tbuckley/cabot-search huggingface dataset:
Abstract P4-16-05: Hsp90 inhibition potentiates chemotherapy effectiveness in triple negative breast cancer: Role of glucocorticoid receptor signaling
Authors: A Agyeman, W Jun, D Proia, N Lee, M Skor, S Conzen
Journal: Cancer Research (2013)

Abstract Background: Few promising molecular targets exist for chemoresistant triple negative breast cancer (TNBC). Our laboratory has previously demonstrated that a subset of TNBCs express high glucocorticoid receptor (GR) levels. In breast epithelial cells, GR transcriptional activity directly upregulates the expression of several anti-apoptotic target genes including serum/glucocorticoid regulated kinase 1 (SGK1). High GR and/or SGK1 expression are both associated with decreased chemotherapy-induced cell death in TNBC models. A meta-analysis of patients with early-stage TNBC found that high primary tumor GR (NR3C1) expression significantly associates with earlier relapse compared to GR-non expressing TNBC. Inhibiting GR/SGK1 activity is therefore a testable strategy for improving TNBC responsiveness to chemotherapy. Both GR and SGK1 require Hsp90 for their activity; therefore, Hsp90 inhibition is predicted to disrupt both GR and SGK1 cell survival signaling in TNBC. Employing a second-generation Hsp90 inhibitor, ganetespib (Synta Pharmaceuticals), we determined the effectiveness of Hsp90 inhibition on GR/SGK1 activity and chemotherapy sensitivity using in vitro and in vivo TNBC models. Hypothesis: Hsp90 inhibition will decrease GR and SGK1 activity in TNBC in association with improved chemotherapy effectiveness. Results: Using TNBC cell lines treated with ganetespib at clinically relevant concentrations, we found that total GR and the relative proportion of phosphorylated Ser211 GR were significantly reduced beginning 2 hours following treatment. Reduced glucocorticoid-induced (SGK1) mRNA expression was also seen when cells were pre-treated with ganetespib. We next used fluorescent microscopy and live cell imaging to measure TNBC cell death over a 96 hour time course following chemotherapy +/- ganetespib therapy. Addition of ganetespib to paclitaxel treatment of MDA-MB-231 cells led to significant in vitro cytotoxic synergy; as hypothesized, this synergy was diminished in GR-depleted MDA-MB-231 cells. Cytotoxic synergy following ganetespib and chemotherapy treatment was also seen in vivo in MDA-MB-231 xenografts. Interestingly, tumor GR expression following Hsp90 inhibitor and paclitaxel treatment was significantly reduced compared to tumors from mice treated with paclitaxel alone. Using GR-depleted or control MDA-MB-231 xenografts, studies are currently underway to further characterize the role of GR/SGK1 activity as a target of Hsp90 inhibition to reverse TNBC chemoresistance. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-05.
THE ANTIGENIC SIMILARITY OF HUMAN LOW DENSITY LIPOPROTEINS
Authors: Lawrence Levine, Dorothy L. Kauffman, Ray K. Brown
Journal: The Journal of Experimental Medicine (1955)

THE FOLLOWING HUMAN LOW DENSITY LIPOPROTEINS WERE PREPARED: beta-lipoproteins of densities greater than 1.040 (A, B,C) a beta-lipoprotein of -S(1.063) = 5 (D), a lipoprotein of -S(1.063) = 19 (E), and a lipoprotein of -S(1.063) = 70 (F). Data are presented which show the immunochemical homogeneity of the D lipoprotein rabbit-anti-D lipoprotein system. Cross-reactions between antibody to A and D lipoproteins and the above lipoproteins have been demonstrated by quantitative precipitation, quanitative complement fixation, and single and double diffusion in agar. The antigenic similarities appear to be associated with the protein portions of the molecule. The antisera produced did not differentiate the low density lipoprotein classes.
Ranolazine as a Cardioplegia Additive Improves Recovery of Diastolic Function in Isolated Rat Hearts
Authors: Hyosook Hwang, Joseph M. Arcidi, Sharon L. Hale, Boris Z. Simkhovich, Luiz Belardinelli, Arvinder K. Dhalla, John C. Shryock, Robert A. Kloner
Journal: Circulation (2009)

Ranolazine (Ran), an antianginal agent, inhibits late Na(+) current. The purpose of this study was to determine whether there was an added benefit of adding Ran to cardioplegia (CP) in a model of global ischemia/reperfusion.Isolated rat hearts were Langendorff-perfused and exposed to 40-minute normothermic, cardioplegic global ischemia and 30 minutes of reperfusion. Before ischemia and during reperfusion, hearts were treated with no drug (control) or with the late Na(+) current inhibitors Ran (5 micromol/L) or tetrodotoxin (1 micromol/L). Ischemic cardioplegic arrest led to an increase of left ventricular end-diastolic pressure (LVEDP) by > or =20 mm Hg (ie, cardiac contracture). Ten out of 11 hearts treated with CP alone developed contracture, whereas 6 out of 11 hearts treated with CP plus Ran developed contracture. Ran added to CP reduced LVEDP at the end of ischemia from 41+/-5 mm Hg in CP alone to 26+/-3 mm Hg in CP plus Ran (P=0.024). Area under the curve for LVEDP during the entire ischemic period was also smaller in CP plus Ran versus CP alone. The percent increase (from baseline) of LVEDP measured at the end of 30-minute reperfusion was smaller for CP plus Ran (66+/-18%) versus CP alone (287+/-90%; P=0.035). The area under the curve for LVEDP during reperfusion was smaller in CP plus Ran versus CP alone. Tetrodotoxin (1 micromol/L) also reduced cardiac contracture during ischemia/reperfusion, compared to CP alone.Our results suggest that Ran may have therapeutic potential as an adjunct to CP and further support a protective role of Na(+) current inhibition during ischemia/reperfusion.
Hour-Glass Contraction of the Uterus Simulated by the Pressure of a Narrow Binder
Authors: W. T. Greene
Journal: BMJ (1867)

<h3>Background</h3> Stable guide catheter position within the cerebral intracranial vasculature allows for safe and effective treatment. Reported herein, an initial experience determining safety and efficacy with the 0.071” ID inner diameter Benchmark guide catheter used in the treatment of intracranial cerebrovascular pathologies. <h3>Methods</h3> This retrospective study reviewed cases from September 2014 through December 2014 that used the Benchmark guide catheter in the treatment of various neuroendovascular intracranial pathologies. Clinical performance and complication rates were assessed. <h3>Results</h3> Overall, 62 Benchmark guide catheters were used, 47 in the anterior circulation, 10 in the posterior circulation, 4 in the external carotid, and 1 in the venous sinus. Five cases were excluded that had access to the external carotid and venous sinus. The Benchmark was capable of crossing at the minimum one 90-degree turn in 49 (86%) out of the 57 patients. Reversal of the catheter was seen in 15% of 47 anterior circulation cases (4 at one 90-degree turn; 3 at two 90-degree turns). No complications of dissection or thromboembolic events were noted. All guide catheter positions were safely achieved over a 0.035 Terumo stiff glidewire without the need for an inner smaller lumen guide catheter for navigation. <h3>Conclusion</h3> With an ideal hybrid of hyper-flexible distal tip and proximal shaft stiffness, Benchmark is a novel guide catheter that provides stability in access for an overall effective neurointerventional procedure. Its ease of use allows physicians to safely position it into the preferred location within intracranial arteries while still maintaining stability throughout the intervention and adequate angiography. <h3>Disclosures</h3> A. Chandran: None. M. Puthuran: None. P. Eldridge: None. H. Nahser: None.
Betrayal Trauma: The Logic of Forgetting Childhood Abuse
Authors: Richard P. Kluft
Journal: JAMA (1997)

In recent years a polarized debate, often polemical and vitriolic, has seized the attention of psychotherapists and the lay public. Some authorities have ascribed a crucial importance to the influence of repressed or dissociated memories of childhood trauma in the etiology of adult psychopathology and distress, while others have attempted to cast doubt on the possibility that true childhood trauma can be banished from memory or later recovered, either spontaneously or in the course of therapy. "... Freyd's betrayal theory is capable of generating numerous testable hypotheses..." One the one hand, voices have been raised to claim that memories of childhood traumatization should be assumed to be accurate unless proven otherwise, while on the other hand, there has been a clamor that recovered memories are almost if not always inaccurate, necessitating that psychotherapists consider such claims unlikely a priori. Furthermore, many researchers and some clinicians who claim that genuine memories are
A RANDOMIZED CONTROLLED TRIAL OF AUTONOMIC REMODELING BY SYMPATHOVAGAL MODULATION IN CORONARY HEART DISEASE
Authors: Puja K. Mehta, Donna Polk, Chrisandra Shufelt, Joan Kirschner-Fusaro, ANP-BC Qiao Yi, Xiuling Ma, Ida Chen, Anna Brantman, Kamlesh Kothawade, C. Noel Bairey Merz, Ning Li
Journal: Journal of the American College of Cardiology (2012)
GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34<sup>+</sup> and erythroid CD71<sup>+</sup> cells in myelodysplastic syndromes
Authors: Christos I. Maratheftis, Pelagia E. Bolaraki, Michael Voulgarelis
Journal: American Journal of Hematology (2007)

GATA-1 is a transcription factor governing the production of erythroid and megakaryocytic cells. Unobstructed GATA-1 expression in early progenitor cells commits them to the myeloid lineage, channeling its differentiation towards erythrocytes and megakaryocytes. Myelodysplastic Syndromes (MDS) are clonal disorders of the hematopoietic stem cell frequently presenting dysplasia in erythroid and/or megakaryocytic lineage. We reasoned that measurement of GATA-1 expression levels in hematopoietic progenitor CD34(+) and the committed erythroid CD71(+) cells, from various MDS subcategories, could demonstrate GATA-1 involvement in the pathogenesis of the syndrome. In this study, MDS patients displayed significantly elevated GATA-1 mRNA expression, in bone marrow mononuclear cells (BMMCs), progenitor CD34(+) and erythroid CD71(+) cells in contrast to the control population (P < 0.001). Additionally, GATA-1 mRNA expression in MDS CD71(+) cells was positively correlated with their apoptotic levels (rho = 0.58, P = 0.03). Furthermore, GATA-1 expression levels were found to correlate with the disease progression. MDS patients in high/INT-2 IPSS risk group expressed significantly higher GATA-1 mRNA levels, in both CD34(+) and CD71(+) cells, as opposed to low/INT-1 patients (P < 0.001). Moreover, the former displayed increased apoptosis in the CD71(+) cells and significantly reduced neutrophil and platelet numbers and hemoglobin levels compared with the latter. We conclude that MDS patients display an increase of GATA-1 mRNA expression in BM cells, with high/INT-2 patients showing significantly higher levels. The higher level of GATA-1 mRNA in erythroid cells was positively correlated with their degree of apoptosis. These findings suggest that the up-regulation of GATA-1 may be responsible for the peripheral cytopenias in MDS.
PARATYPHOID "A" FEVER
Authors: A. H. Safford
Journal: BMJ (1915)

NOV. I3, I9!5 PARATYPHOID " A " FEVER.[ T>u3ml ns 713WOV-I3, 119151[~~~~~~~~~~~~~~~~~~~~~~~~MEDICAL JOURNLE 1 accident observed by colleagues who have inoculated in Serbia more than 120,000 men w"ith the tetravaccine.We h-ave never observed any really serious reactions, either local or general, the.inoculated persons being as a rule able to attend to their duLties in from twenty-four to forty- cigiht liour's after injection. Tlle inoculated persons develop protective substances4or-tlhe four germs-typhoid, paratyphoid A, paratyplhoid B, and chlolera..The amount of agglutinins present for aea of the four germs is practically the same as in con- trol,individuals inoculated with typlhoid, paratyphoid A, paratyplioid B, and clholera monovaceines.4. We are of the opinion, as stated in previous publications, tlhat the tetravaceine should be used as a matter of routine to inoculate the troops taking part in the present war, greatly exposed as tlley are to the four diseases, typhoid, paratyphoid A, paratyphoid B, and eholera.Its use rendlers it possible to give a contemporaneous pro- tection for the four maladies by a simple and rapid procedure.
Lesson of the week: Fractures of the thoracolumbar spine in major trauma patients
Authors: S. Meek
Journal: BMJ (1998)

Thoracolumbar spine fractures may be present in major trauma patients without symptoms

Although much attention has been paid to improving the diagnosis of cervical spine injuries over the past few years, fractures of the thoracolumbar spine have received comparatively little attention. Several reports have indicated that back pain and bony tenderness may be absent in some patients with fractures of the thoracolumbar spine which may lead to a delay in diagnosis.13 and an increased risk of neurological damage.4

We report the cases of six patients with multiple trauma and fractures of the thoracolumbar spine in whom back pain and bony tenderness were absent, radiography of the thoracolumbar spine was not requested, and the diagnosis was delayed or missed. Our experience suggests that in the United Kingdom many doctors in trauma specialties are unaware that back pain and tenderness may be absent in cases of spinal fracture.

These cases were identified by the South West region major trauma outcome study. A total of six hospitals in Bristol, Gloucestershire, and Somerset collected data on all major trauma cases occurring in patients under 40 years of age and selected cases for peer review. Altogether 594 patients were entered into the study between 1994 and 1997, and 58 (10%) had fractures of the thoracolumbar spine.

Case 1 —A driver who was not wearing a safety belt was ejected from a vehicle. His score on the Glasgow coma scale was 15 on arrival at the accident and emergency department. Avulsion fractures of C2 and C3 bodies were noted without neurological deficit. Additionally, an open fracture of the radius and ulna and fractures of the pelvic ring were diagnosed. The patient was “log rolled” (a procedure in which patients are rolled on to their side by a number of staff with minimal movement …
Exogenous Insulin Administration and Cardiovascular Risk in Non-Insulin-dependent and Insulin-dependent Diabetes Mellitus
Authors: Saul Genuth
Journal: Annals of Internal Medicine (1996)

It is currently unknown whether intensive insulin treatment of diabetes decreases the risk for cardiovascular complications by lowering glucose levels or increases the risk by postulated direct atherogenic effects. This article reviews published data from two long-term, randomized clinical trials that compared cardiovascular outcomes associated with different exogenous insulin treatment regimens. STUDY SELECTION AND DATA SOURCES: The University Group Diabetes Program (UGDP) and the Diabetes Control and Complications Trial (DCCT) were selected as the only available randomized intervention trials with long-term follow-up results. Data reviewed were from the major publications of these two trials.The UGDP compared the effects of a fixed-dose standard insulin regimen, a variable-dose insulin regimen, and a diet plus oral placebo regimen in over 600 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were followed for up to 13 years (1962 to 1975). Plasma glucose levels were 1.7 to 2.2 mmol/L lower in the variable-dose insulin regimen group than in the other two treatment groups. No significant differences were found in the final prevalence or the cumulative incidence of total deaths, cardiovascular disease deaths, or myocardial infarctions among the three treatment groups, even when outcomes were adjusted for pertinent baseline cardiovascular risk factors. There was a slight suggestion only from post hoc analysis that patients in both insulin treatment groups, who were defined as having good glucose control, had fewer cardiovascular events than those with fair or poor control. The DCCT compared intensive insulin treatment with conventional insulin treatment (the mean hemoglobin A1c [HbA1c] level was 7.2% and 9.0%, respectively) in over 1400 patients with insulin-dependent diabetes (IDDM) followed for up to 10 years (1983 to 1993). Three major cardiovascular events occurred in the intensive treatment group as compared with 14 in the conventional treatment group (P > 0.05), and low-density lipoprotein cholesterol and triglyceride levels were substantially lower in the intensive treatment group. However, body mass index increased substantially more with intensive than with conventional therapy.The UGDP trial was flawed by inadequate power, insufficient separation of glycemic levels, and ignorance of smoking history as a possible confounder. In the DCCT, the number of cardiovascular events was few because the patients were young and had a relatively short duration of diabetes at baseline. In addition, total daily insulin doses were similar in the two DCCT treatment groups. For these reasons, neither trial provides a definitive answer to the question about the effects of intensive insulin therapy. A better designed clinical trial is needed to determine whether insulin treatment has beneficial or adverse effects, or even offsetting beneficial and adverse effects, on the risk for cardiovascular disease in NIDDM and IDDM.
TI-201 Uptake in Brown Tumors of Hyperparathyroidism
Authors: HATICE DURAK, TULIN ARAS, CEM SUNGUR, GUNAYDIN ERBENGI, COSKUN F. BEKDIK
Journal: Clinical Nuclear Medicine (1991)

TI-201 chloride bone scans were performed on nine patients with primary hyperparathyroidism just after TI-201 and Tc-99m parathyroid subtraction scintigraphy. Bone lesions accumulate TI-201, especially in sites of brown tumor formation. This was proven by the histopathologic examination of two patients. Eight patients had bone scans with Tc-99m MDP. The lesion-to-background ratio was quantified in seven patients for TI-201 and in four patients for Tc-99m MDP. TI-201 uptake of the lesions were quantified in two patients. The lesion-to-background ratio was 1.63 ± 0.21 and 2.51 ± 0.88 for TI-201 and Tc-99m MDP, respectively. A Ga-67 citrate scan was performed on one patient, and the lesion-to-background ratio was 1.49 ± 0.06. The accumulation of TI-201 in brown tumors of bone might be due to increased blood flow and local metabolic activity. TI-201 chloride was inferior to Tc-99m MDP in lesion detection. It is concluded that bone imaging with TI-201 can easily be performed following parathyroid subtraction scintigraphy to delineate the sites of brown tumor formation.
Salmeterol inhaler using a non-chlorinated propellant, HFA134a: systemic pharmacodynamic activity in healthy volunteers.
Authors: S M Kirby, J Smith, G P Ventresca
Journal: Thorax (1995)

BACKGROUND--Metered dose inhalers for the treatment of asthma use chlorofluorocarbons as propellants. These face an international ban due to their effect on the ozone layer. Salmeterol has been reformulated using the non-chlorinated propellant Glaxo inhalation grade HFA134a. METHODS--The safety, tolerability and systemic pharmacodynamic activity of the salmeterol/HFA134a inhaler, the current salmeterol inhaler, and placebo (HFA134a) were compared in 12 healthy volunteers in a double blind, randomised crossover study using a cumulative dosing design. RESULTS--Safety and tolerability were similar and the response was related to the dose over the range used (50-400 micrograms) with both salmeterol inhalers. The salmeterol/HFA134a inhaler showed no differences from the current inhaler for pulse rate, blood pressure, tremor, QTc interval, and plasma glucose levels. The salmeterol/HFA134a inhaler had significantly less effect on plasma potassium levels. CONCLUSIONS--In healthy volunteers the salmeterol/HFA134a inhaler is at least as safe and well tolerated as the current salmeterol inhaler, and has similar systemic pharmacodynamic activity.
Cancer screening---how can we do better?
Authors: R. Roylance
Journal: BMJ (1998)

Cancer is the second most common cause of death in the United Kingdom. Our attempts to reduce cancer deaths are mainly directed towards improving treatments, with comparatively little spent on prevention.

In an attempt to rectify this, expensively advertised government sponsored screening campaigns have been launched in the past decade, sometimes coinciding with election campaigns and often without the support of a medical consensus. Recent high profile mistakes have highlighted the inadequacies of the current service, where human error has led to false negative and positive reporting of breast and cervical cancer. These errors have occurred throughout Britain, most recently for cervical cancer in Kent and for breast cancer in Devon.

These errors have arisen because screening is currently a subjective rather than an objective process depending on an individual's interpretation of microcalcification or architectural distortion on a mammogram or the appearances of nucleus and cytoplasm on a smear. In order to limit these errors computerised screening processes need to be introduced that provide an objective analysis of the risk …
Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.
Authors: N Crimi, R Polosa, G Pulvirenti, S Magri, G Santonocito, G Prosperini, C Mastruzzo, A Mistretta
Journal: Thorax (1995)

Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects.Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20).Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon.The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human asthma.