tbuckley/cabot-search huggingface dataset:
Rationale for a Phase II Trial of Pertuzumab, a HER-2 Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer
Authors: Bruce E. Johnson, Pasi A. Jänne
Journal: Clinical Cancer Research (2006)

In non-small cell lung cancer (NSCLC) HER-2 gene amplification and 3+ staining by immunohistochemistry are present in only 2% to 5% of the tumors. Therefore, relatively few patients with lung cancer are likely to benefit from treatment with trastuzumab, the humanized monoclonal antibody that is effective in the 20% of patients with breast cancer and HER-2 gene amplification and/or 3+ staining by immunohistochemistry. Pertuzumab (rhuMAb 2C4), a humanized HER2 antibody, represents a new class of targeted therapeutics that inhibit dimerization of HER2 with ligand-activated EGFR (HER1), HER3, and HER-4. Pertuzumab can have antitumor activity in patients with HER-2 present on the tumor without gene amplification or 3+ staining by immunohistochemistry. Preclinical xenograft studies have shown efficacy of pertuzumab in treating NSCLC. Therefore, a trial was undertaken for patients with relapsed NSCLC.Subjects with advanced or recurrent NSCLC treated previously with chemotherapy were treated with pertuzumab (840 mg i.v. loading dose then 420 mg every 3 weeks). Mandatory fresh tumor biopsies before treatment were obtained for biomarker analysis including HER-2 phosphorylation. Computed tomography scans were obtained every two cycles to assess tumor response. Tumor response (response evaluation criteria in solid tumors criteria) was the primary end point.As reported in a previous abstract, none of the 33 patients with NSCLC and evaluable disease had a response to the treatment.Pertuzumab has an appropriate rationale for therapeutic use in patients with NSCLC. A phase II trial in patients with NSCLC has completed enrollment, and the details of the trial will be presented in a future publication. This article will review the preclinical rationale for undertaking a study of pertuzumab for patients with relapsed NSCLC.
Prospective Gene Signature Study Using microRNA to Identify the Tissue of Origin in Patients with Carcinoma of Unknown Primary
Authors: Gauri R. Varadhachary, Yael Spector, James L. Abbruzzese, Shai Rosenwald, Huamin Wang, Ranit Aharonov, Heather R. Carlson, Dalia Cohen, Siddharth Karanth, Joanna Macinskas, Renato Lenzi, Ayelet Chajut, Tina B. Edmonston, Martin N. Raber
Journal: Clinical Cancer Research (2011)

Accurate identification of tissue of origin (ToO) for patients with carcinoma of unknown primary (CUP) may help customize therapy to the putative primary and thereby improve the clinical outcome. We prospectively studied the performance of a microRNA-based assay to identify the ToO in CUP patients.Formalin-fixed paraffin-embedded (FFPE) metastatic tissue from 104 patients was reviewed and 87 of these contained sufficient tumor for testing. The assay quantitates 48 microRNAs and assigns one of 25 tumor diagnoses by using a biologically motivated binary decision tree and a K-nearest neighbors (KNN). The assay predictions were compared with clinicopathologic features and, where suitable, to therapeutic response.Seventy-four of the 87 cases were processed successfully. The assay result was consistent or compatible with the clinicopathologic features in 84% of cases processed successfully (71% of all samples attempted). In 65 patients, pathology and immunohistochemistry (IHC) suggested a diagnosis or (more often) a differential diagnosis. Out of those, the assay was consistent or compatible with the clinicopathologic presentation in 55 (85%) cases. Of the 9 patients with noncontributory IHC, the assay provided a ToO prediction that was compatible with the clinical presentation in 7 cases.In this prospective study, the microRNA diagnosis was compatible with the clinicopathologic picture in the majority of cases. Comparative effectiveness research trials evaluating the added benefit of molecular profiling in appropriate CUP subsets are warranted. MicroRNA profiling may be particularly helpful in patients in whom the IHC profile of the metastasis is nondiagnostic or leaves a large differential diagnosis.
AVULSION OF THE SCALP
Authors: A. G. Banks
Journal: BMJ (1928)

O -:7-983RIA breathing was considerably embarrassed and the patient com- plained -of great tightness in the chest and of severe headache.The emphysema had now greatly extended, involving both sides of.the face (distending the eyejids, so -that the patient could not see), both sides of the neck and thorax, the skin.beingtense over these regions, and, to a lesser degree, the abdomen.The scrotum was moderately distended.There was a slight degree of emphysema in the left thigh.During the night the patient was very ill.He was delirious, with a temperature between 1020 and 1030 F.; the pulse was rapid .........
Gonadal Regulation of Hypothalamic Gonadotropin Releasing Hormone Release in Primates*
Authors: TONY M. PLANT
Journal: Endocrine Reviews (1986)

THE DRIVE to the pituitary-gonadal axis originates within the central nervous system (CNS) and is transmitted to the gonadotropes of the adenohypophysis by an intermittent discharge of GnRH into the hypophysial portal circulation, an episodic pattern of hypothalamic neurosecretion that results in striking ultradian fluctuations in the concentration of this releasing factor in portal blood (1–3). In the rhesus monkey, as in nonprimate species (4), when the neurohumoral link between the brain and pituitary gland is interrupted, either by stalk section or by destruction of the arcuate nucleusmedian eminence region of the hypothalamus, pituitary gonadotropin secretion is essentially abolished and gonadal function arrested (5–9). Moreover, in monkeys with an intact hypophysial portal circulation, imraunoneutralization with anti-GnRH 7-globulins, or treatment with a GnRH antagonist, also results in a marked diminution in LH and FSH secretion (10–12). In the human female, a situation analogous to the hypothalamic lesioned monkey is observed in subjects with hypothalamic amenorrhea, as occurs for example in patients with Kailman's syndrome, in which the release of endogenous GnRH is abolished or severely compromised (13, 14).
Oestrogen only arm of women's health initiative trial is stopped
Authors: Janice Hopkins Tanne
Journal: BMJ (2004)

The oestrogen only study of the women's health initiative study sponsored by the US National Institutes of Health has been stopped early because of a slightly increased risk of stroke among women in the trial. The study included only women who did not have a uterus.

Dr Barbara Alving, director of the women's health initiative and acting director of the National Heart, Lung, and Blood Institute, said the study was stopped because treatment with oestrogen neither increased nor decreased the risk of heart disease, a question the study sought to answer.

The study, which involved nearly 11 000 women, showed that oestrogen only treatment did not increase the risk of breast cancer during the seven years of the study and reduced the risk …
Randomized Study on Simple Versus Complex Stenting of Coronary Artery Bifurcation Lesions
Authors: Terje K. Steigen, Michael Maeng, Rune Wiseth, Andrejs Erglis, Indulis Kumsars, Inga Narbute, Pål Gunnes, Jan Mannsverk, Oliver Meyerdierks, Svein Rotevatn, Matti Niemelä, Kari Kervinen, Jan S. Jensen, Anders Galløe, Kjell Nikus, Saila Vikman, Jan Ravkilde, Stefan James, Jens Aarøe, Antti Ylitalo, Steffen Helqvist, Iwar Sjögren, Per Thayssen, Kari Virtanen, Mikko Puhakka, Juhani Airaksinen, Jens F. Lassen, Leif Thuesen
Journal: Circulation (2006)

Background— The optimal stenting strategy in coronary artery bifurcation lesions is unknown. In the present study, a strategy of stenting both the main vessel and the side branch (MV+SB) was compared with a strategy of stenting the main vessel only, with optional stenting of the side branch (MV), with sirolimus-eluting stents. Methods and Results— A total of 413 patients with a bifurcation lesion were randomized. The primary end point was a major adverse cardiac event: cardiac death, myocardial infarction, target-vessel revascularization, or stent thrombosis after 6 months. At 6 months, there were no significant differences in rates of major adverse cardiac events between the groups (MV+SB 3.4%, MV 2.9%; P =NS). In the MV+SB group, there were significantly longer procedure and fluoroscopy times, higher contrast volumes, and higher rates of procedure-related increases in biomarkers of myocardial injury. A total of 307 patients had a quantitative coronary assessment at the index procedure and after 8 months. The combined angiographic end point of diameter stenosis &gt;50% of main vessel and occlusion of the side branch after 8 months was found in 5.3% in the MV group and 5.1% in the MV+SB group ( P =NS). Conclusions— Independent of stenting strategy, excellent clinical and angiographic results were obtained with percutaneous treatment of de novo coronary artery bifurcation lesions with sirolimus-eluting stents. The simple stenting strategy used in the MV group was associated with reduced procedure and fluoroscopy times and lower rates of procedure-related biomarker elevation. Therefore, this strategy can be recommended as the routine bifurcation stenting technique.
A trial of beclomethasone/formoterol in COPD using EXACT-PRO to measure exacerbations
Authors: Dave Singh, Jorg Kampschulte, Jadwiga A. Wedzicha, Paul W. Jones, Géraldine Cohuet, Massimo Corradi, Tim Higenbottam, Stefano Petruzzelli, Jørgen Vestbo
Journal: European Respiratory Journal (2012)

Combination inhalers containing corticosteroids and long-acting β-agonists are used to reduce exacerbation rates in patients with severe chronic obstructive pulmonary disease (COPD). The FORWARD (Foster 48-week Trial to Reduce Exacerbations in COPD) clinical trial in severe COPD patients is a comparison of extrafine beclomethasone dipropionate and formoterol in a combination inhaler with extrafine formoterol; the co-primary end-points are exacerbation rates over 48 weeks and improvement in forced expiratory volume in 1 s over 12 weeks. The traditional physician diagnosis of exacerbations is a co-primary outcome, and the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) means of collecting patient-reported outcome data are also being used to enhance the detection of exacerbation events. EXACT data are being collected using a novel application of a digital platform technology. FORWARD is therefore expected to provide information on the ability of EXACT to detect and measure exacerbations in a large clinical trial setting. The study design of FORWARD is described in this article.
Management of stable angina: summary of NICE guidance
Authors: N. O. Flynn, A. Timmis, R. Henderson, S. Rajesh, E. Fenu
Journal: BMJ (2011)

Stable angina is common. In England about 8% of men and 3% of women aged 55-64 years and about 14% of men and 8% of women aged 65-74 years have or have had angina.1 Stable angina is associated with a low but appreciable risk of acute coronary events and increased mortality. However, evidence exists of inconsistencies in management.2 This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the management of stable angina.3 The diagnosis of stable angina is considered in an earlier NICE guideline.4 NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group's experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Information and support for people with stable angina [ Based on low to high quality evidence from qualitative studies and experience and opinion of the GDG ]
Accuracy of a referral guideline for patients with chronic hepatitis B in primary care to select patients eligible for evaluation by a specialist
Authors: I. K Veldhuijzen, M. C Mostert, H. G M Niesters, J. H. Richardus, R. A de Man
Journal: Gut (2007)

Practice guidelines have been developed to select patients with chronic hepatitis B who might benefit from antiviral treatment.1–3 These sophisticated guidelines are directed at specialist care, and include the assessment of serum hepatitis B virus (HBV) DNA. However, most patients with chronic HBV are diagnosed in primary care where HBV DNA is usually not assessed. A simpler, less expensive guideline that can be used at the primary care level to select patients for referral to specialist care can reduce the number of patients referred who, after evaluation by a specialist, are ineligible for treatment. By preventing the referral of ineligible patients, the disappointment that patients with high expectations experience after referral to a specialist is avoided. Furthermore, it reduces the burden on the healthcare system.

A guideline for the referral of patients with chronic HBV …
Trichomonas in pleural effusion
Authors: G Radosavljevic-Asic, D Jovanovic, D Radovanovic, M Tucakovic
Journal: European Respiratory Journal (1994)

Numerous living trichomonads were seen in a parapneumonic pleural effusion, in a patient who was at risk of aspiration pneumonia because of acute alcoholism. Of all the drugs administered, metronidazole had the most favourable therapeutic effect. However, decortication was necessary for the successful outcome.
LEVAMISOLE AND AGRANULOCYTOSIS
Authors: M. Rosenthal, Y. Breysse, P. Franchimont, K.L. Schmidt, E. Veys, A.StJ. Dixon, E.C. Huskisson, Y. Schuermans, T.L. Vischer, P.A.J. Janssen, J. Brugmans, W.K. Amery, J. De Crepe, J. Symoens, A.L. Macnair
Journal: The Lancet (1977)
Previous injury as a risk factor for injury in elite football: a prospective study over two consecutive seasons
Authors: M Hagglund
Journal: British Journal of Sports Medicine (2006)

<b>Background:</b> Previous injury is often proposed to be a risk factor for football injury, but most studies rely on players reporting their own medical history and are thus potentially subject to recall bias. Little is known about the natural variation in injury pattern between seasons. <b>Objectives:</b> To study whether prospectively recorded injuries during one season are associated with injuries sustained during the following season, and to compare injury risk and injury pattern between consecutive seasons. <b>Methods:</b> The medical staffs of 12 elite Swedish male football teams prospectively recorded individual exposure and time loss injuries over two full consecutive seasons (2001 and 2002). A multivariate model was used to determine the relation between previous injury, anthropometric data, and the risk of injury. <b>Results:</b> The training and match injury incidences were similar between seasons (5.1 <i>v</i> 5.3 injuries/1000 training hours and 25.9 <i>v</i> 22.7/1000 match hours), but analysis of injury severity and injury patterns showed variations between seasons. Players who were injured in the 2001 season were at greater risk of any injury in the following season compared with non-injured players (hazard ratio 2.7; 95% confidence interval 1.7 to 4.3, p&lt;0.0001). Players with a previous hamstring injury, groin injury, and knee joint trauma were two to three times more likely to suffer an identical injury in the following season, whereas no such relation was found for ankle sprain. Age was not associated with an increased injury risk. <b>Conclusions:</b> This study confirmed previous results showing that previous injury is an important risk factor for football injury. Overall injury incidences were similar between consecutive seasons, indicating that an injury surveillance study covering one full season can provide a reasonable overview of the injury problem among elite football players in a specific environment. However, a prolonged study period is recommended for analyses of specific injury patterns.
Impact of Routine Stenting on Clinical Outcome in Diabetic Patients Undergoing Primary Angioplasty for ST-Segment Elevation Myocardial Infarction
Authors: Giuseppe De Luca, Harry Suryapranata, Jorik Timmer, Jan Paul Ottervanger, Arnoud W.J. van’t Hof, Jan C.A. Hoorntje, Jan-Henk Dambrink, A.T. Marcel Gosselink, Menko-Jan de Boer
Journal: Diabetes Care (2006)

STEMI, ST-segment
Activation of Ras/PI3K/ERK Pathway Induces c-Myc Stabilization to Upregulate Argininosuccinate Synthetase, Leading to Arginine Deiminase Resistance in Melanoma Cells
Authors: Wen-Bin Tsai, Isamu Aiba, Yan Long, Hui-Kuan Lin, Lynn Feun, Niramol Savaraj, Macus Tien Kuo
Journal: Cancer Research (2012)

Melanomas and other cancers that do not express argininosuccinate synthetase (AS), the rate-limiting enzyme for arginine biosynthesis, are sensitive to arginine depletion with pegylated arginine deiminase (ADI-PEG20). However, ADI resistance eventually develops in tumors because of AS upregulation. Although it has been shown that AS upregulation involves c-Myc, the underlying mechanisms remain unknown. Here we show that ADI-PEG20 activates Ras signaling and the effector extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT/GSK-3β kinase cascades, resulting in phosphorylation and stabilization of c-Myc by attenuation of its ubiquitin-mediated protein degradation mechanism. Inhibition of the induced cell signaling pathways using PI3K/AKT inhibitors suppressed c-Myc induction and enhanced ADI-mediated cell killing. Notably, in an animal model of AS-negative melanoma, combination therapy using a PI3K inhibitor plus ADI-PEG20 yielded additive antitumor effects as compared with either agent alone. Taken together, our findings offer mechanistic insight into arginine deprivation metabolism and ADI resistance, and they illustrate how combining inhibitors of the Ras/ERK and PI3K/AKT signaling pathways may improve ADI-PEG20 anticancer responses.
Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial
Authors: Friedrich W Mohr, Marie-Claude Morice, A Pieter Kappetein, Ted E Feldman, Elisabeth Ståhle, Antonio Colombo, Michael J Mack, David R Holmes, Marie-angèle Morel, Nic Van Dyck, Vicki M Houle, Keith D Dawkins, Patrick W Serruys
Journal: The Lancet (2013)
Leptin Signaling in Adipose Tissue
Authors: Prachi Singh, Timothy E. Peterson, Fatima H. Sert-Kuniyoshi, Jason A. Glenn, Diane E. Davison, Abel Romero-Corral, Snigdha Pusalavidyasagar, Michael D. Jensen, Virend K. Somers
Journal: Circulation Research (2012)

The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known.To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans.We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis.In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.
<i>EGFR</i> Exon 19 Insertions: A New Family of Sensitizing <i>EGFR</i> Mutations in Lung Adenocarcinoma
Authors: Mai He, Marzia Capelletti, Khedoudja Nafa, Cai-Hong Yun, Maria E. Arcila, Vincent A. Miller, Michelle S. Ginsberg, Binsheng Zhao, Mark G. Kris, Michael J. Eck, Pasi A. Jänne, Marc Ladanyi, Geoffrey R. Oxnard
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Epidermal growth factor receptor (EGFR) genotyping is now standard in the management of advanced lung adenocarcinoma, as this biomarker predicts marked benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). EGFR exon 19 insertions are a poorly described family of EGFR mutations, and their association with EGFR-TKI sensitivity in lung adenocarcinoma is uncertain. Experimental Design: Patients with lung cancers harboring EGFR exon 19 insertions were studied. The predicted effects of the insertions on the structure of the EGFR protein were examined, and EGFR exon 19 insertions were introduced into Ba/F3 cells to assess oncogenicity and in vitro sensitivity to EGFR-TKIs. In patients receiving TKI, response magnitude was assessed with serial computed tomographic (CT) measurement. Results: Twelve tumors harboring EGFR exon 19 insertions were identified; patients were predominately female (92%) and never-smokers (75%). The 11 specimens available for full sequencing all showed an 18-bp insertion that resulted in the substitution of a Pro for Leu at residue 747. The mutant EGFR transformed the Ba/F3 cells, which were then sensitive to EGFR-TKI. Six patients with measurable disease received TKI and five had a response on serial CT. Conclusions: EGFR exon 19 insertions are a newly appreciated family of EGFR-TKI–sensitizing mutations, and patients with tumors harboring these mutations should be treated with EGFR-TKI. While these mutations may be missed through the use of some mutation-specific assays, the addition of PCR product size analysis to multigene assays allows sensitive detection of both exon 19 insertion and deletion mutations. Clin Cancer Res; 18(6); 1790–7. ©2011 AACR.
The vessels and the glue: Space, time, and causation
Authors: Andrei Rodin
Journal: Behavioral and Brain Sciences (2004)

In addition to the “universal glue,” which is the local mechanical causation, the standard explanatory scheme of classical science presumes two “universal vessels,” which are global space and time. I call this outdated metaphysical setting “black-and-white” because it allows for only two principal scales. A prospective metaphysics able to bind existing sciences together needs to be “colored,” that is, allow for scale relativity and diversification by domain.