tbuckley/cabot-search huggingface dataset:
Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development
Authors: Hongjie Li, Wendy Watford, Cuiling Li, Alissa Parmelee, Mark A. Bryant, Chuxia Deng, John O’Shea, Sean Bong Lee
Journal: Journal of Clinical Investigation (2007)

Ewing sarcoma gene EWS encodes a putative RNA-binding protein with proposed roles in transcription and splicing, but its physiological role in vivo remains undefined. Here, we have generated Ews-deficient mice and demonstrated that EWS is required for the completion of B cell development and meiosis. Analysis of Ews(-/-) lymphocytes revealed a cell-autonomous defect in precursor B lymphocyte (pre-B lymphocyte) development. During meiosis, Ews-null spermatocytes were deficient in XY bivalent formation and showed reduced meiotic recombination, resulting in massive apoptosis and complete arrest in gamete maturation. Inactivation of Ews in mouse embryonic fibroblasts resulted in premature cellular senescence, and the mutant animals showed hypersensitivity to ionizing radiation. Finally, we showed that EWS interacts with lamin A/C and that loss of EWS results in a reduced lamin A/C expression. Our findings reveal essential functions for EWS in pre-B cell development and meiosis, with proposed roles in DNA pairing and recombination/repair mechanisms. Furthermore, we demonstrate a novel role of EWS in cellular senescence, possibly through its interaction and modulation of lamin A/C.
Bar Mitzvah for B-1 Cells: How Will They Grow Up?
Authors: Alexander Tarakhovsky
Journal: The Journal of Experimental Medicine (1997)

The discovery of CD5+ B cells by Hayakawa et al. (1) initiated a 13 year-long discussion about the origin and functional properties of these cells. The CD5+ B cells (B-1a) and their phenotypic CD5− “twins” (B-1b cells) differ from conventional peripheral B cells (B-2) by anatomical location, developmental origin, surface marker expression, antibody repertoire and growth properties (2–4). B-1 cells form a dominant population of B lineage cells in the peritoneal cavity, but are rare in the spleen and lymph nodes of adult mice (3–6). The progenitors of B-1a cells are abundant in the fetal omentum and liver but in contrast to the progenitors of conventional B-2 cells, are missing in the bone marrow of adult mice (3, 7–9). The progenitors of B-1b cells are present in the fetal omentum and liver as well as in the bone marrow of adult mice (10, 11). However, a supply of B-1b cells from the bone marrow appears to be restricted by a negative feedback mechanism according to which the entrance of newly generated cells into the adult peripheral pool of B-1 cells is prevented by the presence of the mature B-1 population (12). In the absence of a continuous supply of bone marrow–derived B-1 cells, the size of the B-1 cell population is kept constant due to the self-renewal capacity of B-1 cells (3, 13). Due to their ability to produce large quantities of multireactive IgM, IgG3 and IgA, B-1 cells are considered carriers of “natural immunity” (7). It seems that the maintenance of B-1 cell population at a stable level might be necessary to control the level of antibody production by these cells. Thus the anti– IL-10 antibody-induced ablation of B-1 cells is accompanied by a drastic reduction of serum immunoglobulin titers (14). On the other hand, the expansion of autoreactive B-1 cells is associated with the development of autoimmunity in mice and man (15).
A Guide for the Design of Evolve and Resequencing Studies
Authors: Robert Kofler, Christian Schlötterer
Journal: Molecular Biology and Evolution (2013)

Standing genetic variation provides a rich reservoir of potentially useful mutations facilitating the adaptation to novel environments. Experimental evolution studies have demonstrated that rapid and strong phenotypic responses to selection can also be obtained in the laboratory. When combined with the next-generation sequencing technology, these experiments promise to identify the individual loci contributing to adaption. Nevertheless, until now, very little is known about the design of such evolve & resequencing (E&R) studies. Here, we use forward simulations of entire genomes to evaluate different experimental designs that aim to maximize the power to detect selected variants. We show that low linkage disequilibrium in the starting population, population size, duration of the experiment, and the number of replicates are the key factors in determining the power and accuracy of E&R studies. Furthermore, replication of E&R is more important for detecting the targets of selection than increasing the population size. Using an optimized design, beneficial loci with a selective advantage as low as s = 0.005 can be identified at the nucleotide level. Even when a large number of loci are selected simultaneously, up to 56% can be reliably detected without incurring large numbers of false positives. Our computer simulations suggest that, with an adequate experimental design, E&R studies are a powerful tool to identify adaptive mutations from standing genetic variation and thereby provide an excellent means to analyze the trajectories of selected alleles in evolving populations.
Impaired Pulmonary Inflammatory Responses Are a Prominent Feature of Streptococcal Pneumonia in Mice with Experimental Emphysema
Authors: Sumito Inoue, Hidenori Nakamura, Kazuhisa Otake, Hiroshi Saito, Kyoko Terashita, Jun Sato, Hiroaki Takeda, Hitonobu Tomoike
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Little is known about why patients with chronic obstructive pulmonary disease are susceptible to bacterial infections. Using an animal model of pulmonary emphysema, we investigated the inflammatory responses to bacterial infection. After intratracheal infection with Streptococcus pneumoniae (10(3)-10(7) cfu/mouse), the control mice did not die. However, the mice with emphysema died in a dose-dependent manner. Bronchoalveolar lavage fluid, examined 24 hours after infection showed that the numbers of total cells and neutrophils, in addition to murine tumor necrosis factor-alpha and macrophage inflammatory protein-2 concentrations, were significantly less in the mice with emphysema compared with the control mice. Histopathologic findings revealed that the alveoli were filled with inflammatory cells and exudate in the control mice but not in the mice with emphysema. Seventy-two hours after infection, serum cytokine levels were significantly higher in the mice with emphysema, and significant numbers of S. pneumoniae were detected in both the whole lung tissues and the blood of mice with emphysema. These findings suggest that the inflammatory response in mice with emphysema was impaired at the site of bacterial infection despite the bacteremia, which accelerated severe systemic inflammatory responses. Accordingly, intra-alveolar but not systemic immune responses to bacterial infection were impaired in the presence of experimental emphysema.
Long-acting inhaled bronchodilators in COPD: how many drugs do we need?
Authors: P. M. A. Calverley
Journal: European Respiratory Journal (2005)

Bronchodilators remain the mainstay of chronic obstructive pulmonary disease (COPD) management and are recommended for the treatment of symptomatic patients at all stages of this disease 1. For many years studies of these drugs focussed on changes in forced expiratory volume in one second (FEV1) or, occasionally, forced vital or slow vital capacity, believing that these robust and reproducible end-points were a legitimate surrogate for the changes in symptomatology, which were the real interest of patients and clinicians alike. By the 1990s, this comfortable assumption had been challenged when it became clear that individual improvement in exercise capacity and breathlessness were not closely related to changes in the magnitude of these spirometric indices 2. This stimulated research into the determinants of exercise performance and dyspnoea in COPD, and why spirometry was of so little help in predicting symptomatic improvement. A range of mechanisms have been identified and have recently been reviewed 3. Principal among these is the change in end-expiratory lung volume (EELV) during exercise in COPD patients. When healthy subjects exercise, EELV is reduced helping to keep the operating lung volumes on the steeper part of the pressure-volume relationship. COPD patients with tidal expiratory flow limitation must either allow EELV to rise 4, or try to overcome flow limitation at their initial lung volume an unsatisfactory strategy which limits exercise performance 5. Most patients with more severe disease adopt for the former approach which allows them to exercise longer, but at the cost of increasing difficulty in breathing as …
Enhancement of Coronary Vasodilating Action of ATP and Adenosine by Lidoflazine
Authors: SKODA AFONSO, GEORGE S. O'BRIEN, CHARLES W. CRUMPTON
Journal: Circulation Research (1968)

Lidoflazine, a newly developed coronary vasodilator, greatly enhances the coronary vasodilating action of adenosine and ATP. Experiments were designed to study the combined coronary vasodilating effects of adenosine and lidoflazine and to quantify the enhancement of coronary vasodilation of adenosine and ATP by prior administration of lidoflazine. Results of the experiments showed that the combined coronary vasodilating effects of adenosine and lidoflazine can be classified as supra-additive. For 3 hours after the administration of lidoflazine there was a great intensification (20 to 150 times) of the vasodilating action of adenosine or ATP. An adenosine-sparing effect of lidoflazine in whole blood was also demonstrated, and the enhancement of adenosine action is in part related to this effect. It is suggested that lidoflazine may also produce a change in the sensitivity of the smooth muscle of the coronary vessels to the direct or indirect action of adenosine.
A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets
Authors: Ayumu Taguchi, Allen D. Taylor, Jaime Rodriguez, Müge Çeliktaş, Hui Liu, Xiaotu Ma, Qing Zhang, Chee-Hong Wong, Alice Chin, Luc Girard, Carmen Behrens, Wan L. Lam, Stephen Lam, John D. Minna, Ignacio I. Wistuba, Adi F. Gazdar, Samir M. Hanash
Journal: Cancer Research (2014)

Abstract Cancer/testis (CT) antigens are potential immunotherapeutic targets in cancer. However, the expression of particular antigens is limited to a subset of tumors of a given type. Thus, there is a need to identify antigens with complementary expression patterns for effective therapeutic intervention. In this study, we searched for genes that were distinctly expressed at a higher level in lung tumor tissue and the testes compared with other nontumor tissues and identified members of the VCX/Y gene family as novel CT antigens. VCX3A, a member of the VCX/Y gene family, was expressed at the protein level in approximately 20% of lung adenocarcinomas and 35% of squamous cell carcinomas, but not expressed in normal lung tissues. Among CT antigens with concordant mRNA and protein expression levels, four CT antigens, XAGE1, VCX, IL13RA2, and SYCE1, were expressed, alone or in combination, in about 80% of lung adenocarcinoma tumors. The CT antigen VCX/Y gene family broadens the spectrum of CT antigens expressed in lung adenocarcinomas for clinical applications. Cancer Res; 74(17); 4694–705. ©2014 AACR.
Quality-of-Life Assessment in the Symptom Management Trials of the National Cancer Institute-Supported Community Clinical Oncology Program
Authors: David R. Buchanan, Ann M. O'Mara, Joseph W. Kelaghan, Lori M. Minasian
Journal: Journal of Clinical Oncology (2005)

Purpose To examine how quality of life (QOL) is prospectively conceptualized, defined, and measured in the symptom management clinical trials supported by the National Cancer Institute Community Clinical Oncology Program (CCOP). Methods All QOL research objectives, rationales, assessment instruments, symptoms treated, and types of interventions from the CCOP symptom management portfolio of clinical trials were extracted and analyzed. Results QOL assessments were proposed in 68 (52%) of the 130 total CCOP symptom management trials initiated since 1987. A total of 22 global QOL instruments were identified. Both the frequency of symptom management trials and the frequency of QOL assessment have increased significantly over time. The Functional Assessment of Cancer Therapy and Uniscale instruments were the most widely used QOL instruments, included in 55% of trials assessing QOL. The conceptual framework for QOL inclusion was limited to univariate relationships between symptom relief and global improvements in QOL. No consistent associations were found between QOL assessment and either the symptoms targeted or types of interventions. Conclusion To advance the state of the science, research protocols need to provide more explicit rationales for assessing QOL in symptom management trials and for the selection of the QOL instrument(s) to be used. Conceptual frameworks that specify the hypothesized links between the specific symptom(s) being managed, interactions with other symptoms, different domains of QOL, and global QOL also need to be more precisely described. Methodologic and conceptual advances in QOL symptom management trials are critical to fulfill the promise of alleviating suffering and improving the QOL of cancer patients.
Qualitative Age Interactions in Breast Cancer Studies: Mind the Gap
Authors: William F. Anderson, Ismail Jatoi, Mark E. Sherman
Journal: Journal of Clinical Oncology (2009)

NOTE. Qualitative age interactions are expressed as RRs where one characteristic is compared with a referent characteristic with an assigned RR of 1.0. RR 1.0 shows increased breast cancer risk or harmful effect while RR 1.0 shows reduced breast cancer risk or protection compared with the referent characteristic. The crossover age reflects the approximate age of the crossover where RR switches from 1.0 to 1.0 or vice versa. RRs in the Table refer to the RR prior to the age of crossover. For example, RRbefore 30-44 years 1.0 for parity compared with nulliparity; whereas after age 44 years, RR 1.0 for parity compared with nulliparity. Parity increases breast cancer risk before ages 30-44 years but is protective thereafter. 7,12 Obese BMI (body mass index) is protective for premenopausal women before age 50 years but increases risk for postmenopausal women. 8 Age-specific incidence rates are higher for blacks than whites prior to age 40 years but higher for whites after age 40 years. 9 Poor prognostic factor characteristics (tumor sizes 2.0 centimeters, positive axillary lymph nodes, high tumor grade, estrogen and progesterone receptor negative expression) are more common among women before age 50 years, whereas good prognostic factors are more common after age 50 years. 10 Breast cancer outcome (overall recurrence rate and greater risk for developing metastatic disease) is worse among younger (before age 35 years) than older patients, and this difference is not fully explained by greater frequency of adverse prognostic factors. 38 Adjuvant systemic therapy is associated with higher rates of relapse for ER breast cancers among women before age 35 years than older women. 4 NSABP B18 showed that neoadjuvant (preoperative) chemotherapy was marginally beneficial among women before age 50 years and the reverse was true for older women. 5 Fenretinide chemoprevention demonstrated borderline protective effects (P .045) for premenopausal women before age 51 years and harmful effects for postmenopausal women. 6 Abbreviations: RR, relative risk; BMI, body mass index; ER, estrogen receptor; PR, progesterone receptor; Rx, treatment; NSABP, National Surgical Adjuvant Breast and Bowel Project; AC, doxorubicin and cytoxan.
Response to Ebola in the US: misinformation, fear, and new opportunities
Authors: J. G. Merino
Journal: BMJ (2014)

<h3>Aim of the special session</h3> Intolerance may develop to various everyday environmental exposures at levels that are well below those known to cause adverse health effects. Reactions initiate typically from odorous substances, but also from non-perceivable factors considered harmful to health, e.g. electrical devices. Reactions range from unpleasant sensations and annoyance to multi-organ symptoms, severe disability, and major restrictions in daily life and work. Symptoms often lead to exposure assessments at work and may result in excessive actions to eliminate minor exposures. In environmental intolerance, occupational health care is the front line actor in primary and secondary prevention, and support of recovery. Markku Sainio<sup>1</sup>, Anna-Sara Claeson<sup>2</sup>, Christoph van Thriel<sup>3</sup>, Kenichi Azuma<sup>4</sup>, Lena Hillert<sup>5</sup>, Martin Tondel<sup>6,7</sup> <sup>1</sup>Work Environment, Finnish Institute of Occupational Health, Helsinki, Finland <sup>2</sup>Department of Psychology, Umeå University, Sweden <sup>3</sup>Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund, Dortmund, Germany <sup>4</sup>Kindai University Faculty of Medicine, Osakasayama, Japan <sup>5</sup>Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden <sup>6</sup>Occupational and Environmental Medicine, Uppsala University Hospital, Uppsala, Sweden <sup>7</sup>Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Improving Penetration in Tumors With Nanoassemblies of Phospholipids and Doxorubicin
Authors: N. Tang, G. Du, N. Wang, C. Liu, H. Hang, W. Liang
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundDrug delivery and penetration into neoplastic cells distant from tumor vessels is critical for the effectiveness of solid tumor chemotherapy. We hypothesized that 10- to 20-nm nanoassemblies of phospholipids containing doxorubicin would improve the drug's penetration, accumulation, and antitumor activity.
Influence of lung volume on sympathetic nerve discharge in normal humans.
Authors: D R Seals, N O Suwarno, J A Dempsey
Journal: Circulation Research (1990)

The purpose of this study was to determine the influence of tidal volume, breathing pattern, and beginning lung volume on the modulation of efferent, muscle sympathetic nerve activity (MSNA) in humans. In seven supine, healthy subjects, we measured MSNA (microneurography of the right peroneal nerve) and beat to beat arterial blood pressure during 1) low-frequency breathing (fb = 12 breaths/min) at tidal volumes (VT) of 30% (control), 50%, and 70% of inspiratory capacity and with inspiratory time-to-total breath time ratios (TI/TTOT) of 0.3-0.5 (control), less than 0.3, and greater than 0.5; and 2) simulated exercise hyperpnea (fb = 40 breaths/min; VT = 60-70% inspiratory capacity; minute ventilation, approximately 90 1). To optimize our ability to discern modulatory effects, breathing was performed during three conditions of heightened MSNA: nonhypotensive (less than 20 mm Hg) lower-body negative pressure, isometric handgrip exercise, and posthandgrip vascular occlusion (ischemia). PETCO2 was maintained at normal levels by adjusting the FICO2. Within-breath modulation of MSNA was observed during control tidal breathing with approximately 65% of the burst frequency occurring during the expiratory phase. Deep, low-frequency breathing potentiated this modulatory influence (p less than 0.05 versus control) and produced near-complete sympathoinhibition from onset-mid inspiration to early-mid expiration. Increasing (slow inspiration) and decreasing (fast inspiration) TI/TTOT shifted the onset of sympathoinhibition occurring later (greater change in volume) and earlier (less change in volume) during inspiration, respectively. In two subjects who performed deep breathing from an elevated beginning lung volume, the sympathoinhibition was observed earlier in the inspiratory period and with less change in volume compared with control. These within-breath modulatory effects did not appear to be due solely to changes in arterial pressure. Sustained low- or high ("exerciselike")-frequency deep breathing did not alter total minute MSNA compared with control breathing. These results demonstrate that the depth and pattern of breathing, and possibly the starting lung volume, exert marked influences on the within-breath modulation of MSNA in humans. Our findings also suggest that these modulatory effects may be mediated, at least in part, by pulmonary stretch reflexes.
Mechanisms Involved in Synergistic Anticancer Immunity of Anti-4-1BB and Anti-CD4 Therapy
Authors: Beom K. Choi, Young H. Kim, Woo J. Kang, Sun K. Lee, Kwang H. Kim, Su M. Shin, Wayne M. Yokoyama, Tae Y. Kim, Byoung S. Kwon
Journal: Cancer Research (2007)

Abstract Anti-4-1BB–mediated anticancer effects were potentiated by depletion of CD4+ cells in B16F10 melanoma-bearing C57BL/6 mice. Anti-4-1BB induced the expansion and differentiation of polyclonal tumor-specific CD8+ T cells into IFN-γ–producing CD11c+CD8+ T cells. The CD4+ cell depletion was responsible for facilitating immune cell infiltration into tumor tissues and removing some regulatory barriers such as T regulatory and indoleamine-2,3-dioxygenase (IDO)+ dendritic cells. Both monoclonal antibodies (mAb) contributed to the efficient induction of MHC class I molecules on the tumor cells in vivo. The effectors that mediated the anti-4-1BB effect were NKG2D+KLRG1+CD11c+CD8+ T cells that accumulated preferentially in the tumor tissues. Blocking NKG2D reduced the therapeutic effect by 20% to 26%, which may indicate that NKG2D contributes partially to tumor killing by the differentiated CD8+ T cells. Our results indicate that the combination of the two mAbs, agonistic anti-4-1BB and depleting anti-CD4, results in enhanced production of efficient tumor-killing CTLs, facilitation of their infiltration, and production of a susceptible tumor microenvironment. [Cancer Res 2007;67(18):8891–9]
Long-term effects of intermittent interleukin 2 therapy in patients with HIV infection: characterization of a novel subset of CD4+/CD25+ T cells
Authors: Irini Sereti, Hector Martinez-Wilson, Julia A. Metcalf, Michael W. Baseler, Claire W. Hallahan, Barbara Hahn, Richard L. Hengel, Richard T. Davey, Joseph A. Kovacs, H. Clifford Lane
Journal: Blood (2002)
Reality at the coal face
Authors: L. S. Lewis
Journal: BMJ (2010)

I fear that Connor and O’Donoghue1 are too committed to their cause to appreciate Spence’s perspective.2 All my patients are assigned a chronic kidney disease (CKD) grade. Several healthy patients have been horrified to be classified as “CKD 1.” My efforts to reassure them that they are normal ring hollow. …