tbuckley/cabot-search huggingface dataset:
Evolutionary conservation of regulated longevity assurance mechanisms
Authors: Joshua J McElwee, Eugene Schuster, Eric Blanc, Matthew D Piper, James H Thomas, Dhaval S Patel, Colin Selman, Dominic J Withers, Janet M Thornton, Linda Partridge, David Gems
Journal: Genome biology (2007)

Abstract Background To what extent are the determinants of aging in animal species universal? Insulin/insulin-like growth factor (IGF)-1 signaling (IIS) is an evolutionarily conserved (public) regulator of longevity; yet it remains unclear whether the genes and biochemical processes through which IIS acts on aging are public or private (that is, lineage specific). To address this, we have applied a novel, multi-level cross-species comparative analysis to compare gene expression changes accompanying increased longevity in mutant nematodes, fruitflies and mice with reduced IIS. Results Surprisingly, there is little evolutionary conservation at the level of individual, orthologous genes or paralogous genes under IIS regulation. However, a number of gene categories are significantly enriched for genes whose expression changes in long-lived animals of all three species. Down-regulated categories include protein biosynthesis-associated genes. Up-regulated categories include sugar catabolism, energy generation, glutathione-S-transferases (GSTs) and several other categories linked to cellular detoxification (that is, phase 1 and phase 2 metabolism of xenobiotic and endobiotic toxins). Protein biosynthesis and GST activity have recently been linked to aging and longevity assurance, respectively. Conclusion These processes represent candidate, regulated mechanisms of longevity-control that are conserved across animal species. The longevity assurance mechanisms via which IIS acts appear to be lineage-specific at the gene level (private), but conserved at the process level (or semi-public). In the case of GSTs, and cellular detoxification generally, this suggests that the mechanisms of aging against which longevity assurance mechanisms act are, to some extent, lineage specific.
Modular Organization of Frequency Integration in Primary Auditory Cortex
Authors: Christoph E. Schreiner, Heather L. Read, Mitchell L. Sutter
Journal: Annual Review of Neuroscience (2000)

Two fundamental aspects of frequency analysis shape the functional organization of primary auditory cortex. For one, the decomposition of complex sounds into different frequency components is reflected in the tonotopic organization of auditory cortical fields. Second, recent findings suggest that this decomposition is carried out in parallel for a wide range of frequency resolutions by neurons with frequency receptive fields of different sizes (bandwidths). A systematic representation of the range of frequency resolution and, equivalently, spectral integration shapes the functional organization of the iso-frequency domain. Distinct subregions, or “modules,” along the iso-frequency domain can be demonstrated with various measures of spectral integration, including pure-tone tuning curves, noise masking, and electrical cochlear stimulation. This modularity in the representation of spectral integration is expressed by intrinsic cortical connections. This organization has implications for our understanding of psychophysical spectral integration measures such as the critical band and general cortical coding strategies.
Safety of live attenuated influenza vaccine in atopic children with egg allergy
Authors: Paul J. Turner, Jo Southern, Nick J. Andrews, Elizabeth Miller, Michel Erlewyn-Lajeunesse, Christine Doyle, George Du Toit, Michel Erlewyn-Lajeunesse, Roisin Fitzsimons, Paul T. Heath, Stephen M. Hughes, Louise Michealis, Jürgen Schwarz, Matthew D. Snape, Gary Stiefel, Huw M. Thomas, Paul J. Turner
Journal: Journal of Allergy and Clinical Immunology (2015)

BackgroundLive attenuated influenza vaccine (LAIV) is an intranasal vaccine recently incorporated into the United Kingdom immunization schedule. However, it contains egg protein and, in the absence of safety data, is contraindicated in patients with egg allergy. Furthermore, North American guidelines recommend against its use in asthmatic children.ObjectiveWe sought to assess the safety of LAIV in children with egg allergy.MethodsWe performed a prospective, multicenter, open-label, phase IV intervention study involving 11 secondary/tertiary centers in the United Kingdom. Children with egg allergy (defined as a convincing clinical reaction to egg within the past 12 months and/or >95% likelihood of clinical egg allergy as per published criteria) were recruited. LAIV was administered under medical supervision, with observation for 1 hour and telephone follow-up 72 hours later.ResultsFour hundred thirty-three doses were administered to 282 children with egg allergy (median, 4.9 years; range, 2-17 years); 115 (41%) had experienced prior anaphylaxis to egg. A physician's diagnosis of asthma/recurrent wheezing was noted in 67%, and 51% were receiving regular preventer therapy. There were no systemic allergic reactions (upper 95% CI for population, 1.3%). Eight children experienced mild self-limiting symptoms, which might have been due an IgE-mediated allergic reaction. Twenty-six (9.4%; 95% CI for population, 6.2% to 13.4%) children experienced lower respiratory tract symptoms within 72 hours, including 13 with parent-reported wheeze. None of these episodes required medical intervention beyond routine treatment.ConclusionsIn contrast to current recommendations, LAIV appears to be safe for use in children with egg allergy. Furthermore, the vaccine appears to be well tolerated in children with a diagnosis of asthma or recurrent wheeze.
When and How to Perform Genetic Testing for Inherited Colorectal Cancer Syndromes
Authors: Patrick M. Lynch
Journal: Journal of the National Comprehensive Cancer Network (2013)

The 2013 NCCN Clinical Practice Guidelines in Oncology for Colorectal Cancer Screening address the evaluation and management of patients at risk of inherited susceptibility to colorectal cancer. These patients include the 2 broad categories of patients with familial adenomatous polyposis and its variants, and those with hereditary nonpolyposis colorectal cancer, or Lynch syndrome. This article provides a somewhat personal, yet hopefully evidence-based, approach to the questions of when to test individuals for inherited susceptibility, and how to do so. "When" can be taken to mean "under what circumstance" and "at what age"; this article attempts to speak to each sense of the term.
Systematic Monitoring and Treatment of Physical Symptoms to Alleviate Fatigue in Patients With Advanced Cancer: A Randomized Controlled Trial
Authors: Pleun J. de Raaf, Cora de Klerk, Reinier Timman, Jan J.V. Busschbach, Wendy H. Oldenmenger, Carin C.D. van der Rijt
Journal: Journal of Clinical Oncology (2013)

Purpose Several guidelines on the treatment of cancer-related fatigue recommend optimizing treatment of accompanying symptoms. However, evidence for this recommendation from randomized clinical trials is lacking. We investigated whether monitoring and protocolized treatment of physical symptoms alleviates fatigue. Patients and Methods In all, 152 fatigued patients with advanced cancer were randomly assigned to protocolized patient-tailored treatment (PPT) of symptoms or care as usual. The PPT group had four appointments with a nurse who assessed nine symptoms on a 0 to 10 numeric rating scale (NRS). Patients received a nonpharmacologic intervention for symptoms with a score ≥ 1 and a medical intervention for symptoms with a score ≥ 4. Fatigue dimensions, fatigue NRS score, interference of fatigue with daily life, symptom burden, quality of life, anxiety, and depression were measured at baseline and after 1, 2, and 3 months. Differences between the groups over time were assessed by using mixed modeling. Results Seventy-six patients were randomly assigned to each study arm. Mean age was 58 ± 10 years, 57% were female, and 65% were given palliative chemotherapy. We found significant improvements over time in favor of PPT for the primary outcome general fatigue (P = .01), with significant group differences at month 1 (effect size, 0.26; P = .007) and month 2 (effect size, 0.35; P = .005). Improvements in favor of PPT were also found for the following secondary outcomes: fatigue dimensions “reduced activity” and “reduced motivation,” fatigue NRS, symptom burden, interference of fatigue with daily life, and anxiety (all P ≤ .03). Conclusion In fatigued patients with advanced cancer, nurse-led monitoring and protocolized treatment of physical symptoms is effective in alleviating fatigue.
Vaccination of Colorectal Cancer Patients with Modified Vaccinia Ankara Delivering the Tumor Antigen 5T4 (TroVax) Induces Immune Responses which Correlate with Disease Control: A Phase I/II Trial
Authors: Richard Harrop, Noel Connolly, Irina Redchenko, Juan Valle, Mark Saunders, Matthew G. Ryan, Kevin A. Myers, Noel Drury, Susan M. Kingsman, Robert E. Hawkins, Miles W. Carroll
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The highly attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA), encoding the tumor antigen 5T4 (termed TroVax), has been evaluated in an open-label phase I/II study in colorectal cancer patients. The primary objectives were to assess the safety and immunogenicity of ascending doses of TroVax and to determine the biodistribution of the vector. Experimental Design: TroVax was given to 22 patients with metastatic colorectal cancer. Seventeen patients received doses of TroVax ranging from 5 × 107 up to 5 × 108 plaque-forming units at 0, 4, and 8 weeks and were considered to be evaluable for assessment of immunologic responses. Both antibody and cellular responses specific for the tumor antigen 5T4 and the viral vector were monitored throughout the study. Results: TroVax was well tolerated in all patients with no serious adverse events attributed to vaccination. Of 17 evaluable patients, 16 showed 5T4-specific cellular responses whereas 14 had detectable antibody levels following vaccination. TroVax was able to boost 5T4-specific immune responses in the presence of MVA neutralizing antibodies. Periods of disease stabilization ranging from 3 to 18 months were observed in five patients, all of whom mounted 5T4-specific immune responses. Furthermore, statistical analysis showed a positive association between the development of a 5T4 (but not MVA) antibody response and patient survival or time to disease progression. Conclusion: These data indicate that vaccination with TroVax is safe and well tolerated and that immune responses to 5T4 can be induced without any evidence of autoimmune toxicity. Furthermore, 5T4-specific antibody responses correlate with evidence of disease control.
After the Deluge: The Emerging Landscape of Childbearing Potential in Pediatric Cancer Survivors
Authors: Leslie R. Schover
Journal: JNCI Journal of the National Cancer Institute (2006)

Journal of the National Cancer Institute, Vol. 98, No. 20, October 18, 2006 A woman’s ability to become pregnant, carry the pregnancy successfully, and give birth to a healthy child are all paradoxically threatened by many of the cancer treatments that enable girls to survive to adulthood. Like Hurricane Katrina, pediatric cancer is a tempest that leaves a concealing fl ood of acute treatment effects in its wake. Chronic problems only appear as the waters recede. Or perhaps the story of Noah’s ark is a more apt metaphor of preserving fecundity for the new world that emerges after the deluge. Surveys of the large cohort of the Childhood Cancer Survival Study (CCSG), supplemented by clues from small, clinical case series, are helping us to chart the altered childbearing landscape for women treated in childhood and adolescence. This current report concludes that children of female survivors of pediatric cancer have a moderately higher risk of being born preterm compared with children of siblings ( 1 ) . However, most of this risk is concentrated in children whose mothers had radiation before menarche that included the uterus in the fi eld . These fi ndings, based on self-report questionnaires and medical record reviews for 1264 female survivors, tally with previous observations that radiation reduces uterine capacity and blood supply, especially when administered before adolescence ( 2 , 3 ) . A previous report from the CCSG on pregnancy outcome also showed a trend to higher rates of miscarriage or low birth weight babies in women treated in childhood with pelvic radiation, although treatment with chemotherapy alone did not increase adverse pregnancy outcomes ( 4 ). Adding to this optimistic picture of childbearing potential, only 6.3% of the women in CCSG who were over age 18 but within 5 years of their cancer diagnosis had suffered acute ovarian failure ( 5 ) , suggesting that most could expect to be fertile. In that report as well, women who had received ovarian radiation accounted for a disproportionate number of those with infertility. After the Deluge: The Emerging Landscape of Childbearing Potential in Pediatric Cancer Survivors
The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis.
Authors: L B Schwartz, K Sakai, T R Bradford, S Ren, B Zweiman, A S Worobec, D D Metcalfe
Journal: Journal of Clinical Investigation (1995)

Tryptase, a protease produced by all mast cells, was evaluated as a clinical marker of systemic mastocytosis. Two sandwich immunoassays were evaluated, one which used the mAb G5 for capture, the other which used B12 for capture. The B12 capture assay measured both recombinant alpha- and beta-tryptase, whereas the G5 capture assay measured primarily recombinant beta-tryptase. G5 binds with low affinity to both recombinant alpha-tryptase and tryptase in blood from normal and nonacute mastocytosis subjects, and binds with high affinity to recombinant beta-tryptase, tryptase in serum during anaphylaxis, and tryptase stored in mast cell secretory granules. B12 recognizes all of these forms of tryptase with high affinity. As reported previously, during systemic anaphylaxis in patients without known mastocytosis, the ratio of B12- to G5-measured tryptase was always < 5 and approached unity (Schwartz L.B., T.R. Bradford, C. Rouse, A.-M. Irani, G. Rasp, J.K. Van der Zwan and P.-W.G. Van der Linden, J. Clin. Immunol. 14:190-204). In this report, most mastocytosis patients with systemic disease have B12-measured tryptase levels that are elevated (> 20 ng/ml) and are at least 10-fold greater than the corresponding G5-measured tryptase level. Most of those subjects with B12-measured tryptase levels of < 20 ng/ml had only cutaneous manifestations. The B12 assay for alpha-tryptase and beta-tryptase, particularly when performed in conjunction with the G5 assay for beta-tryptase, provides a more precise measure of mast cell involvement than currently available assessments, a promising potential screening test for systemic mastocytosis and may provide an improved means to follow disease progression and response to therapy.
Downward Trend in Cardiovascular Mortality
Authors: T J Thom, W B Kannel
Journal: Annual Review of Medicine (1981)

The recent decline in the death rate for coronary heart disease has been the subject of special interest to epidemiologists for the past six years. In the context of its previous epidemic rise and the long-term decline for other cardiovascular diseases, especially stroke, speculation about causes of this dramatic turnaround has stirred interest in the possible impact of medical advances, preventive measures, and lifestyle changes.
Higher Blood Alcohol Levels in Women Than in Men: Vive La Petite Diféfrence
Authors: R. Batey, Harold O. Conn
Journal: Hepatology (1990)

After consuming comparable amounts of ethanol, women have higher blood ethanol concentrations than men, even with allowance for differences in size, and are more susceptible to alcoholic liver disease. Recently, we documented significant “first–pass metabolism” of ethanol due to its oxidation by gastric tissue. We report a study of the possible contribution of this metabolism to the sex–related difference in blood alcohol concentrations in 20 men and 23 women. Six in each group were alcoholics. The first–pass metabolism was determined on the basis of the difference in areas under the curves of blood alcohol concentrations after intravenous and oral administration of ethanol (0.3 g per kilogram of body weight). Alcohol dehydrogenase activity was also measured in endoscopic gastric biopsies. In nonalcoholic subjects, the first–pass metabolism and gastric alcohol dehydrogenase activity of the women were 23 and 59 percent, respectively, of those in the men, and there was a significant correlation (r 8 = 0.659) between first–pass metabolism and gastric mucosal alcohol dehydrogenase activity. In the alcoholic men, the first–pass metabolism and gastric alcohol dehydrogenase activity were about half those in the nonalcoholic men; in the alcoholic women, the gastric mucosal alcohol dehydrogenase activity was even lower than in the alcoholic men, and first–pass metabolism was virtually abolished. We conclude that the increased bioavailability of ethanol resulting from decreased gastric oxidation of ethanol may contribute to the enhanced vulnerability of women to acute and chronic complications of alcoholism.
Adaptation of Rhizobium leguminosarum to pea, alfalfa and sugar beet rhizospheres investigated by comparative transcriptomics
Authors: Vinoy K Ramachandran, Alison K East, Ramakrishnan Karunakaran, J Allan Downie, Philip S Poole
Journal: Genome biology (2011)

Abstract Background The rhizosphere is the microbe-rich zone around plant roots and is a key determinant of the biosphere's productivity. Comparative transcriptomics was used to investigate general and plant-specific adaptations during rhizosphere colonization. Rhizobium leguminosarum biovar viciae was grown in the rhizospheres of pea (its legume nodulation host), alfalfa (a non-host legume) and sugar beet (non-legume). Gene expression data were compared to metabolic and transportome maps to understand adaptation to the rhizosphere. Results Carbon metabolism was dominated by organic acids, with a strong bias towards aromatic amino acids, C1 and C2 compounds. This was confirmed by induction of the glyoxylate cycle required for C2 metabolism and gluconeogenesis in all rhizospheres. Gluconeogenesis is repressed in R. leguminosarum by sugars, suggesting that although numerous sugar and putative complex carbohydrate transport systems are induced in the rhizosphere, they are less important carbon sources than organic acids. A common core of rhizosphere-induced genes was identified, of which 66% are of unknown function. Many genes were induced in the rhizosphere of the legumes, but not sugar beet, and several were plant specific. The plasmid pRL8 can be considered pea rhizosphere specific, enabling adaptation of R. leguminosarum to its host. Mutation of many of the up-regulated genes reduced competitiveness for pea rhizosphere colonization, while two genes specifically up-regulated in the pea rhizosphere reduced colonization of the pea but not alfalfa rhizosphere. Conclusions Comparative transcriptome analysis has enabled differentiation between factors conserved across plants for rhizosphere colonization as well as identification of exquisite specific adaptation to host plants.
Intestinal zonulin: open sesame!
Authors: A FASANO
Journal: Gut (2001)

The paracellular route is the dominant pathway for passive solute flow across the intestinal epithelial barrier, and its permeability depends on the regulation of intercellular tight junctions (TJs), also known as the zonula occludens. As a barrier between apical and basolateral compartments, TJs selectively control the passive diffusion of ions and small water soluble solutes from the intestinal lumen to the bloodstream through the paracellular pathway, thereby counterregulating any gradients generated by transcellular pathways.1 Variations in transepithelial conductance can usually be attributed to changes in the permeability of the paracellular pathway as the resistance of the plasma membrane of the cell is relatively high.2 The TJ represents the major barrier within this paracellular pathway and the electrical resistance of the intestinal mucosa seems to depend on the number of transmembrane protein strands and their complexity within the TJ, as observed by freeze fracture electron microscopy. A century ago, TJs were conceptualised as a secreted extracellular cement forming an absolute and unregulated barrier within the paracellular space.3Biological studies of the past several decades have shown that TJs are dynamic structures subjected to structural changes that dictate their functional status under a variety of developmental,4-6physiological,7-10 and pathological circumstances.11-13 To meet the many diverse physiological challenges to which the epithelial and endothelial barriers are subjected, TJs must be capable of rapid and coordinated responses. This requires the presence of a complex regulatory system that orchestrates the state of assembly of the TJ multiprotein network. While our knowledge on TJ ultrastructure and intracellular signalling events have significantly progressed during the past decade, relatively little is known about their pathophysiological regulation secondary to extracellular stimuli. Therefore, the intimate pathogenic mechanisms of diseases in which intestinal permeability is affected and the utility of TJ modulation for drug delivery …
Role of nitric oxide in the biology, physiology and pathophysiology of reproduction
Authors: M Rosselli
Journal: Human Reproduction Update (1998)

Following its benchmark discovery, nitric oxide (NO) is now known to play important functional roles in a variety of physiological systems. Within the vasculature, NO induces vasodilation, inhibits platelet aggregation, prevents neutrophil/platelet adhesion to endothelial cells, inhibits smooth muscle cell proliferation and migration, regulates programmed cell death (apoptosis) and maintains endothelial cell barrier function. NO generated by neurons acts as a neurotransmitter, whereas NO generated by macrophages in response to invading microbes acts as an antimicrobial agent. Because neurons, blood vessels and cells of the immune system are integral parts of the reproductive organs, and in view of the important functional role that NO plays in those systems, it is likely that NO is an important regulator of the biology and physiology of the reproductive system. Indeed, in the past 10 years, NO has established itself as a polyvalent molecule which plays a decisive role in regulating multiple functions within the female as well as the male reproductive system. This review provides an overview of the role of NO in various reproductive organs under physiological and pathological conditions. Keywords:nitric oxide/pathophysiology/physiology/reproductive system/steroidogenesis