tbuckley/cabot-search huggingface dataset:
Abstract 727: Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a diaryl template
Authors: L. W. Lawrence Woo, Toby Jackson, Aurelien Putey, Gyles Cozier, Philip Leonard, K. Ravi Acharya, Surinder K. Chander, Atul Purohit, Michael J. Reed (Deceased), Barry V. l. Potter
Journal: Cancer Research (2010)

Abstract Designing single agents that act against multiple biological targets are of increasing interest and prominence. In recent years, an increasing volume of work has been published exemplifying the successful use of this strategy. Estrogen deprivation has been an effective therapeutic intervention for hormone-dependent breast cancer (HDBC). One established and clinically proven approach involves the inhibition of the aromatase enzyme, although the inhibition of steroid sulfatase (STS) is an emerging new strategy as demonstrated by the promising results of STX64 (BN83495),1 the first STS inhibitor that entered clinical trials. While both aromatase and STS are targets for treating HDBC, it is reasoned that estrogen deprivation may be more comprehensively achieved by dual inhibition of both enzymes. To this end, the reversible aromatase inhibitory pharmacophore, which is principally a heme-ligating nitrogen-containing heterocycle, was thus introduced into a known sulfamate-based STS inhibitor to give a series of dual aromatase-sulfatase inhibitors (DASIs). Several compounds were found to be good aromatase or STS inhibitors individually. However, two compounds show exceptional dual in vitro potency in JEG-3 cells, inhibiting aromatase with IC50 values of 0.5 and 2.0 nM, and STS with IC50 values of 5.5 and 35 nM. Both compounds share the common structural feature of having a sulfamate group on one aryl ring, and a heterocycle and a H-bond acceptor on the other. At 1 mg/kg p.o., both DASIs reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. One of the compounds was found to be non-estrogenic and potently inhibit human carbonic anhydrase II (hCAII IC50 = 86 nM). A complex of hCAII with the inhibitor was crystallized and solved by X-ray crystallography. This class of DASI should encourage further development towards multi-targeted therapeutic intervention in HDBC. Ref 1: a) Stanway, S. J. et al. Clin. Cancer Res. 2006, 12, 1585-1592. b) Stanway, S. J. et al. Oncologist 2007, 12, 370-374. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 727.
Changes in skin-test reactivity do not correlate with clinical efficacy of H<sub>1</sub>-blockers in seasonal allergic rhinitis
Authors: J. Bousquet, W. Czarlewski, J. Cougnard, M. Danzig, F.‐B. Micher
Journal: Allergy (1998)

New‐generation H‐blockers may possess antiallergic properties, and their effect may differ, depending on the target organ. A double‐blind, placebo‐controlled, parallel‐group study was carried out during the pollen season to compare the clinical effect on nasal and conjunctival symptoms of astemizole (10 mg o.d.) and loratadine (10 mg o.d.) with their effect on skin‐test reactivity to allergen and histamine. Thirty‐eight patients (12–56 years of age) were studied. Nasal and ocular symptoms were recorded daily from days 4 to 7. Skin prick tests with serial concentrations of allergens and one concentration of histamine were carried out before and at the end of the 7‐day treatment period. Parallel‐line bioassay, analysis of variance, and covariance were used to analyze skin test data. Loratadine and astemizole significantly decreased symptoms from baseline (P&lt;0.004 and P&lt;0.006), Skin‐test reactivity to allergen and histamine was more profoundly decreased by astemizole than loratadine. The histamine covariant was more important in the allergen effect of astemizole than in that of loratadine. Two Hblockers having the same clinical effect on nasal and ocular symptoms during the pollen season have totally different effects on skin‐test reactivity. Skin‐test reactivity to allergen or histamine is not predictive of the clinical efficacy of H 1 ‐blockers during seasonal allergic rhinitis.
Nutritional Factors and Blood Pressure Control: An Assessment
Authors: C. WAYNE CALLAWAY
Journal: Annals of Internal Medicine (1983)

High blood pressure is a concern because of its associated risks. Hypertension, therefore, is best defined as the level of blood pressure at or above which treatment can be expected to do more good than harm. Blood pressure is subject to multiple systems of feedback control; essential hypertension can result from multiple causes. The heterogeneity of essential hypertension may explain some of the apparent contradictions in existing data, including the disparity between the consistency of the association of sodium intake with blood pressure among various population groups versus the lack of this correlation among persons within a given population. A more sophisticated approach toward statistical modeling is needed. Nutrients, foods, and diet are separate, although interrelated, concepts. Failure to distinguish among these terms has contributed to our current confusion. Consequences of this distinction include difficulty in altering intakes of single nutrients without altering those of other nutrients within the overall diet. Public health efforts should be directed toward changes in nutrient intake rather than toward simplistic and misleading classifications of foods as being "good" or "bad." Scientific and public policy activities can be divided into four categories—original research, expert analysis, formulation of public health policy, and implementation of overall public policy—each with its own appropriate rules and limitations. In regard to dietary factors and blood pressure control, the data on sodium, potassium, alcohol, and body weight are abundant (although not sufficient); data regarding calcium, magnesium, and dietary fats must still be considered preliminary; and data on dietary carbohydrates, fiber, and trace elements are insufficient to warrant further analysis. A panel of experts, chosen to represent the legitimate range of scientific opinion, should assess the strength and consistency of the evidence relating dietary factors to blood pressure control (where data exist) according to one of several schemes for classifying types of studies. Meanwhile, further research, dissemination of credible information, and, in a few circumstances, active programs of education and behavioral intervention would seem warranted with regard to dietary sodium and potassium, alcohol intake, and obesity. Other than voluntary labeling, there currently seems to be little need for more formal regulatory measures. Instead, the attention of the scientific community should be directed toward providing better data and more useful expert analysis, so that public health policy and overall public policy can be founded on as rational a data base as possible.
Population Movement and Sudden Cardiac Arrest Location
Authors: Eloi Marijon, Wulfran Bougouin, Muriel Tafflet, Nicole Karam, Daniel Jost, Lionel Lamhaut, Frankie Beganton, Patricia Pelloux, Hervé Degrange, Guillaume Béal, Jean-Pierre Tourtier, Albert A. Hagège, Jean-Yves Le Heuzey, Michel Desnos, Florence Dumas, Christian Spaulding, David S. Celermajer, Alain Cariou, Xavier Jouven
Journal: Circulation (2015)

Although the benefits of automatic external defibrillators are undeniable, their effectiveness could be dramatically improved. One of the key issues is the disparity between the locations of automatic external defibrillators and sudden cardiac arrests (SCAs).From emergency medical services and other Parisian agencies, data on all SCAs occurring in public places in Paris, France, were prospectively collected between 2000 and 2010 and recorded using 2020 grid areas. For each area, population density, population movements, and landmarks were analyzed. Of the 4176 SCAs, 1255 (30%) occurred in public areas, with a highly clustered distribution of SCAs, especially in areas containing major train stations (12% of SCAs in 0.75% of the Paris area). The association with population density was poor, with a nonsignificant increase in SCAs with population density (P=0.4). Occurrence of public SCAs was, in contrast, highly associated with population movements (P<0.001). In multivariate analysis including other landmarks in each grid cell in the model and demographic characteristics, population movement remained significantly associated with the occurrence of SCA (odds ratio, 1.48; 95% confidence interval, 1.34-1.63; P<0.0001), as well as grid cells containing train stations (odds ratio, 3.80; 95% confidence interval, 2.66-5.36; P<0.0001).Using a systematic analysis of determinants of SCA in public places, we demonstrated the extent to which population movements influence SCA distribution. Our findings also suggested that beyond this key risk factor, some areas are dramatically associated with a higher risk of SCA.
The Not-So-Sick Sinus
Authors: Samuel Vaisrub
Journal: JAMA (1980)

"Sick sinus syndrome" is an anthropomorphic term. Sickness relates to a person, not an organ or tissue. A component part of the human body can become inflamed, degenerated, hypertrophic, or atrophic, but never sick. Still, despite its inappropriateness, the term has survived 13 years of use since Irene Ferrer<sup>1</sup>introduced it in 1967. Perhaps it is just as well. The disease complex itself is too loosely defined to permit a more accurate label. "Sick sinus" may be anatomically inaccurate as well. Kaplan and associates<sup>2</sup>demonstrated lesions in the extranodal atrial tissue and junctional tissue, as well as the sinus in patients with typical clinical manifestations of the syndrome. Moreover, clinical findings are not always characteristic. The classic tachyarrhythmia-bradyarrhythmia sequence may not be present. Severe bradycardia without any other sinus dysfunction has been also subsumed under this syndrome.<sup>3</sup> Drug therapy of the sick sinus may be perplexingly difficult.
Mutations in the Focal Adhesion Targeting Region of Deleted in Liver Cancer-1 Attenuate Their Expression and Function
Authors: Yi-Chun Liao, Yi-Ping Shih, Su Hao Lo
Journal: Cancer Research (2008)

Abstract Deleted in liver cancer-1 (DLC-1) is a RhoGTPase-activating protein (RhoGAP) domain containing tumor suppressor that is often down-regulated in various cancer types. Previously, we have shown that DLC-1 is recruited to focal adhesions by binding to the Src homology 2 domains of tensins and the focal adhesion localization is critical for the tumor suppression activity of DLC-1. To investigate whether mutations in the focal adhesion targeting (FAT) region might occur and attenuate the expression, localization, and function of DLC-1, we have first mapped the FAT region to the amino acid residues from 201 to 500, and then sequenced cDNAs and genomic DNAs encoding the FAT region from cancer patients. Several missense and nonsense mutations were detected. All missense mutations were further examined for the potential effect on the function of DLC-1. Although these mutations did not seem to affect the focal adhesion localization of DLC-1, the activities of suppressing tumor cell growth were impaired in two mutants: T301K and S308I. Consistent with the fact that the RhoGAP activity of DLC-1 is essential for inhibiting tumor cell growth, the RhoGAP activities were significantly reduced in these mutants, suggesting that the FAT region also contains a regulatory element for its COOH-terminal RhoGAP domain. Our studies have shown that mutations in DLC-1 may lead to loss of function and contribute to the tumorigenesis, and have revealed an allosteric regulation site for its RhoGAP activity. [Cancer Res 2008;68(19):7718–22]
Baff Mediates Survival of Peripheral Immature B Lymphocytes
Authors: Marcel Batten, Joanna Groom, Teresa G. Cachero, Fang Qian, Pascal Schneider, Jurg Tschopp, Jeffrey L. Browning, Fabienne Mackay
Journal: The Journal of Experimental Medicine (2000)

B cell maturation is a very selective process that requires finely tuned differentiation and survival signals. B cell activation factor from the TNF family (BAFF) is a TNF family member that binds to B cells and potentiates B cell receptor (BCR)-mediated proliferation. A role for BAFF in B cell survival was suggested by the observation of reduced peripheral B cell numbers in mice treated with reagents blocking BAFF, and high Bcl-2 levels detected in B cells from BAFF transgenic (Tg) mice. We tested in vitro the survival effect of BAFF on lymphocytes derived from primary and secondary lymphoid organs. BAFF induced survival of a subset of splenic immature B cells, referred to as transitional type 2 (T2) B cells. BAFF treatment allowed T2 B cells to survive and differentiate into mature B cells in response to signals through the BCR. The T2 and the marginal zone (MZ) B cell compartments were particularly enlarged in BAFF Tg mice. Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance. These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment. This work provides new clues on mechanisms regulating B cell maturation and tolerance.
Notice of Duplicate Publication
Authors: Gregory D. Curfman, Stephen Morrissey, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2003)

Publication of the same research data in two or more journals (duplicate, or redundant, publication) is a practice that does not serve the interest of the medical community. Virtually all medical journals have policies against duplicate publication, and according to the recommendations of the International Committee of Medical Journal Editors,1 significant infractions should be reported to readers. We do so now with respect to an article by Park et al. published in the April 17, 2003, issue of the Journal.2 The study by Park et al.2 compared paclitaxel-coated coronary stents with uncoated stents for the prevention of restenosis in . . .
Physician's Case Volume of Intensive Care Unit Pneumonia Admissions and In-Hospital Mortality
Authors: Herng-Ching Lin, Sudha Xirasagar, Chi-Hung Chen, Yi-Ting Hwang
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Although several studies have investigated volume-outcome relationships for surgical procedures, there has been no such study of intensive care unit (ICU) patients admitted for pneumonia.This study examines associations between in-hospital mortality of ICU-admitted pneumonia patients and their attending physician's case volume.We used 2002-2004 claims data from Taiwan's National Health Insurance for all 87,479 adult ICU admissions for pneumonia. Patients were assigned to one of four groups, on the basis of their physician's ICU pneumonia case volume (low volume, <36 cases; medium volume, 37-114 cases; high volume, 118-314 cases; and very high volume, > or =315 cases). Generalized estimating equations (conditional on hospital, and unconditional) were used, adjusting for physician demographics and specialty, hospital characteristics, patient characteristics (including clinical severity and comorbidities), and physician-level random effect (clustering effect) to assess whether physicians' case volume predicts in-hospital mortality.In-hospital mortality systematically declined with increasing physician case volume: 14.7, 14.3, 11.4, and 8.1% from low-volume to very-high-volume groups. Adjusted unconditional odds of mortality among low-volume physicians' patients were 2.04 times those of very-high-volume physicians, 1.35 times that of high-volume physicians, and 1.09 times those of medium-volume physicians (all P < 0.001). The relationship is sustained when the odds are estimated conditional on hospital, when initial 5-day mortality is separated from 30-day mortality, and when pulmonologists' and critical care specialists' patients are studied separately.Physician volume significantly predicts inpatient mortality among ICU patients with pneumonia. Detailed study of clinical approaches, decision algorithms, and treatment plans of high-volume physicians is recommended to identify possible mediating factors in this phenomenon.
PGC-1&amp;alpha; AND IGFBP-5 EXPRESSION IN SKELETAL MUSCLE OF HF PATIENTS
Authors: Karla M. Daniels, Stewart Lecker, Alexandra Zavin, Kelly Allsup, Jacob Joseph, Ross Arena, P. Christian Schulze, Antonio Lazzari, Peirang Cao, Mahalakshmi Santhanam, Daniel Forman
Journal: Journal of the American College of Cardiology (2012)
Association of CYP1B1 Germ Line Mutations with Hepatocyte Nuclear Factor 1α–Mutated Hepatocellular Adenoma
Authors: Emmanuelle Jeannot, Karine Poussin, Laurence Chiche, Yannick Bacq, Nathalie Sturm, Jean-Yves Scoazec, Catherine Buffet, Jeanne Tran Van Nhieu, Christine Bellanné-Chantelot, Claudia de Toma, Pierre Laurent-Puig, Paulette Bioulac-Sage, Jessica Zucman-Rossi
Journal: Cancer Research (2007)

Abstract Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1α (HNF1α) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1α germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1α-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1α-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1α-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1α mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line–inactivating mutations might increase the incidence of HCA in women with HNF1α mutations. [Cancer Res 2007;67(6):2611–6]
Protein kinase C activity in normal and psoriatic cells: cultures of fibroblasts and lymphocytes
Authors: F. RAYNAUD, D. EVAIN-BRION
Journal: British Journal of Dermatology (1991)

Protein kinase C (PKC) activity was measured in cultures of fibroblasts from biopsies of the involved and uninvolved skin of seven patients with psoriasis and from the skin biopsies of nine normal controls. PKC activity was significantly increased (P (0.005) in the particulate fraction of fibroblasts obtained from the involved areas of skin (450 ± SKM 89 pmol/mg protein/3 min) and the uninvolved skin (394 ± 94 pmol/mg protein/3 min) in psoriasis as compared to that of controls (103 ± 24 pmol/mg protein/3 min). The soluble fraction of PKC activity was comparable in controls and in the fibroblasts obtained from involved areas and not significantly different from the values in fibroblasts from uninvolved skin. PKC activity was also measured in the soluble and particulate fractions of lymphocytes from 13 patients with psoriasis and from 14 normal controls. The PKC activity did not differ in the lymphocytes of patients with psoriasis from the controls in either the cytosolic or the membrane fractions. The increase in PKC activity as expressed at the membrane level of psoriatic fibroblasts may be related to an increase in sensitivity of these cells to hormones or growth factors involved in the regulation of their growth.
An Identical miRNA of the Human JC and BK Polyoma Viruses Targets the Stress-Induced Ligand ULBP3 to Escape Immune Elimination
Authors: Yoav Bauman, Daphna Nachmani, Alon Vitenshtein, Pinchas Tsukerman, Nir Drayman, Noam Stern-Ginossar, Dikla Lankry, Raizy Gruda, Ofer Mandelboim
Journal: Cell Host & Microbe (2011)
ACUTE TOXOPLASMOSIS
Authors: J. K. Frenkel
Journal: JAMA (1960)

Acute febrile toxoplasmosis acquired accidentally by needle scratch in the laboratory led to a local ulcer on the finger with bilateral axillary and cervical lymphadenopathy and a fine erythematous rash but no pneumonia. Toxoplasma was isolated from the blood stream 9 and 10 days after infection, and antibodies developed. Chemotherapy consisting of 25 mg. of pyrimethamine and 4 Gm. sulfadiazine was instituted on the 9th day and continued for 39 days. By the 11th day the patient was afebrile and toxoplasma was no longer isolated. Moderate leukopenia and thrombocytopenia were antagonized by 5 to 15 mg. of leucovorin calcium and two yeast cakes daily. Thus, the drug-induced hematological deficiency was reversed by substitution of the inhibited vitamin without need of discontinuing the primary objectve, antitoxoplasmic chemotherapy.
The problem of consciousness in habitual decision making
Authors: Javier Bernacer, Gloria Balderas, Ivan Martinez-Valbuena, Maria A. Pastor, Jose Ignacio Murillo
Journal: Behavioral and Brain Sciences (2014)

Abstract Newell &amp; Shanks (N&amp;S) carry out an extremely sharp and static distinction between conscious and unconscious decisions, ignoring a process that dynamically transfers decisions and actions between the conscious and unconscious domains of the mind: habitual decision making. We propose a new categorisation and discuss the main characteristics of this process from a philosophical and neuroscientific perspective.
Barbara Hamilton (née Hunter)
Authors: David Hamilton
Journal: BMJ (2006)

​ConsultantConsultant psychiatrist Sheffield (b 1944; q Belfast 1969; MRCPsych, Dip Psychother), died from bowel infarction on 2 December 2005.



Figure 1



Barbara Hamilton had remarkable musical ability but chose to study medicine. She completed her psychiatry and psychotherapy training in Aberdeen and became a medical officer for the new Scottish Mental Welfare Commission in 1983. In 1988 she became a consultant psychiatrist in Ayrshire, the first such medical officer so to do. When the family moved to England she became a consultant in Sheffield, where she was a capable, energetic, and pragmatic problem solver in an under-resourced area. She was also adept in balancing the priorities of a career and the needs of her children when recognition of such pressures on aspiring women professionals was scant. She leaves a husband and five children.