houston, Texas 77025 Search for other works by this author on: Oxford Academic PubMed Google Scholar G. L. van Hoosier, Jr., G. L. van Hoosier, Jr. Division of Experimental Biology, Baylor University College of Medicine, Houston, Texas 77025 Search for other works by this author on: Oxford Academic PubMed Google Scholar J. J. Trentin J. J. Trentin Division of Experimental Biology, Baylor University College of Medicine, Houston, Texas 77025 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 40, Issue 2, February 1968, Pages 255–261, https://doi.org/10.1093/jnci/40.2.255 Published: 01 February 1968 Article history Received: 29 May 1967 Accepted: 23 August 1967 Published: 01 February 1968
MicroRNAs in bile vesicles: Finding a trade‐off for biomarker discovery
Authors: Henk P. Roest, Cornelia J. Verhoeven, Luc J.W. van der Laan
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. To the Editor: Cholangiocarcinoma (CCA) is increasing in incidence, and surgery is considered the only curative option.1 The similarities in clinical manifestations of CCA with many benign disorders, however, often result in a diagnostic delay for patients. Following up on the article by Shigehara et al.,2 the group of Selaru presented data in Hepatology identifying another set of microRNAs (miRNAs) in bile that could discriminate between CCA patients and control patients with benign or nontumorigenic strictures.3 Where Shigehara et al. used whole bile as a source for miRNA profiling, the Selaru group focused on a subfraction of bile: the extracellular vesicles (EVs). This approach, however, neglects miRNAs that are not EV‐associated. Recent publications have shown that, by performing differential centrifugation procedures, a significant majority of extracellular miRNAs are actually not present in EVs. Estimates suggest that 80‐90% of the miRNA pool remains in the soluble fraction.4 Although not protected through vesicularization, these miRNAs are also RNAse‐insensitive, resulting from interactions with (lipo)proteins.5 From our own experience with investigating the release of miRNAs from the liver,8 we confirmed that in bile only a small fraction of small RNAs and miRNAs is located in the EV pellet. To emphasize that EVs provide a more reliable source for the diagnosis of CCA is, in our opinion, not solidly supported by the supporting data presented.3 Shigehara et al. already showed RNAse activity in bile,2 and confirming this with ribosomal RNA can hardly be considered exemplary for miRNAs and does not favor the use of EVs alone. We do acknowledge the conclusion that the amount of putatively interesting miRNAs can be confounded by contamination of the sample by free‐floating cells. Using the centrifugation procedure shown in Fig. 1A, which was adapted from Shigehara et al.,2 we observed that, for hepatocyte‐ and cholangiocyte‐derived miRNAs, less than 1% is represented in the extracellular vesicle fraction (P3, Fig. 1A), whereas the majority (61‐73%) of the total miRNA pool remain in the unpelleted fraction (sup3, Fig. 1B). Therefore, the vesicle‐free miRNA fraction is most abundant in bile and should not merely be disregarded as confounding material. Based on this, we suggest considering the use cell‐free bile, not just whole bile or only subcellular fractions of bile, to get a complete representation of the small RNA spectrum available for biomarker purposes. Likely this could improve not only specificity, but also the sensitivity of these markers, not only for CCA, but likely also for other liver‐ and bile duct‐associated diseases.Figure 1: Relative distribution of hepatocyte‐derived (HDmiR) in cholangiocyte‐derived (CDmiR) miRNAs in fractionated bile. (A) Differential centrifugation procedure. (B) Relative distribution of CDmiR‐30e, CDmiR‐222, CDmiR‐122 and HDmiR‐148a over the various fractions.
Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.
Authors: E Gamelin, M Boisdron-Celle, R Delva, C Regimbeau, P E Cailleux, C Alleaume, M L Maillet, M J Goudier, M Sire, M C Person-Joly, M Maigre, P Maillart, R Fety, P Burtin, A Lortholary, Y Dumesnil, L Picon, J Geslin, P Gesta, E Danquechin-Dorval, F Larra, J Robert
Journal: Journal of Clinical Oncology (1998)

PURPOSE A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a &gt; or = 50% dose increase. CONCLUSION Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.
Effect of Repeated Glucagon Doses on Hepatic Glycogen in Type 1 Diabetes: Implications for a Bihormonal Closed-Loop System
Authors: Jessica R. Castle, Joseph El Youssef, Parkash A. Bakhtiani, Yu Cai, Jade M. Stobbe, Deborah Branigan, Katrina Ramsey, Peter Jacobs, Ravi Reddy, Mark Woods, W. Kenneth Ward
Journal: Diabetes Care (2015)

OBJECTIVE To evaluate subjects with type 1 diabetes for hepatic glycogen depletion after repeated doses of glucagon, simulating delivery in a bihormonal closed-loop system. RESEARCH DESIGN AND METHODS Eleven adult subjects with type 1 diabetes participated. Subjects underwent estimation of hepatic glycogen using 13C MRS. MRS was performed at the following four time points: fasting and after a meal at baseline, and fasting and after a meal after eight doses of subcutaneously administered glucagon at a dose of 2 µg/kg, for a total mean dose of 1,126 µg over 16 h. The primary and secondary end points were, respectively, estimated hepatic glycogen by MRS and incremental area under the glucose curve for a 90-min interval after glucagon administration. RESULTS In the eight subjects with complete data sets, estimated glycogen stores were similar at baseline and after repeated glucagon doses. In the fasting state, glycogen averaged 21 ± 3 g/L before glucagon administration and 25 ± 4 g/L after glucagon administration (mean ± SEM) (P = NS). In the fed state, glycogen averaged 40 ± 2 g/L before glucagon administration and 34 ± 4 g/L after glucagon administration (P = NS). With the use of an insulin action model, the rise in glucose after the last dose of glucagon was comparable to the rise after the first dose, as measured by the 90-min incremental area under the glucose curve. CONCLUSIONS In adult subjects with well-controlled type 1 diabetes (mean A1C 7.2%), glycogen stores and the hyperglycemic response to glucagon administration are maintained even after receiving multiple doses of glucagon. This finding supports the safety of repeated glucagon delivery in the setting of a bihormonal closed-loop system.
Race and clinical outcome in breast cancer in a series with long-term follow-up evaluation.
Authors: R Heimann, D Ferguson, C Powers, D Suri, R R Weichselbaum, S Hellman
Journal: Journal of Clinical Oncology (1997)

To compare the outcome of African American (AA) and Caucasian (C) breast cancer patients who had equivalent disease extent and were similarly treated.We compared prognostic characteristics, treatment, and outcome of 1,037 C and 481 AA breast cancer patients treated with mastectomy between 1946 and 1987. The median follow-up duration was 15.6 years.During the study period, there was a successive increase in the percent of patients who presented with early breast cancer. Between 1980 and 1987, 35.1% AA versus 47.6% C patients had < or = 2-cm tumors and 50.0% AA versus 61.9% C patients were node-negative, while between 1946 and 1959, 27.7% AA and 31.3% C had < or = 2-cm tumors and 41.5% AA versus 40.4% C patients were node-negative. The treatments were similar during the study period. The 20-year disease-free survival (DFS) rate of AA compared with C patients with node-negative < or = 2-cm, 2.1- to 4-cm, and greater than 4-cm tumors and of patients with one to three and > or = four positive nodes was not significantly different. Equal-size tumors had similar proportion of positive axillary nodes in AA compared with C patients. The DFS for AA patients compared with C patients was similar in the periods 1946 to 1959, 1960 to 1969, and 1970 to 1979, but was lower between 1980 and 1987 (P = .02). In multivariable analysis, race was not a significant variable.In this large group of uniformly treated breast cancer patients, race was not an independent factor that influenced outcome. The racial differences seen between 1980 and 1987 are likely because of a larger percent of greater than 2-cm and node-positive tumors in AA patients. Education and access to early diagnosis should reduce or eliminate the racial differences seen.