tbuckley/cabot-search huggingface dataset:
Altered Hematopoiesis, Behavior, and Sexual Function in μ Opioid Receptor–deficient Mice
Authors: Mingting Tian, Hal E. Broxmeyer, Yi Fan, Zhennan Lai, Shengwen Zhang, Susan Aronica, Scott Cooper, Robert M. Bigsby, Rosemary Steinmetz, Sandra J. Engle, Anton Mestek, Jonathan D. Pollock, Michael N. Lehman, Heiko T. Jansen, Moyin Ying, Peter J. Stambrook, Jay A. Tischfield, Lei Yu
Journal: The Journal of Experimental Medicine (1997)

The μ opioid receptor is thought to be the cellular target of opioid narcotics such as morphine and heroin, mediating their effects in both pain relief and euphoria. Its involvement is also implicated in a range of diverse biological processes. Using a mouse model in which the receptor gene was disrupted by targeted homologous recombination, we explored the involvement of this receptor in a number of physiological functions. Mice homozygous for the disrupted gene developed normally, but their motor function was altered. Drug-naive homozygotes displayed reduced locomotor activity, and morphine did not induce changes in locomotor activity observed in wild-type mice. Unexpectedly, lack of a functional receptor resulted in changes in both the host defense system and the reproductive system. We observed increased proliferation of granulocyte-macrophage, erythroid, and multipotential progenitor cells in both bone marrow and spleen, indicating a link between hematopoiesis and the opioid system, both of which are stress-responsive systems. Unexpected changes in sexual function in male homozygotes were also observed, as shown by reduced mating activity, a decrease in sperm count and motility, and smaller litter size. Taken together, these results suggest a novel role of the μ opioid receptor in hematopoiesis and reproductive physiology, in addition to its known involvement in pain relief.
HISTOCHEMICAL OBSERVATIONS ON FOUR CASES OF CHEIROPOMPHOLYX.
Authors: A. W. ASSCHER
Journal: British Journal of Dermatology (1955)

Journal Article HISTOCHEMICAL OBSERVATIONS ON FOUR CASES OF CHEIROPOMPHOLYX. Get access A. W. ASSCHER, B.Sc. A. W. ASSCHER, B.Sc. Department of Anatomy, London Hospital Medical College Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 67, Issue 1, 1 January 1955, Pages 9–15, https://doi.org/10.1111/j.1365-2133.1955.tb12650.x Published: 01 January 1955
Neuromodulatory State and Sex Specify Alternative Behaviors through Antagonistic Synaptic Pathways in C. elegans
Authors: Heeun Jang, Kyuhyung Kim, Scott J. Neal, Evan Macosko, Dongshin Kim, Rebecca A. Butcher, Danna M. Zeiger, Cornelia I. Bargmann, Piali Sengupta
Journal: Neuron (2012)
High DNA-methyltransferase 3B expression predicts poor outcome in acute myeloid leukemia, especially among patients with co-occurring NPM1 and FLT3 mutations
Authors: D Monteferrario, S M Noordermeer, S Bergevoet, G Huls, J H Jansen, B A van der Reijden
Journal: Blood Cancer Journal (2014)

DNA methyltransferases (DNMTs) are epigenetic regulators targeted to the treatment of hematological malignancies.1, 2, 3, 4 Mutations in the DNA methyltransferase DNMT3A and high expression of its paralogue DNMT3B have been associated with inferior outcome in acute myeloid leukemia (AML) and other hematological malignancies.5, 6, 7, 8 Using a publicly available gene expression data set,9 we studied whether DNMT3B expression correlates with outcome in genetically well-defined AML subgroups. We first validated the expression data from the microarray by quantitative PCR, using 39 patient samples (Supplementary Figure S1A). DNMT3B micro-array analyses showed that the expression was not normally distributed among AML patients; in the quartile with highest expression, a larger variation in expression was observed compared to the three quartiles with relatively lower expression (Supplementary Figure S1B). The median DNMT3B expression in AML samples was significantly lower compared with that observed in normal bone marrow (NBM)-derived CD34+ cells (P 60 years; white blood cell counts >100 × 109/l; transplantation status; karyotypes t(8;21), t(15;17) and inv(16); nucleophosmin 1 (NPM1), FLT3-ITD, DNMT3A and double CEBPA mutations, and ecotropic viral integration site 1 (EVI1) overexpression), which revealed that higher DNMT3B expression carried an independent prognostic risk for both OS and EFS (hazard ratio (HR): 1.768, 95% confidence interval (CI): 1.384–2.260; P<0.001 and HR: 1.706, 95% CI: 1.342–2.168; P<0.001, respectively, Table 1), in line with a recently published study.7 In fact, higher DNMT3B expression showed a higher hazard ratio for OS than that of well-known adverse prognostic factors such as internal tandem duplications of the fms-related tyrosine kinase 3 (FLT3-ITD, HR: 1.675, 95% CI: 1.287–2.179; P<0.001) and overexpression of the EVI1 gene (HR: 1.430, 95% CI: 0.999–2.047; P=0.051).
Diversification at Transcription Factor Binding Sites within a Species and the Implications for Environmental Adaptation
Authors: R. M. Ames, S. C. Lovell
Journal: Molecular Biology and Evolution (2011)

Evolution of new cellular functions can be achieved both by changes in protein coding sequences and by alteration of expression patterns. Variation of expression may lead to changes in cellular function with relatively little change in genomic sequence. We therefore hypothesize that one of the first signals of functional divergence should be evolution of transcription factor–binding sites (TFBSs). This adaptation should be detectable as substantial variation in the TFBSs of alleles. New data sets allow the first analyses of intraspecies variation from large number of whole-genome sequences. Using data from the Saccharomyces Genome Resequencing Project, we have analyzed variation in TFBSs. We find a large degree of variation both between these closely related strains and between pairs of duplicated genes. There is a correlation between changes in promoter regions and changes in coding sequences, indicating a coupling of changes in expression and function. We show that 1) the types genes with diverged promoters vary between strains from different environments and 2) that patterns of divergence in promoters consistent with positive selection are detectable in alleles between strains and on duplicate promoters. This variation is likely to reflect adaptation to each strain's natural environment. We conclude that, even within a species, we detect signs of selection acting on promoter regions that may act to alter expression patterns. These changes may indicate functional innovation in multiple genes and across the whole genome. Change in function could represent adaptation to the environment and be a precursor to speciation.
Monoclonal antibodies with specificity for hairy cell leukemia cells.
Authors: D N Posnett, N Chiorazzi, H G Kunkel
Journal: Journal of Clinical Investigation (1982)

Hairy cell leukemia is a well described clinical entity, but the cell of origin for this leukemic cell and its function are still unknown. There are no totally specific markers for this cell, although tartrate-resistant acid phosphatase staining has been used extensively as a diagnostic test. This study describes three monoclonal murine antibodies with variable specificity for hairy cells. Antibody 1 was highly specific for hairy cells and was not found to react with normal or leukemic cells in this limited study. It did not react with the cells of all patients. It also did not react with all of the hairy cells of some of the positive cases. Antibodies 2 and 3 reacted with virtually all hairy cells but not with normal peripheral blood cells. However, reactions were obtained with certain leukemic myelomonoblasts and some activated B cells. The most obvious use for these three antibodies is for diagnostic purposes. They should also be helpful reagents to investigate the origin of the leukemic hairy cell. The possibility that antibody 1 detects a tumor-specific antigen is discussed.
Genetic control of immune response. The dose of antigen given in aqueous solution is critical in determining which mouse strain is high responder to poly(LTyr, LGlu)-poly(LPro)--poly(LLys).
Authors: S Jormalainen, E Mozes, M Sela
Journal: The Journal of Experimental Medicine (1975)

Antibody response to different doses of (T,G)-Pro--L, given in aqueous solution, was investigated in the high responder SJL and low responder DBA/1 strains by measuring hemolytic plaque-forming cells (PFC) in the spleens as well as hemagglutination titers in the sera. The gene responsible for the difference between the two strains in the response to this antigen, given in complete Freund's adjuvant, has been previously denoted Ir-3. This gene is not linked to the major histocompatibility locus. In the response to the optimal dose (1 mug) of antigen, no difference could be shown between the strains. The peak of the response and the numbers of direct and indirect PFC were similar in both strains in the primary and secondary response. After injection of higher doses (10-100 mug) of antigen, both the direct and indirect PFC responses were lower in the low responder than in the high responder strain. Moreover, the peak of the response occurred earlier in the high responder strain in the primary response to the 10 mu dose of antigen. After administration of a suboptimal dose (0.02 mug) of antigen, the low responder strain produced in the primary response 4-20 times more indirect plaques than the high responder strain. Also the number of direct plaques was higher in the low responder than in the high responder strain. The serum antibody responses to the optimal and higher doses of antigen were parallel to the PFC responses. From inhibition of PFC with free antigen, it was concluded that a similar proportion of cells was producing high and low affinity antibodies to (T,G)-Pro--L in both strains. High and low zone tolerance could be induced in the two strains with (T,G)-Pro--L, but no difference could be shown between the strains. It is suggested that the Ir-3 gene plays a role in the regulation of the balance stimulation and suppression according to the dose of antigen given.
Health Correlates of Recreational Gambling in Older Adults
Authors: Rani A Desai, Paul K Maciejewski, David J Dausey, Barbara J Caldarone, Marc N Potenza
Journal: American Journal of Psychiatry (2004)

Prior studies have found high rates of alcohol use and abuse/dependence, depression, bankruptcy, and incarceration associated with recreational gambling. Despite growing rates of recreational gambling in older adults, little is known regarding its health correlates in this age group. The objective of this study was to identify health and well-being correlates of past-year recreational gambling in adults age 65 years and older, compared to adults age 18-64 years.The Gambling Impact and Behavior Study surveyed by telephone a nationally representative sample of 2,417 adults. Multivariate analyses were used to compare past-year recreational gamblers and nongamblers in the older and younger age groups on measures of alcohol use and abuse/dependence, substance abuse/dependence, depression, mental health treatment, subjective general health, incarceration, and bankruptcy. Additional analyses compared the gambling patterns in older and younger adult past-year recreational gamblers.After the effects of sociodemographic factors were controlled, older adult past-year recreational gamblers were more likely to report past-year alcohol use and better health than were older nongamblers. Multivariate analyses investigating interactions of gambling and age found that higher rates of good to excellent subjective general health in recreational gamblers were mainly attributable to the older age group. Older adult gamblers were more likely than younger adult gamblers to begin gambling after age 18 years, to gamble more frequently, and to report a larger maximum win.Recreational gambling patterns of older adults differ from those of younger adults. In contrast to findings in younger adults, recreational gambling in older adults is not associated with negative measures of health and well-being.
Association between mid-life marital status and cognitive function in later life: population based cohort study
Authors: K. Hakansson, S. Rovio, E.-L. Helkala, A.-R. Vilska, B. Winblad, H. Soininen, A. Nissinen, A. H Mohammed, M. Kivipelto
Journal: BMJ (2009)

<b>Objectives</b> To evaluate whether mid-life marital status is related to cognitive function in later life. <b>Design</b> Prospective population based study with an average follow-up of 21 years. <b>Setting</b> Kuopio and Joensuu regions in eastern Finland. <b>Participants</b> Participants were derived from random, population based samples previously investigated in 1972, 1977, 1982, or 1987; 1449 individuals (73%), aged 65-79, underwent re-examination in 1998. <b>Main outcome measures</b> Alzheimer’s disease and mild cognitive impairment. <b>Results</b> People cohabiting with a partner in mid-life (mean age 50.4) were less likely than all other categories (single, separated, or widowed) to show cognitive impairment later in life at ages 65-79. Those widowed or divorced in mid-life and still so at follow-up had three times the risk compared with married or cohabiting people. Those widowed both at mid-life and later life had an odds ratio of 7.67 (1.6 to 40.0) for Alzheimer’s disease compared with married or cohabiting people. The highest increased risk for Alzheimer’s disease was in carriers of the apolipoprotein E e4 allele who lost their partner before mid-life and were still widowed or divorced at follow-up. The progressive entering of several adjustment variables from mid-life did not alter these associations. <b>Conclusions</b> Living in a relationship with a partner might imply cognitive and social challenges that have a protective effect against cognitive impairment later in life, consistent with the brain reserve hypothesis. The specific increased risk for widowed and divorced people compared with single people indicates that other factors are needed to explain parts of the results. A sociogenetic disease model might explain the dramatic increase in risk of Alzheimer’s disease for widowed apolipoprotein E e4 carriers.
Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop
Authors: Chen Yan, Bo Ding, Tetsuro Shishido, Chang-Hoon Woo, Seigo Itoh, Kye-Im Jeon, Weimin Liu, Haodong Xu, Carolyn McClain, Carlos A. Molina, Burns C. Blaxall, Jun-ichi Abe
Journal: Circulation Research (2007)

Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. beta-Adrenergic receptor activation and subsequent persistent phosphodiesterase 3A (PDE3A) downregulation and concomitant inducible cAMP early repressor (ICER) upregulation (PDE3A/ICER feedback loop) has been proposed to play a key role in the pathogenesis of cardiomyocyte apoptosis. In contrast, insulin-like growth factor-1 can activate cell survival pathways, providing protection against cell death and restoring muscle function. In this study, we found that insulin-like growth factor-1 activates extracellular signal-regulated kinase 5 (ERK5) and inhibits PDE3A/ICER feedback loop. Insulin-like growth factor-1 normalized isoproterenol-mediated PDE3A downregulation and ICER upregulation via ERK5/MEF2 activation, and also inhibited isoproterenol-induced myocyte apoptosis. To determine the physiological relevance of ERK5 activation in regulating PDE3A/ICER feedback loop, we investigated the PDE3A/ICER expression and cardiomyocyte apoptosis in transgenic mice with cardiac specific expression of a constitutively active form of mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) kinase 5alpha (MEK5alpha) (CA-MEK5alpha-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5alpha rescued pressure overload- or doxorubicin-mediated PDE3A downregulation and ICER upregulation and inhibited myocyte apoptosis as well as subsequent cardiac dysfunction in vivo. These data suggest that preventing the feedback loop of PDE3A/ICER by ERK5 activation could inhibit progression of myocyte apoptosis as well as cardiac dysfunction. These data suggest a new therapeutic paradigm for end stage of heart failure by inhibiting the PDE3A/ICER feedback loop via activating ERK5.
Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma
Authors: Maria Romina Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno, Amaya Viros, Malin Pedersen, Bart M.J.M. Suijkerbuijk, Delphine Menard, Robert McLeary, Louise Johnson, Laura Fish, Sarah Ejiama, Berta Sanchez-Laorden, Juliane Hohloch, Neil Carragher, Kenneth Macleod, Garry Ashton, Anna A. Marusiak, Alberto Fusi, John Brognard, Margaret Frame, Paul Lorigan, Richard Marais, Caroline Springer
Journal: Cancer Cell (2014)

BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.
Therapy-Related Myeloid Neoplasms in Patients With Acute Promyelocytic Leukemia Treated With All-<i>Trans</i>-Retinoic Acid and Anthracycline-Based Chemotherapy
Authors: Pau Montesinos, José D. González, José González, Chelo Rayón, Elena de Lisa, Maria L. Amigo, Gert J. Ossenkoppele, María J. Peñarrubia, Manuel Pérez-Encinas, Juan Bergua, Guillermo Debén, María J. Sayas, Javier de la Serna, Josep M. Ribera, Javier Bueno, Gustavo Milone, Concha Rivas, Salut Brunet, Bob Löwenberg, Miguel Sanz
Journal: Journal of Clinical Oncology (2010)

We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR).From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy.Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with > or = 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months.t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted.
Chemotherapy Use, Performance Status, and Quality of Life at the End of Life
Authors: Holly G. Prigerson, Yuhua Bao, Manish A. Shah, M. Elizabeth Paulk, Thomas W. LeBlanc, Bryan J. Schneider, Melissa M. Garrido, M. Carrington Reid, David A. Berlin, Kerin B. Adelson, Alfred I. Neugut, Paul K. Maciejewski
Journal: JAMA Oncology (2015)

Although many patients with end-stage cancer are offered chemotherapy to improve quality of life (QOL), the association between chemotherapy and QOL amid progressive metastatic disease has not been well-studied. American Society for Clinical Oncology guidelines recommend palliative chemotherapy only for solid tumor patients with good performance status.
Left Atrial and Left Ventricular Sound and Pressure in Mitral Stenosis
Authors: CHARLES F. WOOLEY, KARL P. KLASSEN, RICHARD F. LEIGHTON, RICHARD S. GOODWIN, JOSEPH M. RYAN, George F. Rieser
Journal: Circulation (1968)

Left atrial and left ventricular pressure and sound were recorded at the time of mitral commissurotomy in 18 patients with severe, isolated, noncalcific mitral stenosis and sinus rhythm. Catheter tip micromanometers were used, and in eight studies, two equisensitive micromanometers were employed to examine pressure crossover relationships. Analysis of the left atrial and left ventricular sound and pressure crossover relationships is presented; viewed in the perspective provided by cineangiographic studies and surgical observations, a unifying concept of the auscultatory events in mitral stenosis is proposed. Beginning with left ventricular pressure rise, the left ventricle drives the mitral complex through its ascent (or eversion) phase toward the left atrium, clearing the anterior leaflet from the left ventricular outflow tract. The ascent (eversion) terminates abruptly at the first heart sound (S 1 ). Following systole, left ventricular and left atrial pressure fall together after v peak, during and after pressure crossover, until the point where left atrial pressure fall ceases abruptly (opening snap notch), left atrial pressure exceeding that in the left ventricle, and the mitral opening snap occurs. During this interval, the mitral valve complex descends or inverts toward the left ventricle and terminates abruptly with the mitral opening snap. Thus, the mitral opening snap may be considered as the reciprocal of the delayed, accentuated S 1 , in noncalcific mitral stenosis in sinus rhythm.