tbuckley/cabot-search huggingface dataset:
Suicidal erythrocyte death, eryptosis, as a novel mechanism in heart failure-associated anaemia
Authors: Hasan Mahmud, Willem P.T. Ruifrok, B. Daan Westenbrink, Megan V. Cannon, Inge Vreeswijk-Baudoin, Wiek H. van Gilst, Herman H.W. Silljé, Rudolf A. de Boer
Journal: Cardiovascular Research (2013)

Suicidal death of erythrocytes (eryptosis) is characterized by cell shrinkage and exposure of phosphatidylserine (PS) residues at the cell surface. Excessive eryptosis may lead to anaemia. We aimed to study the role of eryptosis in heart failure (HF)-associated anaemia. We measured eryptosis in rodent models of HF. Typical measures of eryptosis including PS-exposure, increased intracellular Ca2+ levels, and decreased cell volume were determined by flow cytometry. Transgenic REN2 rats displayed mild anaemia which was associated with a two-fold increase in erythrocyte PS-exposure when compared with Sprague Dawley (SD) control rats (P < 0.01). Upon stimulation with eryptotic triggers such as oxidative stress, hyperosmotic shock and energy depletion, eryptosis was more prominent in REN2 as shown by increased PS-exposure, cytosolic Ca2+ influx, and cell shrinkage (P < 0.05 vs. SD). Increasing cytosolic Ca2+ levels resulted in a stronger increase in PS-exposure in REN2 erythrocytes (P < 0.01 vs. SD). Accordingly, inhibition of Ca2+ entry blunted the increased PS-exposure upon oxidative stress. The REN2 rats had significantly higher reticulocytes (REN2: 10.6 ± 2.3%; SD: 5.4 ± 0.1%; P < 0.05) and erythrocyte turnover was increased, indicated by increased clearance of eryptotic erythrocytes. Eryptosis was also increased in a rat model of hypertensive cardiac remodelling (uninephrectomized rats implanted with deoxycorticosterone acetate pellets), in mice after transverse aortic constriction, as well as in a small proof-of-concept study in human HF patients. Eryptosis is increased during HF development and could contribute to HF-associated anaemia. Eryptosis may therefore become a novel target for therapy in HF-associated anaemia.
A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study
Authors: L. B. Kilburn, M. Kocak, R. L. Decker, C. Wetmore, M. Chintagumpala, J. Su, S. Goldman, A. Banerjee, R. Gilbertson, M. Fouladi, L. Kun, J. M. Boyett, S. M. Blaney
Journal: Neuro-Oncology (2014)

We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies. Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m2) and twice daily at 440 mg/m2/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m2 given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m2 dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m2/day administered once daily.
HAPTEN-SPECIFIC IgE ANTIBODY RESPONSES IN MICE
Authors: Toshiyuki Hamaoka, David H. Katz, Kurt J. Bloch, Baruj Benacerraf
Journal: The Journal of Experimental Medicine (1973)

The present studies have established conditions for the demonstration of cooperative interactions between specific T and B lymphocyte populations in the development of IgE antibody responses in vivo in mice. This has been accomplished by utilizing a system which permits the successful adoptive transfer to irradiated recipients of DNP-specific secondary IgE responses with spleen cells from suitably primed syngeneic donor mice. Thus, adoptively transferred DNP-KLH or DNP-ASC-primed spleen cells produced high levels of anti-DNP antibodies of both IgE and IgG antibody classes in response to challenge with the appropriate homologous priming conjugate but failed to develop more than meager responses to the reciprocal heterologous conjugate. However, when spleen cells from donors primed to the second carrier were concomitantly transferred with hapten-primed lymphocytes, secondary IgE ant-DNP responses were consistently obtained upon challenge with the heterologous conjugate. Moreover, we have been able to elicit augmented primary IgE anti-DNP antibody responses to either DNP-ASC or DNP-KLH after adoptive transfer of spleen cells from donors primed only to the carrier, ASC or KLH, respectively.

This adoptive transfer system has enabled us to provide direct proof for the participation of θ-bearing T lymphocytes in antibody responses of the IgE class. Thus, the capacity of ASC-primed spleen cells to effectively cooperate with the DNP-KLH-primed lymphocytes in the adoptive secondary response to DNP-ASC could be abolished by in vitro treatment of such cells with anti-θ serum plus complement. This was true not only for the anti-DNP response of the IgG antibody class, but for the IgE antibody class as well.

These studies have, furthermore, demonstrated the capacity to stimulate secondary anti-DNP antibody production in vivo by the concomitant administration of the DNP and relevant carrier determinants on separate molecules. This was more readily seen in the IgE than in the IgG antibody class. Thus, DNP-ASC-primed cells developed significant IgE, but more variable IgG, anti-DNP responses upon challenge with DNP-KLH plus unconjugated ASC. Antibody responses of both classes elicited in this manner were appreciably improved by the transfer of additional carrier (ASC)-primed cells. These and other results presented herein suggest that IgE B lymphocyte precursors may be inherently more sensitive than IgG B cells to at least certain of the functions of T lymphocytes concerned with regulatory mechanisms involved in antibody production.
Design and Statistical Aspects of the African American Study of Kidney Disease and Hypertension (AASK)
Authors: Jennifer J. Gassman, Tom Greene, Jackson T. Wright, Lawrence Agodoa, George Bakris, Gerald J. Beck, Janice Douglas, Ken Jamerson, Julia Lewis, Michael Kutner, Otelio S. Randall, Shin-Ru Wang
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The African American Study of Kidney Disease and Hypertension (AASK) is a multicenter randomized clinical trial designed to test the effectiveness of three anti-hypertensive drug regimens and two levels of BP control on the progression of hypertensive kidney disease. Participants include African-American men and women aged 18 to 70 yr who have hypertensive kidney disease and GFR between 20 and 65 ml/min per 1.73 m2. The three anti-hypertensive drug regimens include an angiotensin converting enzyme inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine) or a beta-blocker (metoprolol) as initial therapy. The BP control levels are a lower goal (mean arterial pressure, ≤92 mmHg) and a usual goal (mean arterial pressure, 102 to 107 mmHg inclusive). The primary outcome is rate of change in renal function as measured by GFR, assessed by 125 I-iothalamate clearance. The main secondary patient outcome is a composite including the following events: (1) reduction in GFR by 50%, (2) end-stage renal disease, or (3) death. E-mail: [email protected]
Double-blind randomised controlled trial of vitamin D<sub>3</sub>supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu)
Authors: Adrian R Martineau, Yasmeen Hanifa, Karolina D Witt, Neil C Barnes, Richard L Hooper, Mital Patel, Natasha Stevens, Zinat Enayat, Zuhur Balayah, Asmat Syed, Aishah Knight, David A Jolliffe, Claire L Greiller, David McLaughlin, Timothy R Venton, Marion Rowe, Peter M Timms, Duncan Clark, Zia Sadique, Sandra M Eldridge, Christopher J Griffiths
Journal: Thorax (2015)

<h3>Rationale</h3> Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional protection against acute respiratory infection (ARI) are lacking. <h3>Objective</h3> To conduct a clinical trial of high-dose versus low-dose vitamin D<sub>3</sub> supplementation for ARI prevention in residents of sheltered-accommodation housing blocks (‘schemes’) and their carers in London, UK. <h3>Measurements and methods</h3> Fifty-four schemes (137 individual participants) were allocated to the active intervention (vitamin D<sub>3</sub> 2.4 mg once every 2 months +10 μg daily for residents, 3 mg once every 2 months for carers), and 54 schemes with 103 participants were allocated to control (placebo once every 2 months +vitamin D<sub>3</sub> 10 μg daily for residents, placebo once every 2 months for carers) for 1 year. Primary outcome was time to first ARI; secondary outcomes included time to first upper/lower respiratory infection (URI/LRI, analysed separately), and symptom duration. <h3>Main results</h3> Inadequate vitamin D status was common at baseline: 220/240 (92%) participants had serum 25(OH)D concentration &lt;75 nmol/L. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with increased risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI. <h3>Conclusions</h3> Addition of intermittent bolus-dose vitamin D<sub>3</sub> supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI. <h3>Trial registration number</h3> clinicaltrials.gov NCT01069874.
Is Tumor Growth Sustained by Rare Cancer Stem Cells or Dominant Clones?
Authors: Jerry M. Adams, Andreas Strasser
Journal: Cancer Research (2008)

Abstract A key issue for cancer biology and therapy is whether the relentless growth of a tumor is driven by a substantial proportion of its cells or exclusively by a rare subpopulation, commonly termed “cancer stem cells.” Support for the cancer stem cell model has been stimulated by experiments in which human tumor cells were transplanted into immunodeficient mice. Most notably, in human acute myeloid leukemia, only a minute proportion of the cells, displaying a defined phenotype, could seed leukemia in mice. Xenotransplantation, however, may fail to reveal many tumor growth–sustaining cells because the foreign microenvironment precludes essential interactions with support cells. In studies that instead have transplanted mouse leukemias and lymphomas into syngeneic animals, most of the tumors seem to be maintained by the dominant cell population, and only a few types of mouse leukemia seem to be sustained by a minor tumor growth–sustaining subpopulation. The collective evidence suggests that various tumors may span the spectrum between the extremes represented by the two models. If tumor growth can indeed be sustained either by rare cancer stem cells or dominant clones or both, as current evidence suggests, curative therapy for many types of tumors will most likely require targeting all the tumor cell populations. [Cancer Res 2008;68(11):4018–21]
Two sides of the medallion: poor treatment tolerance but better survival by standard chemotherapy in elderly patients with advanced-stage diffuse large B-cell lymphoma
Authors: S.A.M. van de Schans, A.N.M. Wymenga, D.J. van Spronsen, H.C. Schouten, J.W.W. Coebergh, M.L.G. Janssen-Heijnen
Journal: Annals of Oncology (2011)
Australian mortality statistics for rheumatoid arthritis 1950-81: analysis of death certificate data.
Authors: I P Wicks, J Moore, A Fleming
Journal: Annals of the Rheumatic Diseases (1988)

An analysis of mortality related to rheumatoid arthritis (RA) in Australia for the period 1950 to 1981 was undertaken based on information recorded in death certificates. These data include every death over a 32 year period where RA was considered to be the underlying cause. Death from RA was commonly reported (0.17% of all deaths). The mean age at death from RA in both sexes exceeded that of the general population for most of the period. There was little difference between patients dying of RA and the general population for age at death in the over 50 years9 age group. There was a significant decrease in mortality for women dying of RA over the age of 75. RA accounted for more deaths in women than in men (in a ratio of 2.2:1). Men tended to die at a younger age from RA than did women. The impact of RA remained relatively constant in relation both to the total causes of death and to deaths due to other musculoskeletal diseases. There was a significant decline, however, in female RA deaths as a percentage of deaths due to all musculoskeletal diseases. Cohort analysis does not indicate any marked effect from extrinsic factors on mortality due to RA.
Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: The Genes-environments and Admixture in Latino Asthmatics (GALA II) study
Authors: Rajesh Kumar, Elizabeth A. Nguyen, Lindsey A. Roth, Sam S. Oh, Christopher R. Gignoux, Scott Huntsman, Celeste Eng, Andres Moreno-Estrada, Karla Sandoval, Rosenda I. Peñaloza-Espinosa, Marisol López-López, Pedro C. Avila, Harold J. Farber, Haig Tcheurekdjian, William Rodriguez-Cintron, Jose R. Rodriguez-Santana, Denise Serebrisky, Shannon M. Thyne, L. Keoki Williams, Cheryl Winkler, Carlos D. Bustamante, Eliseo J. Pérez-Stable, Luisa N. Borrell, Esteban G. Burchard
Journal: Journal of Allergy and Clinical Immunology (2013)
Neonatal Diabetes Mellitus
Authors: Lydia Aguilar-Bryan, Joseph Bryan
Journal: Endocrine Reviews (2008)

An explosion of work over the last decade has produced insight into the multiple hereditary causes of a nonimmunological form of diabetes diagnosed most frequently within the first 6 months of life. These studies are providing increased understanding of genes involved in the entire chain of steps that control glucose homeostasis. Neonatal diabetes is now understood to arise from mutations in genes that play critical roles in the development of the pancreas, of β-cell apoptosis and insulin processing, as well as the regulation of insulin release. For the basic researcher, this work is providing novel tools to explore fundamental molecular and cellular processes. For the clinician, these studies underscore the need to identify the genetic cause underlying each case. It is increasingly clear that the prognosis, therapeutic approach, and genetic counseling a physician provides must be tailored to a specific gene in order to provide the best medical care.
Halogenation and topical steroids
Authors: James R. Murray
Journal: British Journal of Dermatology (1981)

Journal Article Halogenation and topical steroids Get access James R. Murray James R. Murray Medical Director, Brocades Ltd, West Byfieet, Surrey Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 105, Issue 4, 1 October 1981, Pages 484–485, https://doi.org/10.1111/j.1365-2133.1981.tb00787.x Published: 01 October 1981
Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia
Authors: Francesco Lo-Coco, Giuseppe Avvisati, Marco Vignetti, Christian Thiede, Sonia Maria Orlando, Simona Iacobelli, Felicetto Ferrara, Paola Fazi, Laura Cicconi, Eros Di Bona, Giorgina Specchia, Simona Sica, Mariadomenica Divona, Alessandro Levis, Walter Fiedler, Elisa Cerqui, Massimo Breccia, Giuseppe Fioritoni, Helmut R. Salih, Mario Cazzola, Lorella Melillo, Angelo M. Carella, Christian H. Brandts, Enrica Morra, Marie von Lilienfeld-Toal, Bernd Hertenstein, Mohammed Wattad, Michael Lübbert, Matthias Hänel, Norbert Schmitz, Hartmut Link, Maria Grazia Kropp, Alessandro Rambaldi, Giorgio La Nasa, Mario Luppi, Fabio Ciceri, Olimpia Finizio, Adriano Venditti, Francesco Fabbiano, Konstanze Döhner, Michaela Sauer, Arnold Ganser, Sergio Amadori, Franco Mandelli, Hartmut Döhner, Gerhard Ehninger, Richard F. Schlenk, Uwe Platzbecker
Journal: New England Journal of Medicine (2013)

All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).
A Prospective Study of Age-Specific Physical Activity and Premenopausal Breast Cancer
Authors: S. S. Maruti, W. C. Willett, D. Feskanich, B. Rosner, G. A. Colditz
Journal: JNCI Journal of the National Cancer Institute (2008)

Physical activity has been consistently associated with lower risk of postmenopausal breast cancer, but its relationship with premenopausal breast cancer is unclear. We investigated whether physical activity is associated with reduced incidence of premenopausal breast cancer, and, if so, what age period and intensity of activity are critical. A total of 64 777 premenopausal women in the Nurses' Health Study II reported, starting on the 1997 questionnaire, their leisure-time physical activity from age 12 to current age. Cox regression models were used to examine the relationship between physical activity, categorized by age period (adolescence, adulthood, and lifetime) and intensity (strenuous, moderate, walking, and total), and risk of invasive premenopausal breast cancer. During 6 years of follow-up, 550 premenopausal women developed breast cancer. The strongest associations were for total leisure-time activity during participants' lifetimes rather than for any one intensity or age period. Active women engaging in 39 or more metabolic equivalent hours per week (MET-h/wk) of total activity on average during their lifetime had a 23% lower risk of premenopausal breast cancer (relative risk = 0.77; 95% confidence interval = 0.64 to 0.93) than women reporting less activity. This level of total activity is equivalent to 3.25 h/wk of running or 13 h/wk of walking. The age-adjusted incidence rates of breast cancer for the highest (≥54 MET-h/wk) and lowest (<21 MET-h/wk) total lifetime physical activity categories were 136 and 194 per 100 000 person-years, respectively. High levels of physical activity during ages 12–22 years contributed most strongly to the association. Leisure-time physical activity was associated with a reduced risk for premenopausal breast cancer in this cohort. Premenopausal women regularly engaging in high amounts of physical activity during both adolescence and adulthood may derive the most benefit.
Hypothalamic Integration: Organization of the Paraventricular and Supraoptic Nuclei
Authors: L W Swanson, P E Sawchenko
Journal: Annual Review of Neuroscience (1983)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Relocation Facilitates the Acquisition of Short Cis-Regulatory Regions that Drive the Expression of Retrogenes during Spermatogenesis in Drosophila
Authors: Mehran Sorourian, Mansi M. Kunte, Susana Domingues, Miguel Gallach, Fulya Özdil, Javier Río, Esther Betrán
Journal: Molecular Biology and Evolution (2014)

Retrogenes are functional processed copies of genes that originate via the retrotranscription of an mRNA intermediate and often exhibit testis-specific expression. Although this expression pattern appears to be favored by selection, the origin of such expression bias remains unexplained. Here, we study the regulation of two young testis-specific Drosophila retrogenes, Dntf-2r and Pros28.1A, using genetic transformation and the enhanced green fluorescent protein reporter gene in Drosophila melanogaster. We show that two different short (<24 bp) regions upstream of the transcription start sites (TSSs) act as testis-specific regulatory motifs in these genes. The Dntf-2r regulatory region is similar to the known β2 tubulin 14-bp testis motif (β2-tubulin gene upstream element 1 [β2-UE1]). Comparative sequence analyses reveal that this motif was already present before the Dntf-2r insertion and was likely driving the transcription of a noncoding RNA. We also show that the β2-UE1 occurs in the regulatory regions of other testis-specific retrogenes, and is functional in either orientation. In contrast, the Pros28.1A testes regulatory region in D. melanogaster appears to be novel. Only Pros28.1B, an older paralog of the Pros28.1 gene family, seems to carry a similar regulatory sequence. It is unclear how the Pros28.1A regulatory region was acquired in D. melanogaster, but it might have evolved de novo from within a region that may have been preprimed for testes expression. We conclude that relocation is critical for the evolutionary origin of male germline-specific cis-regulatory regions of retrogenes because expression depends on either the site of the retrogene insertion or the sequence changes close to the TSS thereafter. As a consequence we infer that positive selection will play a role in the evolution of these regulatory regions and can often act from the moment of the retrocopy insertion.