tbuckley/cabot-search huggingface dataset:
Abstract 5387: Dual kinase/bromodomain inhibitors for rationally designed polypharmacology
Authors: Elizabeth R. Quinn, Pietro Ciceri, Susanne Müller-Knapp, Alison O'Mahony, Oleg Fedorov, Panagis Filippakopoulos, Jeremy P. Hunt, Elisabeth A. Lasater, Gabriel Pallares, Sarah Picaud, Christopher Wells, Lisa M. Wodicka, Neil P. Shah, Stefan Knapp, Daniel K. Treiber
Journal: Cancer Research (2014)

Abstract Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multi-target profile has, however, necessitated the application of combination therapies, which can pose significant clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as novel targets for cancer therapy. Here we have used BROMOscan™ bromodomain ligand binding assays to identify several clinical kinase inhibitors that also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase/bromodomain inhibitors. Nanomolar activity on BRD4 by clinical PLK1 and JAK2/FLT3 kinase inhibitors is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a novel strategy for rational single agent polypharmacological targeting. Importantly, cell-based data show that these dual inhibitors suppress c-Myc expression (a hallmark of BRD4 inhibition) and induce complex polypharmacological phenotypes reflecting dual kinase/bromodomain inhibition across a panel of primary human cell assay systems that model complex tissue and disease state environments (BioMap™). Furthermore, rich structure-activity relationships for related inhibitors and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase/bromodomain inhibitors. Citation Format: Elizabeth R. Quinn, Pietro Ciceri, Susanne Müller-Knapp, Alison O'Mahony, Oleg Fedorov, Panagis Filippakopoulos, Jeremy P. Hunt, Elisabeth A. Lasater, Gabriel Pallares, Sarah Picaud, Christopher Wells, Lisa M. Wodicka, Neil P. Shah, Stefan Knapp, Daniel K. Treiber. Dual kinase/bromodomain inhibitors for rationally designed polypharmacology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5387. doi:10.1158/1538-7445.AM2014-5387
Geriatric Psychiatry and the Limits of MeSH
Authors: Ira R. Katz, Linda M. G. Katz
Journal: JAMA (1995)

<h3>To the Editor.</h3> —The review of the<i>American Journal of Geriatric Psychiatry</i>by Drs Bowden and Long<sup>1</sup>is positive about the scope and contents of this new journal, now in its third volume. However, the review goes on to state that there were fewer than 120 articles with the subject heading of<i>geriatric psychiatry</i>in MEDLINE for 1990 through mid 1994 and concludes that "the number of articles published thus far does not provide convincing evidence that the need exists for another highly specialized journal." We feel an obligation to point out that the methods used to estimate the number of published articles in this field were incorrect. According to the MEDLINE scope note, the MeSH heading<i>geriatric psychiatry</i>refers to "a subspecialty of psychiatry concerned with the mental health of the aged" and that it is "not for mental disorders in the aged"; thus, the heading is used
NI-47 * GLIOMATOSIS MENINGI AND GLIOMATOSIS CEREBRI: KISSING COUSINS? CASE REPORT AND REVIEW OF THE LITERATURE
Authors: J. Khouri, L. Taylor
Journal: Neuro-Oncology (2014)

Primary Leptomeningeal Gliomatosis is a rare neoplastic disease of the central nervous system. This tumor arises solely in the leptomeninges without a dominant intraparenchymal brain or spinal cord lesion. The diagnosis is very challenging during life, with fewer than 100 reported cases in the medical literature. Initially thought to present as either a nodular or diffuse subtype (Primary Diffuse Leptomeningeal Gliomatosis: PDLG), the nodular forms are currently felt to be more appropriately termed Primary Leptomeningeal Glioma. This tumor is too rare to have been assigned a WHO classification. We propose that the term PDLG be replaced with Gliomatosis Meningi to make the relationship to the other form of Gliomatosis—Gliomatosis Cerebri, clearer. We report the case of a 63 year-old man who first presented with a grand mal seizure followed by progressive neurological decline, hydrocephalus, and spinal radiculopathy. He had an initial tentative diagnosis of neurosarcoidoisis radiographically. He went on to have progressive leptomeningeal enhancement on MRI involving the brain and the spinal cord with a negative initial temporal lobe biopsy followed by a subsequent biopsy of the leptomeninges, which revealed Leptomeningeal Gliomatosis. He continued to decline clinically and died 9 months after symptom onset despite treatment with craniospinal radiation therapy and chemotherapy with oral Temozolamide. We present a comprehensive review of the cases published in the literature to date. We restricted our search to the cases that described diffuse meningeal disease and excluded solitary tumors, non glial tumors as well as secondary leptomeningeal spread. A comprehensive review of the natural history of this disease is provided in the hope that this diagnosis can be made earlier in the future so that treatment can be offered before the tumor is too advanced.
Acute Haemolytic Anaemia following Sulphadimidine Therapy
Authors: H. Sterndale
Journal: BMJ (1956)

TREATMENT OF BARBITURATE POISONING BDJTjLJOURNAI 1101 majority well within this period.No deaths occurred, and there was no incidence of chest infection in any of these cases.The stay of the patients in hospital was cut down dramatically compared with former methods of treatment.Although the number of cases treated is small, I feel that it is worth while reporting them, in view of the results obtained, which, in my opinion, are a vast improvement on the previous methods at our disposal.I am indebted to Drs.W. A. Jaques, G. D.
Cytodynamics in the respiratory tract of the rat.
Authors: R G Shorter, J L Titus, M B Divertie
Journal: Thorax (1966)

The knowledge of cytodynamics in the respiratory tract is still in its infancy.Since Bertalanffy and Leblond (1953) described their findings in a study of the alveolar macrophage cells in the lung of the albino rat, few investigations have been reported in the literature (Koburg, 1962; Spencer and Shorter, 1962; Meyer zum Gottesberge and Koburg, 1963; and Shorter, Titus, and Divertie, 1964b), and these have indicated that the findings may vary greatly in the epithelia in the various parts of the respiratory tract, even between areas in close relationship to one another.The purpose of this paper is to report the findings obtained in a study of the cytodynamics in the trachea, bronchi, and pulmonary alveoli of the normal adult Sprague-Dawley rat by means of the tech- nique of nuclear labelling with tritium-labelled thymidine combined with autoradiography.Tritium-labelled thymidine (3HT) is incorpor- ated specifically by the nuclei of cells synthesizing deoxyribonucleic acid (DNA) (Taylor, Woods, and Hughes, 1957).An assumption is made that labelled cells behave in a fashion identical to that of normal cells.Since it has been shown by Krause and Plaut (1960) that the incorporation of 3HT modifies DNA synthesis in root cells of the bean and enhances the incorporation of thymidine, and since other possible toxic effects of 3HT on various cell systems have been described (Samuels and Kisieleski, 1963), this assumption may not be wholly valid, but its use is accepted generally, at present, in studies of cytodynamics in cell populations. MATERIALS AND METHODSAdult Sprague-Dawley rats2 of both sexes were used.The animals weighed 150 to 160 g. at the start of 'This investigation was Eupported in part by Research
Genome-Wide Mapping of Estrogen Receptor-β–Binding Regions Reveals Extensive Cross-Talk with Transcription Factor Activator Protein-1
Authors: Chunyan Zhao, Hui Gao, Yawen Liu, Zoi Papoutsi, Sadaf Jaffrey, Jan-Åke Gustafsson, Karin Dahlman-Wright
Journal: Cancer Research (2010)

Estrogen signaling can occur through a nonclassical pathway involving the interaction of estrogen receptors (ER) with other transcription factors such as activator protein-1 (AP-1) and SP-1. However, there is little mechanistic understanding about this pathway, with conflicting results from in vitro investigations. In this study, we applied the ChIP-on-chip approach to identify ERbeta-binding sites on a genome-wide scale, identifying 1,457 high-confidence binding sites in ERbeta-overexpressing MCF7 breast cancer cells. Genes containing ERbeta-binding sites can be regulated by E2. Notably, approximately 60% of the genomic regions bound by ERbeta contained AP-1-like binding regions and estrogen response element-like sites, suggesting a functional association between AP-1 and ERbeta signaling. Chromatin immunoprecipitation (ChIP) analysis confirmed the association of AP-1, which is composed of the oncogenic transcription factors c-Fos and c-Jun, to ERbeta-bound DNA regions. Using a re-ChIP assay, we showed co-occupancy of ERbeta and AP-1 on chromatin. Short interfering RNA-mediated knockdown of c-Fos or c-Jun expression decreased ERbeta recruitment to chromatin, consistent with the role of AP-1 in mediating estrogen signaling in breast cancer cells. Additionally, ERalpha and ERbeta recruitment to AP-1/ERbeta target regions exhibited gene-dependent differences in response to antiestrogens. Together, our results broaden insights into ERbeta DNA-binding at the genomic level by revealing crosstalk with the AP-1 transcription factor.
Identification of a synovial fibroblast-specific protein transduction domain for delivery of apoptotic agents to hyperplastic synovium
Authors: Zhibao Mi, Xiaoli Lu, Jeffrey C Mai, Bobby G Ng, Guiqiang Wang, Eric R Lechman, Simon C Watkins, Hannah Rabinowich, Paul D Robbins
Journal: Molecular Therapy (2003)

Synovial hyperplasia, resulting in erosion of cartilage and bone, represents one of the major pathologies associated with rheumatoid arthritis. To develop an approach for efficient delivery of proteins or agents to synovium to induce targeted apoptosis of hyperplastic synovial tissue, we have screened an M13 peptide phage display library for synovial-specific transduction peptides. We identified a novel synovial-targeted transduction peptide, HAP-1, which is able to facilitate specific internalization of protein complexes into human and rabbit synovial cells in culture and rabbit synovial lining in vivo. HAP-1 and a non-tissue-specific cationic protein transduction domain, PTD-5, were fused to an antimicrobial peptide, (KLAK)(2), to generate two proapoptotic peptides termed DP2 and DP1, respectively. Administration of these peptides was able to induce apoptosis of rabbit and human synovial cells in culture, with DP2 inducing synovial cell-specific apoptosis. Intra-articular injection of DP1 and DP2 into arthritic rabbit joints with synovial hyperplasia induced extensive apoptosis of the hyperplastic synovium, while reducing the leukocytic infiltration and synovitis. These results suggest that proapoptotic peptides and, in particular, DP2 can be clinically useful for treatment of synovial hyperplasia, as well as inflammation. Moreover, the results demonstrate the feasibility of identifying tissue-specific transduction peptides capable of mediating efficient transduction in vivo.
Space Motion Sickness, Hearing Loss, and Bifocals Meet Their Match In Vestibular System's Plasticity
Authors: Teri Randall
Journal: JAMA (1991)

MORE THAN HALF of all people who have traveled in space have experienced some form of motion sickness. This is no surprise to many researchers, given that the vestibular system, so finely tuned to respond to gravitational forces and visual cues on earth, is suddenly stripped of these familiar inputs in space.  What has fascinated many scientists, however, is that these unpleasant symptoms vanish after a few days in space. Without any conscious effort, astronauts make behavioral changes that reduce their sensations of disorientation and motion sickness.  For example, if astronauts want to view an object in their peripheral vision, rather than fixating on the object and then moving their head, as they would do on earth, they will unconsciously rotate their body with their head and then fixate on the object after it comes more centrally into view.  Coming Down to Earth  But not only does the astronaut's vestibular
Nephrotic Syndrome Caused by Probenecid
Authors: Albert Sokol
Journal: JAMA (1967)

IN 1961, Ferris and co-workers in reporting the first case of the nephrotic syndrome caused by probenecid<sup>1</sup>mentioned a number of drugs—including trimethadione, paramethadione, mercurials, tolbutamide, sodium perchlorate, and phenylbutazone (Butazolidin)—administration of which resulted in a similar untoward occurrence. A second case of nephrotic syndrome which occurred after use of probenecid has been seen in this hospital. <h3>Report of a Case</h3> A 34-year-old white man was first seen at his physician's office in late 1962 with a chief complaint of arthritis which was diagnosed as gout because of hyperuricemia and an excellent response to colchicine. Results of routine urine examination were normal. On Nov 2, 1963, the patient was placed on a regimen of probenecid, 0.5 gm twice a day. He was not seen again until Jan 30, 1964, when he complained of facial edema, headaches, and dizziness on standing. Following hospitalization, it was discovered that he had mild
Liver abscess formation after local treatment of liver tumors
Authors: T de Baère, A Roche, J M Amenabar, C Lagrange, M Ducreux, P Rougier, D Elias, P Lasser, C Patriarche
Journal: Hepatology (1996)

Our goal was to determine a subset of patients at high risk of developing liver abscesses after local treatment of liver tumors (LTLT) and establish guidelines for the conduct of LTLT in the safest conditions in such patients. Five hundred sixty–one LTLT, 489 transhepatic arterial chemoembolizations (TAC, 10 hepatic embolizations, and 62 percutaneous intratumor injections (PIT), were retrospectively reviewed for liver parenchyma necrosis and abscess formation. Four patients developed abscesses, three after TAC and one after PIT. Despite broad–spectrum antibiotherapy, percutaneous drainage, and surgery, two patients died. A left hepatectomy was required in the other two patients for cure. All four patients had a carcinoid or a neuroendocrine pancreatic tumor. Three out of four patients had bilioenteric anastomoses, and the fourth had recently undergone cholecystectomy and papillotomy. A Lipiodol/doxorubicin mixture without any particulate embolization was injected in the three patients who developed abscesses after TAC. LTLT in patients with bilio enteric anastomosis or papillotomy and/or neuroendocrine or carcinoid tumor should be performed with strict precautions during the procedure and for peri–procedural care.
Lipids, Apolipoproteins, and Their Ratios in Relation to Cardiovascular Events With Statin Treatment
Authors: John J.P. Kastelein, Wim A. van der Steeg, Ingar Holme, Michael Gaffney, Nilo B. Cater, Philip Barter, Prakash Deedwania, Anders G. Olsson, S. Matthijs Boekholdt, David A. Demicco, Michael Szarek, John C. LaRosa, Terje R. Pedersen, Scott M. Grundy
Journal: Circulation (2008)

Low-density lipoprotein (LDL) cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy.A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10,001 ("Treating to New Targets") and 8888 ("Incremental Decrease in End Points through Aggressive Lipid Lowering") patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol was lost. In a model that contained non-HDL cholesterol and apolipoprotein B, neither was significant owing to collinearity. Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters.In patients receiving statin therapy, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol. Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships. These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy. Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I, it seems premature to consider the ratio variables as clinically useful.
Awareness and Knowledge of Patients with Acute Coronary Syndromes About Coronary Artery Disease
Authors: Nüket Bayram Kayar, Fatma Gönül Doğan, Tuba Özdemir, Serap Bilgiç Dalkıran, Fatma Gül, Vüsale Gözütok, Yusuf Kayar, Didem Kafadar, Mustafa Hakan Dinçkal
Journal: Journal of the American College of Cardiology (2013)
Randomised controlled trial of effectiveness of Leicester hospital at home scheme compared with hospital care
Authors: A. Wilson, H. Parker, A. Wynn, C. Jagger, N. Spiers, J. Jones, G. Parker
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objective:</b> To compare effectiveness of patient care in hospital at home scheme with hospital care. <b>Design:</b> Pragmatic randomised controlled trial. <b>Setting:</b> Leicester hospital at home scheme and the city9s three acute hospitals. <b>Participants:</b> 199 consecutive patients referred to hospital at home by their general practitioner and assessed as being suitable for admission. Six of 102 patients randomised to hospital at home refused admission, as did 23 of 97 allocated to hospital. <b>Intervention:</b> Hospital at home or hospital inpatient care. <b>Main outcome measures:</b> Mortality and change in health status (Barthel index, sickness impact profile 68, EuroQol, Philadelphia geriatric morale scale) assessed at 2 weeks and 3 months after randomisation. The main process measures were service inputs, discharge destination, readmission rates, length of initial stay, and total days of care. <b>Results:</b> Hospital at home group and hospital group showed no significant differences in health status (median scores on sickness impact profile 68 were 29 and 30 respectively at 2 weeks, and 24 and 26 at 3 months) or in dependency (Barthel scores 15 and 14 at 2 weeks and 16 for both groups at 3 months). At 3 months9 follow up, 26 (25%) of hospital at home group had died compared with 30 (31%) of hospital group (relative risk 0.82 (95% confidence interval 0.52 to 1.28)). Hospital at home group required fewer days of treatment than hospital group, both in terms of initial stay (median 8 days <i>v</i> 14.5 days, P=0.026) and total days of care at 3 months (median 9 days <i>v</i> 16 days, P=0.031). <b>Conclusions:</b> Hospital at home scheme delivered care as effectively as hospital, with no clinically important differences in health status. Hospital at home resulted in significantly shorter lengths of stay, which did not lead to a higher rate of subsequent admission. <h3>Key messages</h3> The effectiveness of hospital at home schemes for avoiding hospital admission has not been tested in a trial In this study patients suitable for hospital at home care were randomised to hospital at home or hospital care and followed up for three months There were no clinically or statistically significant differences in outcome as measured by the sickness impact profile 68, Barthel index, Philadelphia geriatric morale scale, and EuroQol Length of stay in care and total days of care were about 45% less for patients randomised to hospital at home For patients who meet the admission criteria, hospital at home schemes can provide an effective and acceptable alternative to hospital admission
Enhancement of endothelium-dependent vasodilation by low-dose nitroglycerin in patients with congestive heart failure.
Authors: M Schwarz, S D Katz, L Demopoulos, H Hirsch, J L Yuen, G Jondeau, T H LeJemtel
Journal: Circulation (1994)

BACKGROUND Since organic nitroesters and endothelium-derived nitric oxide mediate vasodilation through a final common pathway, that is, by activation of soluble guanylate cyclase in vascular smooth muscle, nitroglycerin (NTG) could specifically enhance the endothelium-dependent vasodilatory response to acetylcholine (Ach) in patients with congestive heart failure (CHF) and endothelial cell dysfunction. Accordingly, the net effects of an intra-arterial infusion of NTG (10(-9) mol/L) on endothelium-dependent and endothelium-independent vasodilation were assessed in the forearm circulation of patients with CHF. METHODS AND RESULTS The forearm blood flow responses to intra-arterial administration of graded concentrations of Ach (10(-7) to 10(-5) mol/L) were determined by venous occlusion plethysmography (mL/min per 100 mL) in 18 patients with CHF and 5 age-matched normal subjects before and during intra-arterial infusion of NTG (10(-9) mol/L) for 20 minutes. In eight patients, the duration of the infusion of NTG (n = 5) or vehicle control solution (n = 3) was extended to 12 hours with measurement of the forearm blood flow responses to Ach at 20 minutes, 4 hours, and 12 hours. In five additional patients, forearm blood flow response to intra-arterial administration of two doses of phentolamine (0.05 and 0.5 mg) were determined before and during a 20-minute NTG infusion. Regional administration of NTG 10(-9) mol/L did not change resting forearm blood flow in either normal subjects or patients with CHF. Before administration of NTG 10(-9) mol/L, intra-arterial infusions of Ach 10(-7), 10(-5) and 10(-5) mol/L increased forearm blood flow to 14.7 +/- 6.2, 20.2 +/- 4.7, and 38.4 +/- 7.9 mL/min per 100 mL in normal subjects and to 4.1 +/- 0.8, 5.0 +/- 1.1, and 10.6 +/- 2.3 mL/min per 100 mL in patients with CHF. After administration of NTG 10(-9) mol/L for 20 minutes, the vasodilatory response to Ach significantly increased to 5.6 +/- 1.0, 6.9 +/- 1.6, and 17.7 +/- 3.4 mL/min per 100 mL in patients with CHF but did not change in normal subjects. The enhanced forearm blood flow responses to administration of Ach observed after 20 minutes of NTG administration in patients with CHF were sustained throughout a 12-hour NTG infusion. In contrast, regional administration of NTG did not change the vasodilatory responses to phentolamine. CONCLUSIONS NTG, when administered intra-arterially for 20 minutes at a dose that does not affect resting forearm blood flow, specifically increased the vasodilatory response to intra-arterial administration of Ach in patients with CHF but not in normal subjects. The vasodilatory response to Ach was consistently enhanced by low-dose NTG throughout a 12-hour period. The vasodilating effects of organic nitroesters on the peripheral vasculature of patients with CHF may result in part from an interaction with the vascular endothelium.