tbuckley/cabot-search huggingface dataset:
A New Diagnostic Marker for Secreted Epstein-Barr Virus–Encoded LMP1 and BARF1 Oncoproteins in the Serum and Saliva of Patients with Nasopharyngeal Carcinoma
Authors: Karim Houali, Xiaohui Wang, Yuko Shimizu, Djamel Djennaoui, John Nicholls, Sylvie Fiorini, Abdelmadjid Bouguermouh, Tadamasa Ooka
Journal: Clinical Cancer Research (2007)

Abstract Purpose: EBV has been associated with nasopharyngeal carcinomas (NPC). In North Africa, the incidence is bimodal—the first peak occurring at ∼20 years of age and the second peak occurring at ∼50 years. Standard diagnostic tests based on immunofluorescence using anti-IgA EBV have shown that young North African patients have a negative serology compared with older patients. We are interested in two EBV-encoded oncoproteins, LMP1 and BARF1, which have thus far not been studied in terms of their potential as diagnostic markers for NPC. These two viral oncoproteins have been detected in cell culture media, so we tested whether they could be detected in the serum and saliva of patients with NPC. Experimental Design: LMP1 and BARF1 proteins were analyzed in the sera and saliva of young patients and adult patients with NPC from North Africa and China. We then examined whether the secreted proteins had biological activity by analyzing their mitogenic activity. Results: Both LMP1 and BARF1 were present in the serum and saliva from North African and Chinese patients with NPC. All young North African patients secreted both proteins, whereas 62% and 100% of adult patients secreted LMP1 and BARF1, respectively. From animal studies, the secreted LMP1 was associated with exosome-like vesicles. These secreted EBV oncoproteins showed a powerful mitogenic activity in B cells. Conclusion: Both proteins will be a good diagnostic marker for NPC whereas BARF1 is a particularly promising marker for all ages of patients with NPC. Their mitogenic activity suggests their implication in the oncogenic development of NPC.
Incremental value of rare genetic variants for the prediction of multifactorial diseases
Authors: Raluca Mihaescu, Michael J Pencina, Alvaro Alonso, Kathryn L Lunetta, Susan R Heckbert, Emelia J Benjamin, A JW Janssens
Journal: Genome Medicine (2013)

It is often assumed that rare genetic variants will improve available risk prediction scores. We aimed to estimate the added predictive ability of rare variants for risk prediction of common diseases in hypothetical scenarios.In simulated data, we constructed risk models with an area under the ROC curve (AUC) ranging between 0.50 and 0.95, to which we added a single variant representing the cumulative frequency and effect (odds ratio, OR) of multiple rare variants. The frequency of the rare variant ranged between 0.0001 and 0.01 and the OR between 2 and 10. We assessed the resulting AUC, increment in AUC, integrated discrimination improvement (IDI), net reclassification improvement (NRI(>0.01)) and categorical NRI. The analyses were illustrated by a simulation of atrial fibrillation risk prediction based on a published clinical risk model.We observed minimal improvement in AUC with the addition of rare variants. All measures increased with the frequency and OR of the variant, but maximum increment in AUC remained below 0.05. Increment in AUC and NRI(>0.01) decreased with higher AUC of the baseline model, whereas IDI remained constant. In the atrial fibrillation example, the maximum increment in AUC was 0.02 for a variant with frequency = 0.01 and OR = 10. IDI and NRI showed at most minimal increase for variants with frequency greater than or equal to 0.005 and OR greater than or equal to 5.Since rare variants are present in only a minority of affected individuals, their predictive ability is generally low at the population level. To improve the predictive ability of clinical risk models for complex diseases, genetic variants must be common and have substantial effect on disease risk.
High incidence and unique features of antigen receptor gene rearrangements in TEL–AML1-positive leukemias
Authors: S Hübner, G Cazzaniga, T Flohr, V H J van der Velden, M Konrad, U Pötschger, G Basso, M Schrappe, J J M van Dongen, C R Bartram, A Biondi, E R Panzer-Grümayer
Journal: Leukemia (2003)
Estimate of deaths attributable to passive smoking among UK adults: database analysis
Authors: Konrad Jamrozik
Journal: BMJ (2005)

To estimate deaths from passive smoking in employees of the hospitality industry as well as in the general workforce and general population of the United Kingdom.Calculation, using the formula for population attributable proportion, of deaths likely to have been caused by passive smoking at home and at work in the UK according to occupation. Sensitivity analyses to examine impact of varying assumptions regarding prevalence and risks of exposure.National UK databases of causes of death, employment, structure of households, and prevalences of active and passive smoking.Estimates of deaths due to passive smoking according to age group (< 65 or > or = 65) and site of exposure (domestic or workplace).Across the United Kingdom as a whole, passive smoking at work is likely to be responsible for the deaths of more than two employed people per working day (617 deaths per year), including 54 deaths in the hospitality industry each year. Each year passive smoking at home might account for another 2700 deaths in persons aged 20-64 years and 8000 deaths among people aged > or = 65.Exposure at work might contribute up to one fifth of all deaths from passive smoking in the general population aged 20-64 years, and up to half of such deaths among employees of the hospitality industry. Adoption of smoke free policies in all workplaces and reductions in the general prevalence of active smoking would lead to substantial reductions in these avoidable deaths.
Vertebrate Olfactory Reception
Authors: D Lancet
Journal: Annual Review of Neuroscience (1986)

Through his sense of smell man has long encountered the phenomenon of molecular recognition. As early as first century BC, the Roman poet and philosopher Lucretius wrote (based on Democritus' atomic theory), Such substances as agreeably titilate the senses are composed of smooth round atoms; those that seem bitter and harsh are more tightly compacted of hooked particles . . .  (Lucretius 55 BC). The last century has brought the realization that similar recognition of atomic or molecular configurations constitutes the basis of all life processes. Probably because olfaction has been a subject of study and speculation long before the advent of modern biochemistry, numerous olfactory theories have been proposed (Davies 1971, Amoore 1982). However, in the eyes of a contemporary molecular biologist, a special theory accounting for the initial steps in olfaction may seem superfluous, as the sensory cells in the nose are not unique in their ability to receive chemical signals selectively. It would be most parsi­ monious to assume that odorant recognition involves membrane protein receptors and transduction components analogous to those which mediate the specific responses to hormones, growth factors, neurotransmitters, and antigens. This notion, which corresponds to the combined Stereo­ chemical/Functional-group theories of olfaction (Amoore 1982, Beets 1971), is validated by many of the studies reviewed here. Olfactory recognition is mediated by a large ensemble' of sensory cells, each conveying a fraction of the information that signifies the nature of the odorant and its concentration. The sensory neurons receive chemical signals at their dendritic membrane and respond by firing action potentials down their axons. The olfactory response is therefore analogous to neurotransmitter reception, and the sensory organ is a simple but
Gonadotropin-Releasing Hormone Type II Antagonists Induce Apoptotic Cell Death in Human Endometrial and Ovarian Cancer Cells <i>In vitro</i> and <i>In vivo</i>
Authors: Stefanie Fister, Andreas R. Günthert, Günter Emons, Carsten Gründker
Journal: Cancer Research (2007)

Abstract In human endometrial and ovarian cancers, gonadotropin-releasing hormone type I (GnRH-I), GnRH-II, and their receptors are parts of a negative autocrine regulatory system of cell proliferation. Based on a tumor-specific signal transduction, GnRH-I and GnRH-II agonists inhibit the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in down-regulation of cancer cell proliferation. Induction of apoptosis is not involved. In this study, we show that treatment of human endometrial and ovarian cancer cells with GnRH-II antagonists results in apoptotic cell death via dose-dependent activation of caspase-3. The antitumor effects of the GnRH-II antagonists could be confirmed in nude mice. GnRH-II antagonists inhibited the growth of xenotransplants of human endometrial and ovarian cancers in nude mice significantly, without any apparent side effects. Thus, GnRH-II antagonists seem to be suitable drugs for an efficacious and less toxic endocrine therapy for endometrial and ovarian cancers. [Cancer Res 2007;67(4):1750–6]
Generation of a fibroblast chemotactic factor in serum by activation of complement.
Authors: A E Postlethwaite, R Snyderman, A H Kang
Journal: Journal of Clinical Investigation (1979)

When serum complement is activated by either the classical or alternative pathways, a factor with an apparent 80,000 mol wt is generated that is chemotactic for human dermal fibroblasts. The origin of this serum-derived chemotactic factor (SDCF) is not known; however, it may be a cleavage product from C5 because it is inactivated by monospecific antiserum to human C5, and it is not generated when the complement system is activated in human serum deficient in C5. SDCF is not chemotactic for human neutrophils or monocytes. Because SDCF is generated when serum complement is activated, it may function in vivo to attract connective tissue fibroblasts to sites of inflammatory reactions in which the complement system participates.
B<scp>RAIN</scp>R<scp>EPRESENTATION OF</scp>O<scp>BJECT</scp>-C<scp>ENTERED</scp>S<scp>PACE IN</scp>M<scp>ONKEYS AND</scp>H<scp>UMANS</scp>
Authors: Carl R. Olson
Journal: Annual Review of Neuroscience (2003)

▪ Abstract Visuospatial cognition requires taking into account where things are relative to each other and not just relative to the viewer. Consequently it would make sense for the brain to form an explicit representation of object-centered and not just of ego-centered space. Evidence bearing on the presence and nature of neural maps of object-centered space has come from two sources: single-neuron recording in behaving monkeys and assessment of the visual abilities of human patients with hemispatial neglect. Studies of the supplementary eye field of the monkey have revealed that it contains neurons with object-centered spatial selectivity. These neurons fire when the monkey has selected, as target for an eye movement or attention, a particular location defined relative to a reference object. Studies of neglect have revealed that in some patients the condition is expressed with respect to an object-centered and object-aligned reference frame. These patients neglect one side of an object, as defined relative to its intrinsic midline, regardless of its location and orientation relative to the viewer. The two sets of observations are complementary in the sense that the loss of neurons, such as observed in the monkey, could explain the spatial distribution of neglect in these patients.
Testing the Dose–Response Specification in Epidemiology: Public Health and Policy Consequences for Lead
Authors: Stephen J. Rothenberg, Jesse C. Rothenberg
Journal: Environmental Health Perspectives (2005)

Statistical evaluation of the dose-response function in lead epidemiology is rarely attempted. Economic evaluation of health benefits of lead reduction usually assumes a linear dose-response function, regardless of the outcome measure used. We reanalyzed a previously published study, an international pooled data set combining data from seven prospective lead studies examining contemporaneous blood lead effect on IQ (intelligence quotient) of 7-year-old children (n = 1,333). We constructed alternative linear multiple regression models with linear blood lead terms (linear-linear dose response) and natural-log-transformed blood lead terms (log-linear dose response). We tested the two lead specifications for nonlinearity in the models, compared the two lead specifications for significantly better fit to the data, and examined the effects of possible residual confounding on the functional form of the dose-response relationship. We found that a log-linear lead-IQ relationship was a significantly better fit than was a linear-linear relationship for IQ (p = 0.009), with little evidence of residual confounding of included model variables. We substituted the log-linear lead-IQ effect in a previously published health benefits model and found that the economic savings due to U.S. population lead decrease between 1976 and 1999 (from 17.1 microg/dL to 2.0 microg/dL) was 2.2 times (319 billion dollars) that calculated using a linear-linear dose-response function (149 billion dollars). The Centers for Disease Control and Prevention action limit of 10 microg/dL for children fails to protect against most damage and economic cost attributable to lead exposure.
Effective Targeting of the P53–MDM2 Axis in Preclinical Models of Infant <i>MLL</i>-Rearranged Acute Lymphoblastic Leukemia
Authors: Jennifer Richmond, Hernan Carol, Kathryn Evans, Laura High, Agnes Mendomo, Alissa Robbins, Claus Meyer, Nicola C. Venn, Rolf Marschalek, Michelle Henderson, Rosemary Sutton, Raushan T. Kurmasheva, Ursula R. Kees, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Although the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor-suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts. Experimental Design: Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell-cycle arrest, and apoptosis in vivo was evaluated. Results: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, cell-cycle arrest, and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft. Conclusions: The utility of targeting the p53–MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation. Clin Cancer Res; 21(6); 1395–405. ©2015 AACR.
The genetic and cardiovascular aspects of obstructive sleep apnoea/hypopnoea syndrome
Authors: Renata Riha, W. T. McNicholas
Journal: European Respiratory Journal (2008)

In November 2006, the COST B26 action on cardiovascular disease in obstructive sleep apnoea/hypopnoea syndrome (OSAHS) convened a symposium in Copenhagen (Denmark). The symposium was an attempt to bring experts together to define the direction in which the fast pace of change in the fields of molecular biology and genetics was pushing frontiers, particularly in the context of cardiovascular diseases and OSAHS. An upcoming series that will be published over the next 6 months in the European Respiratory Journal ( ERJ ), presents some of the key papers from the symposium. The first paper in the series, by MacLeod et al. 1, introduces the importance of meticulous design, data collection and storage in studies of complex disease, using the example of Generation Scotland. The paper serves as the background for further contributions to the series, which continue with a discussion of the difficulties in phenotyping and, by inference, the difficulties inherent to genotyping such a complex disorder as OSAHS 2. The epidemiological aspects of OSAHS and sleep-disordered breathing (SDB) are discussed separately 3. The sequelae of OSAHS are considered in detail, particularly the molecular biology of oxidative stress mechanisms 4, as well as inflammatory pathways 5 which determine the comorbidities increasingly recognised in the context of SDB. Finally, the series concludes with evidence for and against the coexistence of and increased propensity of developing metabolic syndrome, hypertension and insulin resistance in SDB with and without hypoxaemia 6.

In the first paper of the series, MacLeod et al. 1 demonstrate that when studying genetic aspects of complex diseases such as hypertension and OSAHS, good sample and data management is necessary to ensure that the data collected are stored accurately and efficiently, and passed through the process of analysis in an orderly manner. In order to be able to collect …
P-Selectin Glycoprotein Ligand-1 (PSGL-1) on T Helper 1 but Not on T Helper 2 Cells Binds to P-Selectin and Supports Migration into Inflamed Skin
Authors: Eric Borges, Wolfgang Tietz, Martin Steegmaier, Thomas Moll, Rupert Hallmann, Alf Hamann, Dietmar Vestweber
Journal: The Journal of Experimental Medicine (1997)

We have shown recently that mouse Th1 cells but not Th2 cells are selectively recruited into inflamed sites of a delayed-type hypersensitivity (DTH) reaction of the skin. This migration was blocked by monoclonal antibodies (mAb) against P- and E-selectin. Here we show that Th1 cells bind to P-selectin via the P-selectin glycoprotein ligand-1 (PSGL-1). This is the only glycoprotein ligand that was detectable by affinity isolation with a P-selectin–Ig fusion protein. Binding of Th1 cells to P-selectin, as analyzed by flow cytometry and in cell adhesion assays, was completely blocked by antibodies against PSGL-1. The same antibodies blocked partially the migration of Th1 cells into cutaneous DTH reactions. This blocking activity, in combination with that of a mAb against E-selectin, was additive. PSGL-1 on Th2 cells, although expressed at similar levels as on Th1 cells, did not support binding to P-selectin. Thus, the P-selectin–binding form of PSGL-1 distinguishes Th1 cells from Th2 cells. Furthermore, PSGL-1 is relevant for the entry of Th1 cells into inflamed areas of the skin. This is the first demonstration for the importance of PSGL-1 for mouse leukocyte recruitment in vivo.
Inhibition of Death Receptor Signaling by Flice-Inhibitory Protein as a Mechanism for Immune Escape of Tumors
Authors: Lars E. French, Jürg Tschopp
Journal: The Journal of Experimental Medicine (1999)

Cell death by apoptosis is a tightly regulated physiological process that enables the elimination of unwanted cells. It is crucial for embryonic development and the maintenance of tissue homeostasis, but also for defense against certain infectious diseases and cancer.

Apoptosis can be triggered
A Systems Biology Approach to Personalizing Therapeutic Combinations
Authors: Lawrence N. Kwong, Timothy P. Heffernan, Lynda Chin
Journal: Cancer Discovery (2013)

Abstract Summary: The identification of evidence-based, efficacious drug combinations for each cancer, among thousands of potential permutations, is a daunting task. In this perspective, we propose a systematic approach to defining such combinations by molecularly benchmarking a drug against a desired state of efficacy using model systems. Cancer Discov; 3(12); 1339–44. ©2013 AACR.
Hypothesis: Metabolic Activity of the Colonic Bacteria Influences Organ Injury from Ethanol
Authors: Michael D. Levitt, William Doizaki, Allen S. Levine
Journal: Hepatology (2007)

Incubation of human fecal homogenates with ethanol (0.078 gm per dl) resulted in accumulation of increased quantities of higher alcohols and other unidentified metabolites when compared with homogenates incubated without ethanol. Studies in rats demonstrated nearly perfect equilibration between blood and colonic luminal ethanol suggesting that the colonic flora in alcoholics is chronically exposed to ethanol concentrations in the range used in the homogenate experiments. The higher alcohols produced by the homogenates were rapidly absorbed from the colon. We hypothesize that, when exposed to ethanol, the colonic flora produced toxic compounds which are absorbed and influence the body's response to ingested ethanol. Individual differences in this bacterial metabolism may account for the wide individual differences in susceptibility to ethanol-related organ injury.
Downregulation of miR-452 Promotes Stem-Like Traits and Tumorigenicity of Gliomas
Authors: Liping Liu, Kun Chen, Jueheng Wu, Ling Shi, Bo Hu, Shiyuan Cheng, Mengfeng Li, Libing Song
Journal: Clinical Cancer Research (2013)

Abstract Purpose: miR-452 is reported to be required for neural crest stem cell differentiation during neural crest development. However, the biologic role of miR-452 in gliomas remains unclear. The aim of the present study was to evaluate the effect of miR-452 on the stem-like properties and tumorigenesis of glioma cells. Experimental Design: The expression of miR-452 was examined in glioma cells and glioma tissues using real-time PCR. The effects of miR-452 on stem-like traits and tumorigenesis were investigated in vitro and in vivo using patient-derived glioma cells and glioma cell lines. Western blotting and luciferase reporter assays were conducted to examine the negative regulation of Bmi-1, LEF1, and TCF4 by miR-452. The methylation of the miR-452 promoter region was examined by bisulfite genomic sequencing PCR. Results: miR-452 was markedly downregulated in glioma cells and clinical glioma tissues. miR-452 levels were inversely correlated with World Health Organization (WHO) grades and patient survival. miR-452 directly targeted and suppressed multiple stemness regulators, including Bmi-1, LEF1, and TCF4, resulting in reduced stem-like traits and tumorigenesis of glioma cells in vitro and in vivo. Furthermore, we showed that downregulation of miR-452 in gliomas was caused by hypermethylation of its promoter region. Conclusions: Downregulation of miR-452 plays an important role in promoting the stem-like traits and tumorigenesis of gliomas and may represent a novel prognostic biomarker and therapeutic target for the disease. Clin Cancer Res; 19(13); 3429–38. ©2013 AACR.