tbuckley/cabot-search huggingface dataset:
Evolution of the vertebrate twist family and synfunctionalization: a mechanism for differential gene loss through merging of expression domains
Authors: Inna Gitelman
Journal: Molecular Biology and Evolution (2007)

Twist genes are essential for embryonic development and are conserved from jellyfish to human. To study the vertebrate twist family and its evolution, the entire complement of twist genes was obtained for 9 representative species. Phylogenetic analysis showed that a single protochordate twist gene was duplicated at least twice before the teleost-tetrapod split to give rise to 3 ancestral genes, which were further duplicated or deleted, resulting in fluctuating number of twist paralogs in different vertebrate lineages. To find whether changes in gene copy number were associated with changes in gene function, embryonic expression patterns of twist orthologs were evaluated against the number of twist paralogs in different species. The results showed evidence for both neo- and subfunctionalization, and, in addition, for loss of an ancestral regulatory gene. For example, in Xenopus, twist2 was lost, but the twist1 paralog acquired, and therefore preserved, twist2 function. A general model is proposed to explain the data. In this process, termed synfunctionalization, one paralog acquires the expression domain(s) of another. The merging may lead to function shuffle. Alternatively, it may leave one paralog redundant and thus subject to deletion—while its function is retained by the surviving paralog(s). Synfunctionalization is a mechanism that, together with neo- and subfunctionalization, may work to establish equilibrium in the number of genes that regulate developmental processes; it may regulate the complexity of regulatory regions as well as gene copy number and therefore may play a role in evolution of gene function and the structure of genome.
Incidence and Determinants of IgE-mediated Sensitization in Apprentices
Authors: DENYSE GAUTRIN, HEBERTO GHEZZO, CLAIRE INFANTE-RIVARD, JEAN-LUC MALO
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We investigated prospectively the incidence and determinants of work-related specific skin sensitization in a cohort of 769 apprentices, including 417 in animal health technology, 230 in pastry-making, and 122 in dental-hygiene technology. Subjects were recruited when starting exposure to laboratory animals, flour, or latex. A questionnaire and skin-prick tests with common and work-related allergens were administered on entry and at follow-up visits from 8 to 44 mo; information on number of hours of exposure to specific allergens was obtained. Among 769 apprentices, 698 attended >/= 1 follow-up visit. A total of 111 subjects developed specific sensitization over the study period. The incidence of work-related sensitization (per person-year) was 8.9% (95% CI 7.3 to 11.0%) in the animal-health program, 4.2% (95% CI 1.8 to 8.2%) in the pastry-making program, and 2.5% (95% CI = 0.7 to 4.3%) in the dental-hygiene program. In the animal health group, Cox regression analyses showed that atopy, nasal, and respiratory symptoms in the pollen season, and exposure assessed by the school attended or by duration of exposure to rodents were the most significant predictors of sensitization. In the dental-hygiene program, atopy and asthma were significant determinants. This study shows that: (1) an apprenticeship in animal-health technology carries a greater risk of developing specific sensitization than do apprenticeships in pastry-making and dental-hygiene; (2) atopy, respiratory symptoms in the pollen season, and number of hours in contact with rodents determine the risk of sensitization in apprentices in the animal health program.
Activation of normal and cystic fibrosis Cl- channels by voltage, temperature, and trypsin.
Authors: M J Welsh, M Li, J D McCann
Journal: Journal of Clinical Investigation (1989)

In cystic fibrosis (CF) phosphorylation-dependent activation of outwardly rectifying apical membrane Cl- channels is defective. To further understand regulation of this channel we examined several other mechanisms of channel activation in normal and CF cells. Previous studies have shown that strong membrane depolarization can activate channels in excised cell-free membrane patches. Here we show that such activation is dependent on both the absolute membrane voltage and the duration of depolarization. Moreover, activation was reversible by membrane hyperpolarization. In some cases, excising patches of membrane from the cell caused channel activation, even in the absence of depolarization. However, the frequency of channel activation with patch excision increased when bath temperature was increased from 23 to 37 degrees C. Although the channel remained in the activated state when temperature was reduced to 23 degrees C, subsequent hyperpolarization inactivated the channel. In cell-attached patches, neither depolarization nor increasing bath temperature to 37 degrees C activated channels, suggesting that neither is physiologically important in regulation of the channel. Thus changes in membrane voltage and bath temperature appear to cause a nonenzymatic change in the channel's conformation; the interactions between voltage and temperature suggest that they may affect the same process. To determine if a proteolytic alteration of the channel could also cause activation, we added trypsin to the cytosolic surface of excised membrane patches. Trypsin activated channels, which could not then be inactivated by either hyperpolarization or phosphorylation with PKC, suggesting that trypsin removed or altered a region of the channel involved in inactivation. All of these interventions activated Cl- channels from both normal and CF cells. Thus many aspects of Cl- channel activation are normal in CF; only phosphorylation-dependent activation is defective.
Superoxide Radical: An Endogenous Toxicant
Authors: I Fridovich
Journal: The Annual Review of Pharmacology and Toxicology (1983)

The Two Faces of Oxygen Molecular oxygen is both benign and malign. On the one hand it provides enormous advantages and on the other it imposes a universal toxicity. This toxicity is largely due to the intermediates of oxygen reduction, i.e. 0;, H202, and OH·, and any organism that avails itself of the benefits of oxygen does so at the cost of maintaining an elaborate system of defenses against these intermediates. We will here concern ourselves with the superoxide dismutases which, by catalytically scavenging 0;, provide a defense against it and against any reactive radical species which can be derived from it.
Change in Cognitive Function After Chemotherapy: a Prospective Longitudinal Study in Breast Cancer Patients
Authors: Sanne B. Schagen, Martin J. Muller, Willem Boogerd, Gideon J. Mellenbergh, Frits S. A. M. van Dam
Journal: JNCI Journal of the National Cancer Institute (2006)

Some breast cancer survivors experience cognitive decline following chemotherapy. We prospectively examined changes in cognitive performance among high-risk breast cancer patients who had received high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTC group; n = 28) or standard-dose chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC group; n = 39); stage-I breast cancer patients who had received no systemic chemotherapy (no-CT group; n = 57); and healthy control subjects (n = 60). All patients underwent neuropsychologic testing before and 6 months after treatment (12-month interval); control subjects underwent repeated testing over a 6-month interval. No differences in cognitive functioning between the four groups were observed at the first assessment. More of the CTC group than the control subjects experienced a deterioration in cognitive performance over time (25% versus 6.7%; odds ratio [OR] = 5.3, 95% confidence interval [CI] = 1.3 to 21.2, P = .02). No such difference was observed for the FEC or the no-CT groups (FEC versus control: OR = 2.2, 95% CI = 0.5 to 9.1, P = .27; no-CT versus Control: OR = 2.2, 95% CI = 0.6 to 8.0; P = .21). Some cytotoxic treatment for breast cancer affects cognition in a subset of women.
A cost-effective and universal strategy for complete prokaryotic genome sequencing proposed by computer simulation
Authors: Jingwei Jiang, Jun Li, Frederick C Leung
Journal: Genome biology (2011)

Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health.
Quantitative methods for genome-scale analysis of in situ hybridization and correlation with microarray data
Authors: Chang-Kyu Lee, Susan M Sunkin, Chihchau Kuan, Carol L Thompson, Sayan Pathak, Lydia Ng, Chris Lau, Shanna Fischer, Marty Mortrud, Cliff Slaughterbeck, Allan Jones, Ed Lein, Michael Hawrylycz
Journal: Genome biology (2008)

Abstract With the emergence of genome-wide colorimetric in situ hybridization (ISH) data sets such as the Allen Brain Atlas, it is important to understand the relationship between this gene expression modality and those derived from more quantitative based technologies. This study introduces a novel method for standardized relative quantification of colorimetric ISH signal that enables a large-scale cross-platform expression level comparison of ISH with two publicly available microarray brain data sources.
Novel packages of viral and self-antigens are generated during apoptosis.
Authors: A Rosen, L Casciola-Rosen, J Ahearn
Journal: The Journal of Experimental Medicine (1995)

Immune context is an essential determinant of the host response to potential autoantigens. The clustering of the autoantigens targeted in systemic lupus erythematosus within surface blebs of apoptotic cells generates high concentrations of autoantigen within discrete subcellular packages. We demonstrate here that when apoptosis is induced by Sindbis virus infection, viral antigens and autoantigens cocluster exclusively in small surface blebs of apoptotic cells. The surface of these blebs is rich in viral glycoproteins, and virions can be seen blebbing from their surface. We propose that these blebs of mixed foreign and self-origin define a novel immune context that may challenge self-tolerance.
Combined Inhibition of MEK and Mammalian Target of Rapamycin Abolishes Phosphorylation of Cyclin-Dependent Kinase 4 in Glioblastoma Cell Lines and Prevents Their Proliferation
Authors: Sabine Paternot, Pierre P. Roger
Journal: Cancer Research (2009)

The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) signaling pathways are aberrantly activated in many tumors, including highly proliferative glioblastomas, but how they are wired with the cell cycle remains imperfectly understood. Inhibitors of MEK/ERK and mTOR pathways are tested as anticancer agents. They are generally considered to induce a G(1) cell cycle arrest through down-regulation of D-type cyclins and up-regulation of p27(kip1). Here, we examined the effect of targeting mTOR by rapamycin and/or MEK by PD184352 in human glioblastoma cell lines. In combination, these drugs cooperatively and potently inhibited the G(1)-S transition and retinoblastoma protein phosphorylation. Their cooperation could not be explained by their partial and differential inhibitory effects on cyclin D1 or D3 but instead by their synergistic inhibition of the activating T172 phosphorylation of cyclin-dependent kinase (CDK) 4. This appeared independent of p27 and unrelated to weak modulations of the CDK-activating kinase activity. The T172 phosphorylation of CDK4 thus appears as a crucial node integrating the activity of both MEK/ERK and mTOR pathways. Combined inhibition of both pathways should be considered as a promising strategy for treatment of tumors harboring a deregulated CDK4 activity.
Resolving the frustration of fatigue
Authors: W. S. Harpham
Journal: CA A Cancer Journal for Clinicians (1999)

Fatigue is a ubiquitous side effect of many cancer therapies. Nevertheless, after treatment is complete, many survivors continue to feel a profound tiredness that affects almost all aspects of life. Even after recovery, patients are often frustrated by their continuing need for extra rest. In this deeply personal, first-person account, a physician relates the various ways that cancer-related fatigue can affect family dynamics, job responsibilities, social interactions, finances, and intimacy. Clinicians can help by searching for treatable medical conditions, but also by taking cancer-related fatigue, and the frustrations it causes, seriously. Patients should be reassured that the fatigue they feel is real, and that by learning personal energy conservation, they should be able to improve their abilities to function, to socialize, to interact with others, and ultimately to adjust to a "new normal" baseline. (CA Cancer J Clin 1999;49:178–189.)
Comparison of Two Handheld Fractional Exhaled Nitric Oxide Measurements in the Assessment of Asthma Patients
Authors: Sujeong Kim, Woo-Jung Song, Jong-Myung Lee, Hye-Ryun Kang, Heung-Woo Park, Sang Heon Cho, Kyung-Up Min
Journal: Journal of Allergy and Clinical Immunology (2015)
Ultimate Fate of Oncology Drugs Approved by the US Food and Drug Administration Without a Randomized Trial
Authors: Apostolia-Maria Tsimberidou, Fadi Braiteh, David J. Stewart, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2009)

Purpose To approve a new anticancer drug, the US Food and Drug Administration often requires randomized trials. However, several oncology drugs have been approved on the basis of objective end points without a randomized trial. We reviewed the long-term safety and efficacy of such agents. Methods We searched the Web site of the US Food and Drug Administration's Center for Drug Evaluation and Research and MEDLINE for initial applications of investigational anticancer drugs from 1973 through 2006. Results Overall, 68 oncology drugs, excluding hormone therapy and supportive care, were approved, including 31 without a randomized trial. For these 31 drugs, a median of two clinical trials (range, one to seven) and 79 patients (range, 40 to 413) were used per approval. Objective response was the most common end point used for approval; median response rate was 33% (range, 11% to 90%). Thirty drugs are still fully approved. United States marketing authorization for one drug, gefitinib (an epidermal growth factor receptor [EGFR] inhibitor), was rescinded after a randomized trial showed no survival improvement; however, this trial was performed in unselected patients, and it was subsequently demonstrated that patients with EGFR mutation are more likely to respond. Nineteen of the 31 drugs have additional uses (per National Comprehensive Cancer Network or National Cancer Institute Physician Data Query guidelines), and subsequent formal US Food and Drug Administration approvals were obtained for 11 of these (range, one to 18 new indications). No drug has demonstrated safety concerns. Conclusion Nonrandomized clinical trials with definitive end points can yield US Food and Drug Administration approvals, and these drugs have a reassuring record of long-term safety and efficacy.
Too old to help
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Clean living staves off autoimmunityAutoreactive T cells are harmless until they are prodded into action by exposure to common microbes, according to Yoshitomi and colleagues on page 949.These results may help explain the contribution of environmental factors to human autoimmune diseases like rheumatoid arthritis and diabetes.While studying an arthritis-prone strain of mouse, Yoshitomi et al. noted that these mice did not develop disease when housed in a microbe-free environment, despite the presence of T cells that could induce arthritis when transferred to nude mice.Only when mice were moved to nonsterile conditions (where they acquired fungal infections) or were injected with ␤ -glucans from fungal cell walls did the telltale symptoms of arthritis appear.Treatment of the mice with antifungal drugs or antibodies that blocked binding of ␤ -glucans to cells reversed this effect, suggesting a direct link between exposure to fungi and development of disease.The same fungal products that triggered arthritis stimulated dendritic cells (DCs), the cells responsible for activating T cells, to upregulate costimulatory molecules and secrete cytokines.The authors suspect that ␤ -glucans, detectable in the circulation during infection, reach the local lymph nodes where they prompt DCs to activate autoreactive T cells.Once activated, the T cells invade the joints.The group now plans to investigate possible defects in regulatory T cells in this model, as these cells normally keep autoreactive T cells in check.
Predictors of Initial Nontherapeutic Anticoagulation With Unfractionated Heparin in ST-Segment Elevation Myocardial Infarction
Authors: Susan Cheng, David A. Morrow, Sarah Sloan, Elliott M. Antman, Marc S. Sabatine
Journal: Circulation (2009)

Although weight-based nomograms have improved the efficacy and safety of dosing unfractionated heparin in ST-segment elevation myocardial infarction, achieving therapeutic anticoagulation in practice remains challenging.In the Enoxaparin and Thrombolysis in Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 study, 20 506 patients with ST-segment elevation myocardial infarction were randomized to enoxaparin or unfractionated heparin, the latter dosed according to the American College of Cardiology/American Heart Association weight-based nomogram with centrally monitored activated partial thromboplastin times (aPTTs). A total of 6055 patients received study unfractionated heparin and a fibrin-specific lytic and had an initial aPTT drawn within 4 to 8 hours of starting therapy. Despite close adherence to recommended dosing, only 33.8% of initial aPTTs were therapeutic (1.50 to 2.00 times control); 13.2% were markedly low (<1.25 times); and 16.3% were markedly high (> or =2.75 times). Markedly high aPTTs were more likely in patients who were older (adjusted risk ratio [RR(adj)], 1.14 per decade; P=0.001), were female (RR(adj), 1.46; P<0.001), were of lower weight (RR(adj), 1.19 per 10-kg decrease; P<0.001) or had renal dysfunction (RR(adj), 1.08 per 0.2-mg/dL increase in serum creatinine; P=0.006). Markedly high aPTTs were associated with increased risk of TIMI major or minor bleeding by 48 hours (odds ratio, 2.11; P=0.004); markedly low aPTTs tended to be associated with increased risk of fatal or nonfatal reinfarction by 48 hours (odds ratio, 2.19; P=0.057).Despite the use of a standard weight-based unfractionated heparin nomogram in ST-segment elevation myocardial infarction, nontherapeutic anticoagulation is frequent and more likely among certain vulnerable patient groups, with excess anticoagulation associated with increased bleeding and inadequate anticoagulation associated with reinfarction. These findings should be considered when dosing unfractionated heparin in support of fibrinolytic therapy.
Child uptake of smoking by area across the UK
Authors: Nicholas S Hopkinson, Adam Lester-George, Nick Ormiston-Smith, Alison Cox, Deborah Arnott
Journal: Thorax (2013)

Smoking is a major public health problem. As smokers age and die prematurely, the tobacco industry must continue to recruit new, young smokers. Survey data indicate that currently in the UK around 207,000 children aged 11-15 start smoking every year. We used local data on adult smoking rates to apportion national data on child smoking uptake to specific areas. The presentation of data for individual local authorities, which now have responsibility for public health, can be used to focus attention locally. For example, this analysis demonstrates that each day, 67 children, more than two classrooms full, start smoking in London.
Keratinocyte-Specific Stat3 Heterozygosity Impairs Development of Skin Tumors in Human Papillomavirus 8 Transgenic Mice
Authors: Marco De Andrea, Massimo Rittà, Manuela M. Landini, Cinzia Borgogna, Michele Mondini, Florian Kern, Karin Ehrenreiter, Manuela Baccarini, Gian Paolo Marcuzzi, Sigrun Smola, Herbert Pfister, Santo Landolfo, Marisa Gariglio
Journal: Cancer Research (2010)

Abstract Human papillomaviruses (HPV) of the genus β are thought to play a role in human skin cancers, but this has been difficult to establish using epidemiologic approaches. To gain insight into the transforming activities of β-HPV, transgenic mouse models have been generated that develop skin tumors. Recent evidence suggests a central role of signal transducer and activator of transcription 3 (Stat3) as a transcriptional node for cancer cell–autonomous initiation of a tumor-promoting gene signature associated with cell proliferation, cell survival, and angiogenesis. Moreover, high levels of phospho-Stat3 have been detected in tumors arising in HPV8-CER transgenic mice. In this study, we investigate the in vivo role of Stat3 in HPV8-induced skin carcinogenesis by combining our established experimental model of HPV8-induced skin cancer with epidermis-restricted Stat3 ablation. Stat3 heterozygous epidermis was less prone to tumorigenesis than wild-type epidermis. Three of the 23 (13%) Stat3+/−:HPV8 animals developed tumors within 12 weeks of life, whereas 54.3% of Stat3+/+:HPV8 mice already exhibited tumors in the same observation period (median age for tumor appearance, 10 weeks). The few tumors that arose in the Stat3+/−:HPV8 mice were benign and never progressed to a more malignant phenotype. Collectively, these results offer direct evidence of a critical role for Stat3 in HPV8-driven epithelial carcinogenesis. Our findings imply that targeting Stat3 activity in keratinocytes may be a viable strategy to prevent and treat HPV-induced skin cancer. Cancer Res; 70(20); 7938–48. ©2010 AACR.