tbuckley/cabot-search huggingface dataset:
Exploiting the Mutanome for Tumor Vaccination
Authors: John C. Castle, Sebastian Kreiter, Jan Diekmann, Martin Löwer, Niels van de Roemer, Jos de Graaf, Abderraouf Selmi, Mustafa Diken, Sebastian Boegel, Claudia Paret, Michael Koslowski, Andreas N. Kuhn, Cedrik M. Britten, Christoph Huber, Özlem Türeci, Ugur Sahin
Journal: Cancer Research (2012)

Multiple genetic events and subsequent clonal evolution drive carcinogenesis, making disease elimination with single-targeted drugs difficult. The multiplicity of gene mutations derived from clonal heterogeneity therefore represents an ideal setting for multiepitope tumor vaccination. Here, we used next generation sequencing exome resequencing to identify 962 nonsynonymous somatic point mutations in B16F10 murine melanoma cells, with 563 of those mutations in expressed genes. Potential driver mutations occurred in classical tumor suppressor genes and genes involved in proto-oncogenic signaling pathways that control cell proliferation, adhesion, migration, and apoptosis. Aim1 and Trrap mutations known to be altered in human melanoma were included among those found. The immunogenicity and specificity of 50 validated mutations was determined by immunizing mice with long peptides encoding the mutated epitopes. One-third of these peptides were found to be immunogenic, with 60% in this group eliciting immune responses directed preferentially against the mutated sequence as compared with the wild-type sequence. In tumor transplant models, peptide immunization conferred in vivo tumor control in protective and therapeutic settings, thereby qualifying mutated epitopes that include single amino acid substitutions as effective vaccines. Together, our findings provide a comprehensive picture of the mutanome of B16F10 melanoma which is used widely in immunotherapy studies. In addition, they offer insight into the extent of the immunogenicity of nonsynonymous base substitution mutations. Lastly, they argue that the use of deep sequencing to systematically analyze immunogenicity mutations may pave the way for individualized immunotherapy of cancer patients.
Health and Environment Information Systems for Exposure and Disease Mapping, and Risk Assessment
Authors: Lars Jarup
Journal: Environmental Health Perspectives (2004)

A large number of chemicals are used on a regular basis in modern society. Thousands of new chemicals are added each year, many of which may have toxic properties constituting potential health hazards. Rapid assessment of the risk associated with the use of these chemicals is therefore essential to protect people from exposure to potentially harmful substances. Exposures to chemicals (and physical agents) are typically unevenly distributed geographically as well as temporally. Disease occurrence also shows geographically varying patterns. Geographic information systems (GIS) may be used to produce maps of exposure and/or disease to reveal spatial patterns. Exposure mapping using advanced GIS modeling may enhance exposure assessment in environmental epidemiology studies. Disease maps can be valuable tools in risk assessment to explore changes in disease patterns potentially associated with changes in environmental exposures. Spatial variations in risk and trends related to distance from pollution sources may be studied using software tools such as the Rapid Inquiry Facility, developed by the U.K. Small Area Health Statistics Unit and enhanced in the European Health and Environment Information System project, for an initial quick evaluation of any potential health hazards associated with an environmental pollutant.
Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy
Authors: R. Soong, N. Shah, M. Salto-Tellez, B.C. Tai, R.A. Soo, H.C. Han, S.S. Ng, W.L. Tan, N. Zeps, D. Joseph, R.B. Diasio, B. Iacopetta
Journal: Annals of Oncology (2008)
Evolution of accelerometer methods for physical activity research
Authors: Richard P Troiano, James J McClain, Robert J Brychta, Kong Y Chen
Journal: British Journal of Sports Medicine (2014)

The technology and application of current accelerometer-based devices in physical activity (PA) research allow the capture and storage or transmission of large volumes of raw acceleration signal data. These rich data not only provide opportunities to improve PA characterisation, but also bring logistical and analytic challenges. We discuss how researchers and developers from multiple disciplines are responding to the analytic challenges and how advances in data storage, transmission and big data computing will minimise logistical challenges. These new approaches also bring the need for several paradigm shifts for PA researchers, including a shift from count-based approaches and regression calibrations for PA energy expenditure (PAEE) estimation to activity characterisation and EE estimation based on features extracted from raw acceleration signals. Furthermore, a collaborative approach towards analytic methods is proposed to facilitate PA research, which requires a shift away from multiple independent calibration studies. Finally, we make the case for a distinction between PA represented by accelerometer-based devices and PA assessed by self-report.
SET IN THE SCHIZOPHRENIC AS MEASURED BY A COMPOSITE REACTION TIME INDEX
Authors: E. H. RODNICK, DAVID SHAKOW
Journal: American Journal of Psychiatry (1940)

Twenty-five schizophrenic patients and 10 normal subjects were used in an experiment on reaction time employing preparatory intervals of 1, 2, 4, 7.5, 15 and 25 seconds in length. Two procedures were used. In the regular warning procedure each particular interval was presented a number of times in succession. In the irregular warning procedure the various preparatory intervals were presented in a systematically random fashion. The principal findings were: 1. Normals showed significantly shorter reaction times than did the patients, although there was a small degree of overlap. The shortest reaction times of the normals occurred at the 2-second interval in both procedures. The patients on the other hand showed their minimum times with somewhat longer intervals. 2. In the normal subjects the reaction times of the regular procedure are significantly shorter than those of the irregular procedure at each interval except the 25-second, at which point the two curves crossed. The differences between the two procedures diminished with increase in length of interval. The schizophrenics gave shorter times in the regular procedure at only the 1-, 2-and 4-second intervals. At the longer intervals, the times of the regular procedure were actually longer than those of the irregular procedure. 3. A composite index was constructed on the basis of these differences between patients and normals, which effectively separated the two groups with practically no overlap. This composite index, which can be expressed in terms of a single number, is more effective in differentiating the two groups than is simple reaction time level. 4. The suggestion is made that such an index has practical value as a clinical device.
Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction
Authors: Akio Kawakami, Mizuko Osaka, Mariko Tani, Hiroshi Azuma, Frank M. Sacks, Kentaro Shimokado, Masayuki Yoshida
Journal: Circulation (2008)

Background— Apolipoprotein CIII (apoCIII) is a component of some triglyceride-rich very-low-density and low-density lipoprotein and is elevated in dyslipidemia with insulin resistance and the metabolic syndrome. We previously reported that apoCIII directly activates proinflammatory and atherogenic signaling in vascular endothelial cells through protein kinase C-β (PKCβ). Because PKCβ impairs the response of vascular endothelial cells to insulin, we tested the hypothesis that apoCIII affects insulin signaling in vascular endothelial cells and its function in vitro and in vivo. Methods and Results— ApoCIII inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells. These effects of apoCIII led to reduced endothelial nitric oxide synthase (eNOS) activation and NO release into the media. ApoCIII activated PKCβ in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKCβ. The impaired insulin signaling was restored by PKCβ inhibitor or MEK1 inhibitor. ApoCIII-rich very-low-density lipoprotein and apoCIII impaired insulin signaling in the aorta of C57BL/6J mice and in human umbilical vein endothelial cells, which was recovered by PKCβ inhibitor. They also inhibited endothelium-dependent relaxation of the aortas of C57BL/6J mice. In summary, apoCIII in very-low-density lipoprotein impaired insulin stimulation of NO production by vascular endothelium and induced endothelial dysfunction in vivo. This adverse effect of apoCIII was mediated by its activation of PKCβ, which inhibits the IRS-1/PI3K/Akt/eNOS pathway. Conclusion— Our results suggest that apoCIII is a crucial link between dyslipidemia and insulin resistance in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions.
Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.
Authors: Y P Zhou, V E Grill
Journal: Journal of Clinical Investigation (1994)

We tested effects of long-term exposure of pancreatic islets to free fatty acids (FFA) in vitro on B cell function. Islets isolated from male Sprague-Dawley rats were exposed to palmitate (0.125 or 0.25 mM), oleate (0.125 mM), or octanoate (2.0 mM) during culture. Insulin responses were subsequently tested in the absence of FFA. After a 48-h exposure to FFA, insulin secretion during basal glucose (3.3 mM) was several-fold increased. However, during stimulation with 27 mM glucose, secretion was inhibited by 30-50% and proinsulin biosynthesis by 30-40%. Total protein synthesis was similarly affected. Conversely, previous palmitate did not impair alpha-ketoisocaproic acid (5 mM)-induced insulin release. Induction and reversibility of the inhibitory effect on glucose-induced insulin secretion required between 6 and 24 h. Addition of the carnitine palmitoyltransferase I inhibitor etomoxir (1 microM) partially reversed (by > 50%) FFA-associated decrease in secretory as well as proinsulin biosynthetic responses to 27 mM glucose. The inhibitory effect of previous palmitate was similar when co-culture was performed with 5.5, 11, or 27 mM glucose. Exposure to palmitate or oleate reduced the production of 14CO2 from D-[U-14C]glucose, and of 14CO2 from D-[3,4-14C]-glucose, both effects being reversed by etomoxir. Conclusions: long-term exposure to FFA inhibits glucose-induced insulin secretion and biosynthesis probably through a glucose fatty acid cycle.
FII haemagglutination test for serum antigammaglobulin factors in arthritides sero-positive and sero-negative by other tests.
Authors: D W Zutshi, C A Reading, W V Epstein, B M Ansell, E J Holborow
Journal: Annals of the Rheumatic Diseases (1969)

were also tested by the FIT method.This report deals with results obtained on single serum samples received from each patient during this period of time.Control sera were obtained as described.The sex distribution varied somewhat between the different groups of cases distinguished, but this could not be related to the serological findings. MethodsDifferential Agglutination Test (DAT).-Thiswas performed as described by Bywaters and Scott (1960).The latex fixation test was performed by the single tube method, based on Singer and Plotz (1956) as described by Bywaters and Scott (1960).F!! Haemagglutination Test (a) Preparation ofFII Coated Tanned Sheep Cells.-Sheep blood was taken from freshly slaughtered sheep into acid-citrate dextrose solution and kept at 4°C. for 1 week.Sheep red cells were washed four times in phosphate buffered saline (0 15 M Na2HPO4 4720 ml., 0-15 M KH2PO4 280 ml., 0 15 M NaCI 5000 ml., 289
Clinical Trial Designs for Predictive Biomarker Validation: Theoretical Considerations and Practical Challenges
Authors: Sumithra J. Mandrekar, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2009)

Biomarkers can add substantial value to current medical practice by providing an integrated approach to prediction using the genetic makeup of the tumor and the genotype of the patient to guide patient-specific treatment selection. We discuss and evaluate various clinical trial designs for the validation of biomarker-guided therapy.
Premarital AIDS Testing: Public Policy Abandoned at the Altar
Authors: Stephen C. Joseph
Journal: JAMA (1989)

In detailing the impact over 6 months of the legislatively mandated premarital human immunodeficiency virus (HIV) screening program in Illinois, Turnock and Kelly's<sup>1</sup>article in this issue ofThe Journalis an important effort by a public health agency to subject a legislative initiative to a comprehensive impact analysis. The article establishes that eight seropositive individuals were identified out of 70 846 applicants for marriage licenses, at an estimated cost of $2.5 million. After analyzing the economic, social, and public health implications of the program, the article concludes that Illinois' experience with premarital HIV screening shows mandatory or publicly supported HIV antibody screening of low-prevalence populations is not cost-effective and has no positive impact on disease prevention. This adds firm evidence to the impressions in other localities attempting or considering such programs. In New York City, premarital HIV screening was one of a range of public policy issues that
Properties of the antigen-specific suppressive T-cell factor in the regulation of antibody response of the mouse. III. Dual gene control of the T-cell-mediated suppression of the antibody response.
Authors: M Taniguchi, T Tada, T Tokuhisa
Journal: The Journal of Experimental Medicine (1976)

The antigen-specific suppressive T-cell factor of mice, which had previously been shown to be an I region gene product, could effectively suppress the in vitro secondary antibody response of spleen cells from syngeneic or H-2 compatible mouse strains but not that of H-2 incompatible strains. The identities among genes in the left side half (K, I-A, and I-B) of the H-2 complex between the donor and recipient strains were found to be both necessary and sufficient for the induction of suppression. This suggests that the acceptor site for the suppressive T-cell factor is also determined by the gene present in the left side half of the H-2 complex. The cell type which expresses the acceptor site was found to be a subset of T cell. In general, the suppressive T-cell factor obtained from F1 mice could suppress the responses of both parental strains, and the parental factors could suppress the response of F1 mice. The results indicate that both suppressor and acceptor molecules are codominantly expressed on F1 T cells. There were found two types of defects in the expression of suppressor and acceptor molecules among mouse strains: A/J mice could not produce the suppressive T-cell factor despite that they could accept the factor produced by other H-2 compatible mouse strains. In contrast, all the B10 congeneic lines could produce the T-cell factor, but could not accept the factor produced by syngeneic and H-2 compatible non-B10 congeneic lines. The F1 hybrid of A/J and B10. A could both produce and accept the T-cell factor, and thus the expressions of suppressor and acceptor molecules were found to be dominant traits. These results indicate that the antigen-specific T-cell-mediated suppression is regulated by at least two genes both present in the H-2 complex, and that the complementation of these two genes is required for the induction of suppression.
Why ritual works: A rejection of the by-product hypothesis
Authors: Candace Storey Alcorta, Richard Sosis
Journal: Behavioral and Brain Sciences (2006)

We argue that ritual is not a by-product as Boyer &amp; Lienard (B&amp;L) claim, but rather an evolved adaptation for social communication that facilitates non-agonistic social interactions among non-kin. We review the neurophysiological effects of ritual and propose neural structures and networks beyond the cortical-striato-pallidal-thalamic circuit (CSPT) likely to be implicated in ritual. The adaptationist approach to ritual offers a more parsimonious model for understanding these effects as well as the findings B&amp;L present.
Does post-exercise massage treatment reduce delayed onset muscle soreness? A systematic review
Authors: E Ernst
Journal: British Journal of Sports Medicine (1998)

Delayed onset muscle soreness (DOMS) is a frequent problem after unaccustomed exercise. No universally accepted treatment exists. Massage therapy is often recommended for this condition but uncertainty exists about its effectiveness.To determine whether post-exercise massage alleviates the symptoms of DOMS after a bout of strenuous exercise.Various computerised literature searches were carried out and located seven controlled trials.Most of the trials were burdened with serious methodological flaws, and their results are far from uniform. However, most suggest that post-exercise massage may alleviate symptoms of DOMS.Massage therapy may be a promising treatment for DOMS. Definitive studies are warranted.
Hepatotoxicity caused by the combined action of isoniazid and rifampicin.
Authors: D S Askgaard, T Wilcke, M Dossing
Journal: Thorax (1995)

A 35 year old black Somalian woman with miliary tuberculosis developed hepatotoxicity after a few days of treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol. After withdrawal of all drugs the liver profile returned to normal and remained so after challenge with isoniazid. Hepatotoxicity recurred when rifampicin was added, but it was well tolerated when reintroduced without isoniazid.
A novel protective effect of erythropoietin in the infarcted heart
Authors: Cyrus J. Parsa, Akio Matsumoto, Jihee Kim, Ryan U. Riel, Laura S. Pascal, G. Brant Walton, Richard B. Thompson, Jason A. Petrofski, Brian H. Annex, Jonathan S. Stamler, Walter J. Koch
Journal: Journal of Clinical Investigation (2003)

Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury. EPO treatment leads to significantly improved cardiac function following myocardial infarction. This protection is associated with mitigation of myocyte apoptosis, translating into more viable myocardium and less ventricular dysfunction. EPO-mediated myocyte survival appears to involve Akt activation. Importantly, cardioprotective effects of EPO were seen without an increase in hematocrit (eliminating oxygen delivery as an etiologic factor in myocyte survival and function), demonstrating that EPO can directly protect the ischemic and infarcted heart.
Best books on obstetrics: a personal choice
Authors: D Campbell
Journal: BMJ (1994)

\***| Essential Obstetrics and Gynaecology. E M Symonds. (pounds sterling 20.99.) Churchill Livingstone, 1992. ISBN 0-443-02207-0.

** Obstetrics by Ten Teachers. 15th edn. T Lewis, G Chamberlain. (pounds sterling 15.99.) Edward Arnold, 1990. ISBN 0-340-515650-X.

** Fundamentals of Obstetrics and Gynaecology. D Llewellyn Jones. (pounds sterling 15.00.) Faber, 1990. ISBN 0-571-142273.

\**\*|\* Illustrated Textbook of Obstetrics. G Chamberlain, C Gibbons, J Dewhurst. (pounds sterling 16.95.) Gower, 1989. ISBN 0-397-44580-6.

* Lecture Notes on Obstetrics. 6th edn. G Chamberlain, M J Pearce. (pounds sterling 12.95.) Blackwell Scientific, 1992. ISBN 0-632-02771-1.

* Student Notes on Obstetrics and Gynaecology. J Willox, J Neilson. (pounds sterling 11.50.) Churchill Livingstone, 1990. ISBN 0-443-041504.

For undergraduate students there is no ideal book on obstetrics. Some of the smaller books - for example, Lecture Notes on Obstetrics, Student Notes on Obstetrics and Gynaecology - tend to issue brief lists of facts. In many medical schools the amount of time allocated to obstetrics and gynaecology together is often only a few weeks, and currently the amount of core knowledge that students have to assimilate is considerable. The emphasis for undergraduates studying obstetrics, and thus all potential medical practitioners, should be geared towards the normal rather than the abnormal, therefore including physiological adaptations to pregnancy, fetal growth and wellbeing, and normal …
Phosphorylated Pak1 Level in the Cytoplasm Correlates with Shorter Survival Time in Patients with Glioblastoma
Authors: Hiroshi Aoki, Tomohisa Yokoyama, Keishi Fujiwara, Ana M. Tari, Raymond Sawaya, Dima Suki, Kenneth R. Hess, Kenneth D. Aldape, Seiji Kondo, Rakesh Kumar, Yasuko Kondo
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Glioblastoma is the most common primary malignant tumor in the brain. It aggressively invades the surrounding parenchyma, often allowing the tumor to progress after surgery. Accumulating evidence has shown that phosphorylated p21-activated kinase 1 (Pak1), a mediator of small guanosine triphosphatases, plays a role in the proliferation, survival, and invasiveness of cancer cells. Thus, we examined patterns of Pak1 expression in glioblastoma and sought to determine whether the level of phosphorylated Pak1 in glioblastoma cells is associated with patient survival time. Experimental Design: We carried out immunohistochemical staining for phosphorylated Pak1 in tumor specimens from 136 patients with glioblastoma; the tumors were classified according to Pak1 protein levels in the cytoplasm and nucleus. We compared the patients' overall survival times using Kaplan-Meier analysis and estimated the effects of levels of cytoplasmic or nuclear phosphorylated Pak1. We then down-regulated Pak1 by using small interfering RNA to knock down Pak1 in two glioblastoma cell lines to determine whether Pak1 contributed to cell viability and invasion. Results: Median overall survival was significantly shorter in patients with tumors showing a moderate or high level of cytoplasmic phosphorylated Pak1 than in patients with tumors showing no cytoplasmic phosphorylated Pak1. The level of nuclear phosphorylated Pak1 was not related to survival time. Knockdown of Pak1 suppressed the invasion, but not the viability, of U87-MG and U373-MG cells. Conclusions: The presence of phosphorylated Pak1 in the cytoplasm of glioblastoma cells is associated with shorter survival, and Pak1 plays a role in the invasiveness of glioblastoma. These data suggest that Pak1 might be a potential target for the management of glioblastoma.