tbuckley/cabot-search huggingface dataset:
First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer
Authors: Geoffrey I. Shapiro, Katherine M. Bell-McGuinn, Julian R. Molina, Johanna Bendell, James Spicer, Eunice L. Kwak, Susan S. Pandya, Robert Millham, Gary Borzillo, Kristen J. Pierce, Lixin Han, Brett E. Houk, Jorge D. Gallo, Maria Alsina, Irene Braña, Josep Tabernero
Journal: Clinical Cancer Research (2015)

To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors.Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation.Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies.These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies.
Authors' reply to Nestel, Choudhary and Choudhary, Al Wakeel, and Helliwell and colleagues
Authors: W. T. Hamilton, J. Watson, A. Round
Journal: BMJ (2012)

The erythrocyte sedimentation rate (ESR) calculator is useful,1 although our local laboratory has stopped analysing ESRs (preferring viscosity) for the reasons given in our article.2 We were interested to hear of differential rises in inflammatory markers in systemic lupus erythematosus, and that these differences may help to differentiate …
Evidence based management of hypertension: What to do when blood pressure is difficult to control
Authors: Jane E O'Rorke, W Scott Richardson
Journal: BMJ (2001)

There is no universally accepted definition of blood pressure that is difficult to control, uncontrolled, resistant, or refractory. One consensus based US national guideline defines resistant hypertension as blood pressure that cannot be reduced below 140/90 mm Hg (below 160 mm Hg for isolated systolic hypertension) in patients who are complying with adequate triple drug regimens in appropriate dosage.1 This definition covers many hypertensive patients but not those for whom the target is an even lower pressure.

#### Summary points

Consider the following causes for apparently resistant blood pressure: inaccurate measurement, antagonising substances such as non-steroidal anti-inflammatory drugs, aggravating conditions such as obesity or sleep apnoea, suboptimal treatment regimens, non-compliance

When apparent resistance remains unexplained or when there are clues suggesting white coat hypertension, consider this and arrange for multiple measurements by self monitoring, visits to or by nurses or health visitors, or ambulatory monitoring

If hypertension is still unexplained, or for patients who fit specific patterns of higher risk, consider a selective, sequential evaluation for secondary causes of hypertension, starting with relatively common conditions, such as renovascular causes and renal parenchymal disease

Work closely with patients to identify preferred and feasible solutions for correcting any cause that is found

Consider referral of patients with severe or persistently resistant hypertension to a centre specialising in its diagnosis and treatment

Both clinical experience and research surveys suggest that resistant blood pressure is common in everyday practice. For example, population and clinic surveys in North America, Europe, and Australia show that in as many as 50% to 75% of people being treated for hypertension target blood pressure levels are not achieved.2 Fifty per cent of the 19 196 participants in one recent trial had uncontrolled blood pressure levels when enrolled despite already being treated for hypertension; 59% of these uncontrolled patients were being …
STUDIES ON THE NATURE AND THE PURIFICATION OF THE COAGULASE-REACTING FACTOR AND ITS RELATION TO PROTHROMBIN
Authors: Morris Tager
Journal: The Journal of Experimental Medicine (1956)

The coagulase-reacting factor (CRF) of human plasma has been purified, concentrated, and largely freed of prothrombin activity by Seitz filtration, absorbtion on hyflo-amphogel columns, controlled phosphate buffer elution, and fractional ammonium sulfate precipitation. The purified CRF preparations localized between the beta and the gamma globulin position on paper electrophoresis, and the principal of two components observed on analytical ultracentrifugation gave sedimentation rates between 2.75 and 3.07. Highly purified prothrombin preparations of Seegers effectively react with staphylocoagulase to lead to the coagulation of plasma. The electrophoretic and ultracentrifugal properties of the human prothrombin preparations examined differ significantly from those of the purified CRF. Derivatives of prothrombin, involving a loss of prothrombin activity, such as thrombin and "autoprothrombin," do not correspondingly lose in CRF function. The hypothesis is proposed that CRF activity is resident in some component or components of the prothrombin molecule not involved in prothrombin function per se, and that therefore prothrombin and CRF activity may either parallel each other when the molecule is intact or diverge when the smaller units only are involved.
A comparative immunohistochemical study of MART-1 expression in Spitz nevi, ordinary melanocytic nevi, and malignant melanomas
Authors: Reuven Bergman, Halim Azzam, Eli Sprecher, Lena Manov, Mariana Munichor, Rachel Friedman-Birnbaum, Offer Ben-Itzhak
Journal: Journal of the American Academy of Dermatology (2000)
ADAM10 Regulates Endothelial Permeability and T-Cell Transmigration by Proteolysis of Vascular Endothelial Cadherin
Authors: Beate Schulz, Jessica Pruessmeyer, Thorsten Maretzky, Andreas Ludwig, Carl P. Blobel, Paul Saftig, Karina Reiss
Journal: Circulation Research (2008)

Vascular endothelial (VE)-cadherin is the major adhesion molecule of endothelial adherens junctions. It plays an essential role in controlling endothelial permeability, vascular integrity, leukocyte transmigration, and angiogenesis. Elevated levels of soluble VE-cadherin are associated with diseases like coronary atherosclerosis. Previous data showed that the extracellular domain of VE-cadherin is released by an unknown metalloprotease activity during apoptosis. In this study, we used gain-of-function analyses, inhibitor studies, and RNA interference experiments to analyze the proteolytic release of VE-cadherin in human umbilical vein endothelial cells (HUVECs). We found that VE-cadherin is specifically cleaved by the disintegrin and metalloprotease ADAM10 in its ectodomain, releasing a soluble fragment and generating a carboxyl-terminal membrane-bound stub, which is a substrate for a subsequent gamma-secretase cleavage. This ADAM10-mediated proteolysis could be induced by Ca(2+) influx and staurosporine treatment, indicating that ADAM10-mediated VE-cadherin cleavage contributes to the dissolution of adherens junctions during endothelial cell activation and apoptosis, respectively. In contrast, protein kinase C activation or inhibition did not modulate VE-cadherin processing. Increased ADAM10 expression was functionally associated with an increase in endothelial permeability. Remarkably, our data indicate that ADAM10 activity also contributes to the thrombin-induced decrease of endothelial cell-cell adhesion. Moreover, knockdown of ADAM10 in HUVECs as well as in T cells by small interfering RNA impaired T-cell transmigration. Taken together, our data identify ADAM10 as a novel regulator of vascular permeability and demonstrate a hitherto unknown function of ADAM10 in the regulation of VE-cadherin-dependent endothelial cell functions and leukocyte transendothelial migration.
Mechanisms Limiting Body Growth in Mammals
Authors: Julian C. Lui, Jeffrey Baron
Journal: Endocrine Reviews (2011)

Recent studies have begun to provide insight into a long-standing mystery in biology—why body growth in animals is rapid in early life but then progressively slows, thus imposing a limit on adult body size. This growth deceleration in mammals is caused by potent suppression of cell proliferation in multiple tissues and is driven primarily by local, rather than systemic, mechanisms. Recent evidence suggests that this progressive decline in proliferation results from a genetic program that occurs in multiple organs and involves the down-regulation of a large set of growth-promoting genes. This program does not appear to be driven simply by time, but rather depends on growth itself, suggesting that the limit on adult body size is imposed by a negative feedback loop. Different organs appear to use different types of information to precisely target their adult size. For example, skeletal and cardiac muscle growth are negatively regulated by myostatin, the concentration of which depends on muscle mass itself. Liver growth appears to be modulated by bile acid flux, a parameter that reflects organ function. In pancreas, organ size appears to be limited by the initial number of progenitor cells, suggesting a mechanism based on cell-cycle counting. Further elucidation of the fundamental mechanisms suppressing juvenile growth is likely to yield important insights into the pathophysiology of childhood growth disorders and of the unrestrained growth of cancer. In addition, improved understanding of these growth-suppressing mechanisms may someday allow their therapeutic suspension in adult tissues to facilitate tissue regeneration.
A Comparison of Basal Insulin Delivery
Authors: Allen B. King, Dana Armstrong
Journal: Diabetes Care (2003)

Continuous subcutaneous insulin infusion (CSII) is believed to more closely mimic pancreatic function and therefore to create more stability in blood glucose than multiple daily insulin injections (MDIs). One of the unique features of CSII is the ability to preprogram changes in basal insulin delivery. This feature is especially useful during the night when insulin pharmacokinetics and the dawn phenomenon may change basal insulin requirements (1). Glargine is an insulin analog designed to mimic endogenous insulin secretion patterns and has been proposed as a longer-acting, peakless insulin that can be administered once a day, usually at bedtime (2). In the present study, glargine was compared, during nighttime hours, with preprogrammed …
Pulmonary Embolectomy
Authors: Walter H. Janke
Journal: JAMA (1968)

Pulmonary angiograms of patients with massive pulmonary embolism will often demonstrate complete occlusion of one pulmonary artery with little involvement of the other lung. In this group of patients, a unilateral pulmonary embolectomy through a posterolateral approach will afford a simple way of performing a meticulous cleaning of the affected pulmonary artery and all its branches. This method was used successfully in a 64-year-old woman.
Repetition priming: Memory or attention?
Authors: Peter M. Milner
Journal: Behavioral and Brain Sciences (1997)

There is no general agreement as to the meaning of long-term potentiation, but this cannot be resolved by using it to explain additional phenomena. Increased attention to recently experienced stimuli is a form of learning known to neuropsychologists as repetition priming. As more is learned about the neurochemistry of synaptic change, the term LTP will wither.
LUNG EDEMA FOLLOWING BILATERAL VAGOTOMY
Authors: Victor Lorber
Journal: The Journal of Experimental Medicine (1939)

1. Small animals (rat and guinea pig) vagotomized in the neck die within a period of hours, the lungs showing extensive congestion and edema. 2. Tracheotomy permits appreciably longer survival with minimal lung changes approximating those seen in the control animals. 3. Intrathoracic vagotomy (sparing the recurrent laryngeal nerve) on one side, and cervical vagotomy on the other, permits almost indefinite survival (guinea pig and rabbit), unless laryngeal paralysis from the unilateral denervation produces respiratory obstruction (rat, guinea pig, and rabbit). 4. Pulmonary edema following bilateral vagotomy probably results primarily from respiratory obstruction. It is suggested that circulatory failure may also be a factor of some importance. The rôle of vagotomy itself is considered in relationship to these two phenomena. 5. The reaction of smaller animals to bilateral vagotomy, with regard to lung changes, apparently differs in no way from that of the larger animals, but is less readily demonstrated because of the smaller diameters of the air passages.
Use of a prokinetic agent after double-balloon endoscopy reduces abdominal distension and discomfort, and shortens recovery time: potential adjunct or alternative to CO<sub>2</sub>
Authors: D. Mishkin
Journal: Endoscopy (2009)

Over the past few years, greater depth of insertion into the small intestine has allowed gastroenterologists to explore this last uncharted area in the ambulatory setting. A greater amount of experience is being gained with the increased usage of the balloon-assisted enteroscopy. A significant number of patients suffer from abdominal distension after the procedure and in order to reduce this and the associated discomfort, many gastroenterologists have tried using caps on the endoscope or carbon dioxide instead of room air for insufflation [1].
In Hot Water: Global Warming Takes a Toll on Coral Reefs
Authors: Charles W. Schmidt
Journal: Environmental Health Perspectives (2008)

I n the summer of 2005, while Atlantic hurricanes battered coastlines from Cuba to Mexico, the Eastern Caribbean baked under a relentless sun with barely a breeze to cool the air.Tourists and locals alike wilted in the heat, and below the sea, marine life and corals in particular suffered as well.The windless calm settled in just as a buildup of unusually warm water began accumulating in the region.Ordinarily, easterly trade winds would have churned the sea, helping it to cool.But thanks to an unprecedented heat wave beginning in May-the result of a confluence of factors related to climate change, scientists say-water temperatures in the Eastern Caribbean climbed and stayed high for months, reaching levels that by September would be warmer than any recorded in 150 years.The heat disturbed a symbiotic partnership that coral animals normally maintain with a type of algae called zooxanthellae.Zooxanthellae supply corals with essential nutrients produced by photosynthesis, particularly carbon, in return for
Endogenous fibrinolytic system in chronic large-vessel thromboembolic pulmonary hypertension.
Authors: M A Olman, J J Marsh, I M Lang, K M Moser, B R Binder, R R Schleef
Journal: Circulation (1992)

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a disorder characterized by pulmonary arterial hypertension as a consequence of organized thrombotic material in the central pulmonary arteries. Incomplete resolution of acute pulmonary emboli is believed to be pathogenically important; however, the mechanism for poor thrombus dissolution remains to be explained. We undertook this study to assess the major determinants of plasma fibrinolysis in patients with CTEPH (n = 32). METHODS AND RESULTS Immunological and functional levels of tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) were quantified in platelet-poor plasma (PPP) from patients with CTEPH as well as age-matched controls. Although basal PPP t-PA antigen levels (CTEPH mean, 29.5 ng/ml; control mean, 2.7 ng/ml) and PAI-1 antigen levels (CTEPH mean, 55.8 ng/ml; control mean, 21.0 ng/ml) were higher in the CTEPH group, no between-group differences were detected in the enzymatic activities of these two molecules. The CTEPH group demonstrated a greater rise in t-PA antigen (CTEPH mean rise, 53.0 ng/ml; control mean rise, 5.6 ng/ml) and PA activity (CTEPH mean rise, 10.5 IU/ml; control mean rise, 1.2 IU/ml) than controls in response to an experimentally induced venous occlusion. Immunoprecipitation and fibrin autography of PPP from two patients with markedly elevated basal t-PA antigen levels demonstrate that the t-PA antigen was present in PPP primarily in complex with PAI-1. CONCLUSIONS Although abnormalities of the fibrinolytic system were detected, neither a high resting plasma PAI-1 activity nor a blunted response of t-PA to venous occlusion can be invoked as an etiology for CTEPH:
Cost effectiveness of endosonography versus surgical staging in potentially resectable lung cancer: a health economics analysis of the ASTER trial from a European perspective
Authors: Robert C Rintoul, Matthew J Glover, Christopher Jackson, Victoria Hughes, Kurt G Tournoy, Christophe Dooms, Jouke T Annema, Linda D Sharples
Journal: Thorax (2013)

In the ASTER study, mediastinal staging was more accurate for patients randomised to combined endobronchial and endoscopic ultrasound, followed by surgical staging if endoscopy was negative, versus surgical staging alone. Here, we report survival, quality of life and cost effectiveness up to 6 months, for the UK, The Netherlands and Belgium, separately. Survival in the two arms of the study was similar. In all three countries, the endosonography strategy had slightly higher quality-adjusted life years over 6 months, and was cheaper. Therefore, based on clinical accuracy and cost effectiveness, we conclude that mediastinal staging should commence with endosonography.
Elevated Brain Natriuretic Peptide Predicts Blood Pressure Response After Stent Revascularization in Patients With Renal Artery Stenosis
Authors: Jose A. Silva, Albert W. Chan, Christopher J. White, Tyrone J. Collins, J. Stephen Jenkins, John P. Reilly, Stephen R. Ramee
Journal: Circulation (2005)

Background— A significant number (20% to 40%) of hypertensive patients with renal artery stenosis will not have blood pressure improvement after successful percutaneous revascularization. Identifying a group of patients with refractory hypertension and renal artery stenosis who are likely to respond to renal stent placement would be beneficial. Methods and Results— Brain natriuretic peptide (BNP) was measured in 27 patients with refractory hypertension and significant renal artery stenosis before and after successful renal artery stent placement. This neuropeptide was elevated (median, 187 pg/mL; 25th to 75th percentiles, 89 to 306 pg/mL) before stent placement and fell within 24 hours of the successful stent procedure (96 pg/mL; 25th to 75th percentiles, 61 to 182 pg/mL; P =0.002), remaining low (85 pg/mL; 25th to 75th percentiles, 43 to 171 pg/mL) at follow-up. Clinical improvement in hypertension was observed in the patients with a baseline BNP &gt;80 pg/mL (n=22) in 17 patients (77%) compared with 0% of the patients with a baseline BNP ≤80 pg/mL (n=5) ( P =0.001). After correction for glomerular filtration rate, BNP was strongly correlated with improvement in hypertension. Conclusions— BNP is increased in patients with severe renal artery stenosis and decreases after successful stent revascularization. In addition, an elevated baseline BNP level of &gt;80 pg/mL appears to be a good predictor of a blood pressure response after successful stent revascularization.
A comparison of techniques to assess skin blanching following the topical application of glucocorticoids
Authors: J.P. NOON, C.E. EVANS, W.G. HAYNES, D.J. WEBB, B.R. WALKER
Journal: British Journal of Dermatology (1996)

Summary Glucocorticoid-induced dermal blanching provides a useful research tool to study steroid potency and sensitivity. Conventional measurement of the intensity of blanching relies on subjective assessment by a trained observer using a visual score. Several objective techniques have recently been reported to detect skin blanching, but their sensitivity has not been compared previously with subjective visual recordings. In this report we aimed to establish whether objective methods offer sufficient sensitivity to be employed in epidemiological studies of glucocorticoid responsiveness. ealthy subject we applied beclomcthasone dipropionate at three concentrations (1. 10 and 100 μg/ml) under an occluded dressing overnight. The following morning we measured blanching using a visual score, laser Doppler velocimetry with the MBF 3D monitor (Moor Instruments Ltd. U.K.) and a perfusion imager (Lisca. Sweden), and reflectance spectrophotometry with the Dia-Stron ‘erythemameter’. Using the visual score, blanching was detected at all concentrations of steroid. Neither laser Doppler instrument detected vasoconstriction at any concentration. By contrast, the rellectance spectrophotometer successfully recorded blanching at 10 and 100 μg/ml. but not at 1 μg/ml. We conclude that laser Doppler instruments, including the novel scanning perfusion imager. do not detect glucocorticoidinducced skin blanching perhaps because it reflects venular rather than arteriolar vasoconstriction. By contrast, the Dia-Stron reflectance spectrophotometer has sufficient sensitivity to be used as an alternative to visual assessment in epidemiological studies of human glucocorticoid-induced dermal blanching.