tbuckley/cabot-search huggingface dataset:
Estrogen Receptor Genotypes Influence Hot Flash Prevalence and Composite Score Before and After Tamoxifen Therapy
Authors: Yan Jin, Daniel F. Hayes, Lang Li, Jason D. Robarge, Todd C. Skaar, Santosh Philips, Anne Nguyen, Anne Schott, Jill Hayden, Suzanne Lemler, Anna Maria Storniolo, David A. Flockhart, Vered Stearns
Journal: Journal of Clinical Oncology (2008)

Hot flashes are common and frequently lead to drug discontinuation among women prescribed tamoxifen. We determined whether genetic polymorphisms in estrogen receptors (ESRs) alpha and beta (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes.We determined ESR1 PvuII and XbaI and ESR2-02 genotypes in 297 women who were initiating tamoxifen. One-week hot flash diaries were collected to calculate a hot flash score (frequency x severity) before and 1, 4, 8, and 12 months after starting tamoxifen.Approximately 80% of 297 participants reported hot flashes before or during the first year of tamoxifen. After 4 months of tamoxifen, premenopausal women who did not receive adjuvant chemotherapy had a four-fold increase in hot flash score (from 5.9 to 23.6; P = .003) compared with a 1.17-fold increase (from 19.6 to 23; P = .34) in those who received chemotherapy. In premenopausal women, increased number of ESR1 PvuII and XbaI CG alleles was associated with higher baseline hot flash scores compared with those who had other haplotypes (P = .0026). At 4 months, postmenopausal women with ESR1 PvuII CC and ESR2-02 GG genotypes had 4.6 times increases in hot flash scores than other postmenopausal women (56 v 12; P = .0007). Women who had the ESR2-02 AA genotype were significantly less likely to experience tamoxifen-induced hot flashes than women who carried at least one ESR-02 G allele (hazard ratio, 0.26; 95% CI, 0.10 to 0.63; P = .001).Knowledge of menopausal status, prior chemotherapy, and ESR genotype may help predict which women are most likely to suffer hot flashes during tamoxifen treatment.
Effects of β-Lipotropin and β-Lipotropin-derived Peptides on Aldosterone Production in the Rat Adrenal Gland
Authors: Hiroaki Matsuoka, Patrick J. Mulrow, Roberto Franco-Saenz, Choh Hao Li
Journal: Journal of Clinical Investigation (1981)

To investigate the role of non-ACTH pituitary peptides on steroidogenesis, we studied the effects of synthetic β-lipotropin, β-melanotropin, and β-endorphin on aldosterone and corticosterone stimulation using rat adrenal collagenase-dispersed capsular and decapsular cells. β-lipotropin induced a significant aldosterone stimulation in a dose-dependent fashion (10 nM-1 μM). β-endorphin, which is the carboxyterminal fragment of β-lipotropin, did not stimulate aldosterone production at the doses used (3 nM-6 μM). β-melanotropin, which is the middle fragment of β-lipotropin, showed comparable effects on aldosterone stimulation. β-lipotropin and β-melanotropin did not affect corticosterone production in decapsular cells. Although ACTH1-24 caused a significant increase in cyclic AMP production in capsular cells in a dose-dependent fashion (1 nM-1 μM), β-lipotropin and β-melanotropin did not induce an increase in cyclic AMP production at the doses used (1 nM-1 μM). The β-melanotropin analogue (glycine[Gly]10-β-melanotropin) inhibited aldosterone production induced by β-lipotropin or β-melanotropin, but did not inhibit aldosterone production induced by ACTH1-24 or angiotensin II. Corticotropin-inhibiting peptide (ACTH7-38) inhibited not only ACTH1-24 action but also β-lipotropin or β-melanotropin action; however it did not affect angiotensin II-induced aldosterone production. (saralasin [Sar]1; alanine [Ala]8)-Angiotensin II inhibited the actions of β-lipotropin and β-melanotropin as well as angiotensin II. These results indicate that (a) β-lipotropin and β-melanotropin cause a significant stimulation of aldosterone production in capsular cells, (b) β-lipotropin and β-melanotropin have a preferential effect on zona glomerulosa cells, (c) β-melanotropin contains the active peptide core necessary for aldosterone stimulation, (d) the effects of these peptides on aldosterone production may be independent of cyclic AMP, and (e) the receptors for β-lipotropin or β-melanotropin may be different from those for ACTH or angiotensin II.
Spinal Delivery of AAV Vector Restores Enzyme Activity and Increases Ventilation in Pompe Mice
Authors: Kai Qiu, Darin J Falk, Paul J Reier, Barry J Byrne, David D Fuller
Journal: Molecular Therapy (2011)

Pompe disease is a form of muscular dystrophy due to lysosomal storage of glycogen caused by deficiency of acid α-glucosidase (GAA). Respiratory failure in Pompe disease has been attributed to respiratory muscle dysfunction. However, evaluation of spinal tissue from Pompe patients and animal models indicates glycogen accumulation and lower motoneuron pathology. We hypothesized that restoring GAA enzyme activity in the region of the phrenic motor nucleus could lead to improved breathing in a murine Pompe model (the Gaa−/− mouse). Adeno-associated virus serotype 5 (AAV5), encoding either GAA or green fluorescent protein (GFP), was delivered at the C3–C4 spinal level of adult Gaa−/− mice and the spinal cords were harvested 4 weeks later. AAV5-GAA injection restored spinal GAA enzyme activity and GAA immunostaining was evident throughout the cervical ventral horn. The periodic acid Schiff (PAS) method was used to examine neuronal glycogen accumulation, and spinal PAS staining was attenuated after AAV5-GAA injection. Lastly, plethysmography revealed that minute ventilation was greater in unanesthetized AAV5-GAA versus AAV5-GFP treated Gaa−/− mice at 1–4 months postinjection. These results support the hypothesis that spinal cord pathology substantially contributes to ventilatory dysfunction in Gaa−/− mice and therefore requires further detailed evaluation in patients with Pompe disease. Pompe disease is a form of muscular dystrophy due to lysosomal storage of glycogen caused by deficiency of acid α-glucosidase (GAA). Respiratory failure in Pompe disease has been attributed to respiratory muscle dysfunction. However, evaluation of spinal tissue from Pompe patients and animal models indicates glycogen accumulation and lower motoneuron pathology. We hypothesized that restoring GAA enzyme activity in the region of the phrenic motor nucleus could lead to improved breathing in a murine Pompe model (the Gaa−/− mouse). Adeno-associated virus serotype 5 (AAV5), encoding either GAA or green fluorescent protein (GFP), was delivered at the C3–C4 spinal level of adult Gaa−/− mice and the spinal cords were harvested 4 weeks later. AAV5-GAA injection restored spinal GAA enzyme activity and GAA immunostaining was evident throughout the cervical ventral horn. The periodic acid Schiff (PAS) method was used to examine neuronal glycogen accumulation, and spinal PAS staining was attenuated after AAV5-GAA injection. Lastly, plethysmography revealed that minute ventilation was greater in unanesthetized AAV5-GAA versus AAV5-GFP treated Gaa−/− mice at 1–4 months postinjection. These results support the hypothesis that spinal cord pathology substantially contributes to ventilatory dysfunction in Gaa−/− mice and therefore requires further detailed evaluation in patients with Pompe disease.
The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study
Authors: Hyon K Choi, Young-Hee Rho, Yanyan Zhu, Lucia Cea-Soriano, Juan Antonio Aviña-Zubieta, Yuqing Zhang
Journal: Annals of the Rheumatic Diseases (2012)

Background Recent hospital-based studies have suggested a sixfold increased risk of pulmonary embolism (PE) in rheumatoid arthritis (RA) in the year following admission. We evaluated the risk of PE and deep vein thrombosis (DVT) and associated time trend among RA patients (84.5% without a history of hospitalisation during the past year) derived from the general population. Methods We conducted a cohort study using an electronic medical records database representative of the UK general population, collected from 1986 to 2010. Primary definitions of the RA cohort (exposure) and PE/DVT outcomes required physician diagnoses followed by corresponding treatments. We estimated relative risks (RRs) of PE and DVT compared with a matched non-RA comparison cohort, adjusting for age, sex, smoking, body mass index, comorbidities and hospitalisations. Results Among 9589 individuals with RA (69% female, mean age of 58 years), 82 developed PE and 110 developed DVT (incidence rates, 1.5 and 2.1 per 1000 person-years). Compared with non-RA individuals (N=95 776), the age-, sex- and entry-time-matched RRs were 2.23 (95% CI 1.75 to 2.86) for PE and 2.20 (CI 1.78 to 2.71) for DVT. Adjusting for other covariates, the corresponding RRs were 2.16 (CI 1.68 to 2.79) and 2.16 (CI 1.74 to 2.69). The time-specific RRs for PE were 3.27, 1.88 and 2.35 for follow-up times of &lt;1 year, 1–4.9 years, and ≥5 years, and corresponding RRs for DVT were 3.16, 1.82 and 2.32. Conclusions This population-based study indicates an increased risk of PE and DVT in RA, supporting increased monitoring of venous-thromboembolic complications and risk factors in RA, regardless of hospitalisation.
Team Work Matters: Dual Inhibition Puts Non-Hodgkin Lymphoma Under Siege
Authors: Giada Bianchi, Irene M. Ghobrial
Journal: Clinical Cancer Research (2014)

Inhibitors of PI3K/mTOR and histone deacetylases (HDAC) are effective in non-Hodgkin lymphoma (NHL). However, clinical resistance eventually ensues and combinatory therapies are sought to prevent it. Preclinical evaluation of dual PI3K/mTOR and HDAC inhibition is synergistic against NHL, paving the way for bench-to-bedside translation.
How Evolution of Genomes Is Reflected in Exact DNA Sequence Match Statistics
Authors: Florian Massip, Michael Sheinman, Sophie Schbath, Peter F. Arndt
Journal: Molecular Biology and Evolution (2014)

Genome evolution is shaped by a multitude of mutational processes, including point mutations, insertions, and deletions of DNA sequences, as well as segmental duplications. These mutational processes can leave distinctive qualitative marks in the statistical features of genomic DNA sequences. One such feature is the match length distribution (MLD) of exactly matching sequence segments within an individual genome or between the genomes of related species. These have been observed to exhibit characteristic power law decays in many species. Here, we show that simple dynamical models consisting solely of duplication and mutation processes can already explain the characteristic features of MLDs observed in genomic sequences. Surprisingly, we find that these features are largely insensitive to details of the underlying mutational processes and do not necessarily rely on the action of natural selection. Our results demonstrate how analyzing statistical features of DNA sequences can help us reveal and quantify the different mutational processes that underlie genome evolution.
Is Socioeconomic Position Related to the Prevalence of Metabolic Syndrome?
Authors: Sheena E. Ramsay, Peter H. Whincup, Richard Morris, Lucy Lennon, S.G. Wannamethee
Journal: Diabetes Care (2008)

OBJECTIVE—To examine whether adult social class and childhood social class are related to metabolic syndrome in later life, independent of adult behavioral factors. RESEARCH DESIGN AND METHODS—This was a population-based cross-sectional study comprising 2,968 men aged 60–79 years. RESULTS—Adult social class and childhood social class were both inversely related to metabolic syndrome. Mutual adjustment attenuated the relation of metabolic syndrome with childhood social class; that with adult social class was little affected. However, the relation with adult social class was markedly attenuated by adjustment for smoking status, physical activity, and alcohol consumption. High waist circumference was independently associated with adult social class. CONCLUSIONS—The association between adult social class and metabolic syndrome was largely explained by behavioral factors. In addition, central adiposity, a component of metabolic syndrome, was associated with adult social class. Focusing on healthier behaviors and obesity, rather than specific efforts to reduce social inequalities surrounding metabolic syndrome, is likely to be particularly important in reducing social inequalities that affect people with coronary disease.
Researchers Explore Mechanisms That May Link Obesity and Cancer
Authors: S. Jenks
Journal: JNCI Journal of the National Cancer Institute (2010)

As obesity’s ties to multiple cancers strengthen, a new study suggests that inflammation may be the primary culprit in at least one malignancy: liver cancer. The Cell study, published January 22, found that high levels of interleukin 6 and tumor necrosis factor, which are associated with obesity, turned healthy cells into malignant ones through chronic low-grade inflammation of the liver. Using knockout mice to unravel the mechanism, Michael Karin, Ph.D., and his team at the University of California, San Diego, concluded that enhanced production of these signaling molecules during obesity leads to persistent infl ammation, which activates STAT3, a tumor-promoting transcription factor. That, in turn, causes proliferation of aberrant hepatic cells and leads to hepatocellular carcinoma. Similar mechanisms may underlie, and perhaps markedly increase, the risk for pancreatic, gastrointestinal, and kidney cancers as well, according to Karin. Epidemiological studies show associations with obesity and at least fi ve different cancers: colon, postmenopausal breast, endometrial, kidney, and esophageal. Excessive weight plays a suspected role in other cancers and recently has been implicated as a risk factor for poor survival in several of them, including prostate, breast, and colon.
PM<sub>10</sub>, and children's respiratory symptoms and lung function in the PATY study
Authors: Gerard Hoek, Sam Pattenden, Saskia Willers, Temenuga Antova, Eleonora Fabianova, Charlotte Braun-Fahrländer, Francesco Forastiere, Ulrike Gehring, Heike Luttmann-Gibson, Leticia Grize, Joachim Heinrich, Danny Houthuijs, Nicole Janssen, Boris Katsnelson, Anna Kosheleva, Hanns Moshammer, Manfred Neuberger, Larisa Privalova, Peter Rudnai, Frank Speizer, Hana Slachtova, Hana Tomaskova, Renata Zlotkowska, Tony Fletcher
Journal: European Respiratory Journal (2012)

Studies of the impact of long-term exposure to outdoor air pollution on the prevalence of respiratory symptoms and lung function in children have yielded mixed results, partly related to differences in study design, exposure assessment, confounder selection and data analysis. We assembled respiratory health and exposure data for &gt;45,000 children from comparable cross-sectional studies in 12 countries. 11 respiratory symptoms were selected, for which comparable questions were asked. Spirometry was performed in about half of the children. Exposure to air pollution was mainly characterised by annual average concentrations of particulate matter with a 50% cut-off aerodynamic diameter of 10 μm (PM 10 ) measured at fixed sites within the study areas. Positive associations were found between the average PM 10 concentration and the prevalence of phlegm (OR per 10 μg·m −3 1.15, 95% CI 1.02–1.30), hay fever (OR 1.20, 95% CI 0.99–1.46), bronchitis (OR 1.08, 95% CI 0.98–1.19), morning cough (OR 1.15, 95% CI 1.02–1.29) and nocturnal cough (OR 1.13, 95% CI 0.98–1.29). There were no associations with diagnosed asthma or asthma symptoms. PM 10 was not associated with lung function across all studies combined. Our study adds to the evidence that long-term exposure to outdoor air pollution, characterised by the concentration of PM 10 , is associated with increased respiratory symptoms.
Targeted Disruption of the Chemokine Eotaxin Partially Reduces Antigen-induced Tissue Eosinophilia
Authors: Marc E. Rothenberg, James A. MacLean, Eric Pearlman, Andrew D. Luster, Philip Leder
Journal: The Journal of Experimental Medicine (1997)

The chemokines are a large group of chemotactic cytokines that regulate leukocyte trafficking and have recently been shown to inhibit human immunodeficiency virus entry into cells. Eotaxin is a C–C chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders and, unlike all other eosinophil chemoattractants, is eosinophil specific. However, given the large number of chemoattractants that have activities on eosinophils, it is unclear whether eotaxin has an important role in vivo. Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation. To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin. Such mice demonstrate that eotaxin enhances the magnitude of the early (but not late) eosinophil recruitment after antigen challenge in models of asthma and stromal keratitis. Surprisingly, a role for eotaxin in regulating the constitutive number of eosinophils in the peripheral circulation is also demonstrated. These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.
Application of management guidelines to the assessment of new medicines: driving us forward or holding us back?
Authors: P.M.A. Calverley, S.I. Rennard
Journal: European Respiratory Journal (2004)

Clinical management guidelines have made an invaluable contribution in many areas of medicine. By providing recommendations based on an expert assessment of the available evidence, guidelines can identify “best practice” approaches, help drive consistent quality of care, reduce morbidity and mortality, and improve cost-effectiveness. The considerable time, effort and organisation needed to prepare authoritative sets of guidelines provides an imperative to gain the maximum utility from their development. However, it is also important that guidelines are used appropriately. The use of guidelines to address issues other than those for which they were designed can potentially have a detrimental effect on patient care.

In chronic obstructive pulmonary disease (COPD), for instance, guidelines from bodies such as the Global Initiative for Chronic Lung Disease (GOLD) 1, the European Respiratory Society (ERS) 2 and the American Thoracic Society (ATS) 3 have helped to establish standards of care, and help drive improved management of COPD. However, the guidelines have also been used increasingly by regulatory authorities to define the requirements for new agents to gain approval, a role that they were never designed to fill.

The GOLD guidelines provide a working definition of COPD as a disease state characterised by airflow limitation, which is not fully reversible, and is usually both progressive and associated with an abnormal inflammatory response to noxious particles 1. They also, however, recognise both the heterogeneity of COPD and the difficulties of providing …
High incidence of a male-specific genetic marker in phenotypic female chinook salmon from the Columbia River.
Authors: J J Nagler, J Bouma, G H Thorgaard, D D Dauble
Journal: Environmental Health Perspectives (2001)

Numerous populations of anadromous salmonids in the northwestern United States have been declining for many years, resulting in Endangered Species Act listings and in some cases extinction. The degradation of river ecosystems has been proposed as one of the major reasons for the inability of salmon to maintain their populations. However, the specific factors interfering with the reproduction and survival of salmon during the freshwater phase of their life cycle have not been fully described. This study was initiated to determine the incidence of phenotypic sex reversal in wild, fall chinook salmon (Oncorhynchus tshawytcha) that returned to spawn in the Columbia River. Fish were sampled at different locations within this watershed to determine whether they were faithfully expressing their genotype. We report a high incidence (84%) of a genetic marker for the Y chromosome in phenotypic females sampled from the wild, which was not observed in female fish raised in hatcheries. It appears likely that female salmon with a male genotype have been sex reversed, creating the potential for an abnormal YY genotype in the wild that would produce all-male offspring and alter sex ratios significantly.
Effect of outflow pressure upon lymph flow from dog lungs.
Authors: R E Drake, D K Adcock, R L Scott, J C Gabel
Journal: Circulation Research (1982)

The pulmonary lymph flow rate (QL) should be a function of the lymph vessels' resistance and the pressure gradient along the vessels. We attempted to study how these factors affect lymph flow. We assumed that the lymph system could be represented by a single pressure generated within the lung (PL) and a single resistance (RL). Thus, QL should be a function of the lymph vessel outflow pressure (Po): QL = (PL - Po)/RL. We cannulated tracheobronchial lymph vessels in eight anesthetized dogs and varied Po by raising the outflow end of the cannula. QL decreased linearly when we increased Po. We estimated RL as - delta Po/ delta QL and PL as the extrapolated Po at which QL = 0. At baseline PL = 7.7 +/- 2.7 (SD) cm H2O and RL = 0.36 +/- 0.25 cm H2O. min/microliters. After we increased capillary pressure to produce edema, PL and RL averaged 22.8 +/- 8.8 and 0.14 +/- 0.12, respectively. After we reduced the capillary pressure to baseline in the edematous lungs, PL and RL averaged 11.6 +/- 2.8 and 0.08 +/- 0.09, respectively. All changes in PL and RL were significant (P less than 0.05). These results show that (1) lymph flow rate depends upon lymph vessel outflow pressure, and (2) the QL vs. Po relationship is changed by edema. PL may be equal to the pressure causing lymph to flow and RL may equal the lymph vessel resistance.
A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2
Authors: Jian Hua Qi, Quteba Ebrahem, Nina Moore, Gillian Murphy, Lena Claesson-Welsh, Mark Bond, Andrew Baker, Bela Anand-Apte
Journal: Nature Medicine (2003)
Propagation of stress fracture of the patella
Authors: M A A Crowther, A Mandal, P P Sarangi
Journal: British Journal of Sports Medicine (2005)

Anterior knee pain in athletes is common and usually self limited. There should be a high index of suspicion and low threshold for special imaging in cases with acute onset and specific tenderness. The risk of propagation of stress fracture of the patella in athletes is highlighted. The case report presented illustrates the potential sequence of events.
Chemokines are important cytokines in the pathogenesis of interstitial lung disease
Authors: MP Keane, TJ Standiford, RM Strieter
Journal: European Respiratory Journal (1997)

Interstitial lung disease (ILD) is characterized by al-veolar and interstitial inflammation, followed by theprogressive derangement of alveolar architecture anddeposition of extracellular matrix components. The dis-ease is initiated by an unknown alveolar insult, whichis followed by the influx of inflammatory cells to thelung. This recruitment phase results in a several foldincrease in all cell types within the airspace, includingneutrophils, eosinophils, lymphocytes and macropha-ges. In addition, substantial interstitial inflammation isapparent, consisting predominantly of newly recruitedmonocytes and lymphocytes. Alveolar and interstitialinflammation is followed by the loss of type I epithe-lial cells and endothelial cells, proliferation of type IIcells, and expansion of the pulmonary interstitium