tbuckley/cabot-search huggingface dataset:
A phase I dose escalation trial of BI 2536, a novel Plk1 inhibitor, with standard dose pemetrexed in previously treated advanced or metastatic non-small cell lung cancer (NSCLC)
Authors: P. M. Ellis, Q. S. Chu, N. B. Leighl, S. A. Laurie, D. Trommeshauser, G. Hanft, G. Munzert, S. Gyorffy
Journal: Journal of Clinical Oncology (2008)

8115 Background: BI 2536 is a novel, highly selective, potent inhibitor of Polo-like kinase 1 (Plk1), a key regulator of mitotic progression. BI 2536 has demonstrated favorable tolerability and antitumor activity in Phase I trials. We investigated the MTD, safety and PK of BI 2536 in combination with standard dose pemetrexed in patients (pts) with previously treated advanced or metastatic NSCLC. Methods: Eligible pts included stage IIIB/IV NSCLC and ECOG PS 0–2, relapsing after 1st line platinum-based therapy. Pts were treated with 500 mg/m2 pemetrexed and escalating doses of BI 2536 given as a 1h i.v. infusion on Day 1 every three weeks. A standard Phase I 3+3 trial design was used. The primary objective was to determine the MTD of BI 2536 given with pemetrexed. Secondary endpoints were response rate (RECIST), overall safety and PK. AEs were evaluated using NCI-CTCAE v. 3.0. Pts not progressing after 6 cycles of combination therapy were eligible to continue BI 2536 monotherapy until tumor progression. Results: 33 pts were treated at doses from 100–325 mg BI 2536. The MTD was defined at 300 mg BI 2536 after the occurrence of dose limiting toxicities (Grade 3 rash and Grade 4 neutropenia) at 325 mg. The most common drug related AEs were mostly mild to moderate nausea (36%), rash (33%), anorexia (27%), stomatitis (24%) and pruritus (24%). Reversible Grade 3/4 neutropenia occurred in 18% of pts. Other drug related Grade 3 events were rash (n=2), acute renal failure (n=1) and confusion (n=1). There were 2 confirmed durable partial responses; 7 pts were treated for >4 courses. Up to 15 courses of BI 2536 therapy have been administered without cumulative toxicity. The MTD is being confirmed in expanded pt cohorts treated at doses of 200–300 mg. PK analysis showed similar BI 2536 exposure with/without pemetrexed. Pemetrexed exposure was not altered after co-administration of BI 2536. Conclusion: Preliminary results demonstrate that a combination of BI 2536 and pemetrexed has an acceptable safety profile in relapsed NSCLC without any PK interaction. Encouraging antitumor activity was observed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim, Eli Lilly Boehringer Ingelheim Pharma
Commentary: General practitioners are wary of treating sickness in pregnancy
Authors: Roger Gadsby
Journal: BMJ (2004)

Sickness in pregnancy causes symptoms that vary from mild to so severe that hospital admission is required. It is associated with an appreciable loss of time from work1 and disruption of normal social activities,2 and it has been the stated reason for 25-29 terminations of pregnancy every year in the United Kingdom.3 However, many general practitioners in the United Kingdom feel frightened of suggesting any treatment to women presenting with pregnancy sickness because they believe that it would be ineffective and could cause fetal abnormalities.

There were 20 rapid responses after the first part of the case history, some of which discussed the use of nutritional and complementary therapies. The problem is that few data exist on the effectiveness and safety of such therapies for pregnancy sickness. There were fewer responses after the second part of the history, which perhaps suggests that doctors are not used to the idea of n of 1 trials in general practice.

Pregnancy sickness is difficult to measure, and the methods described in the case report might not have been sensitive enough to detect any improvement resulting from treatment with pyridoxine. One respondent also suggested that the treatment intervals should have been longer.

The Rhodes score, which was first used to assess nausea and vomiting during cancer chemotherapy, has been proposed as the method of choice for assessing treatments for pregnancy sickness.4 This score gives a validated and quantifiable measure of the severity of the condition.
Abstract 13165: Dapagliflozin for Reduction of Blood Pressure in Diabetic Patients Inadequately Controlled With Combination Antihypertensive Regimen
Authors: Michael A Weber, Traci A Mansfield, Caroline T'joen, Agata Ptaszynska
Journal: Circulation (2013)

Hypertension is a frequent comorbidity of type 2 diabetes (T2D); dual antihypertensive agents (ACEi or ARB plus a second agent) may not provide adequate control. Dapagliflozin (DAPA), a sodium gluc...
Abstract P282: First-ever Ischemic Stroke in the Very Elderly: Trends, Characteristics and Outcome in a National Registry
Authors: Alex Y Gur, David Tanne, Natan M Bornstein, Ron Milo, Eitan Auriel, Ludmila Shopin, Silvia Koton
Journal: Circulation (2012)

Background: The incidence of ischemic stroke significantly increases with age. With increasing life expectancy, very old subjects will constitute the majority of stroke patients. However, epidemiological and clinical features of very elderly patients with stroke are still uncertain. Our aim was to study the patients' characteristics, outcome and trends in the very elderly (aged ≥ 85 years) in comparison with patients aged 65–84 years with a first-ever ischemic stroke in the National Acute Stroke Israeli Survey (NASIS) registry. Methods: The NASIS registry is a nationwide prospective hospital-based study performed triennially (2004, 2007, 2010). Patients with ischemic stroke aged ≥85 years were compared with those 65–84 years old regarding their baseline characteristics, stroke severity, etiology of stroke and stroke outcomes. Stroke severity was determined according to the National Institute of Health stroke scale (NIHSS) score and functional disability using the modified Rankin scale (mRS). Logistic regression analyses were used in the comparison of outcomes adjusting for potential confounders. Trends in patients' characteristics and stroke outcome were studied. Results: A first-ever ischemic stroke was diagnosed in 3125 patients. The proportion of very elderly (≥85 years) patients among the NASIS population increased from 18.3% in 2004 to 19.9% in 2007 and 24.5% in 2010 (p=0.005). The percentage of women was higher in patients aged ≥85 years (p&lt;0.0001). Atrial fibrillation, congestive heart disease and prior disability were significantly more prevalent in the very elderly. The very elderly presented with more severe strokes: 36.3% of the ≥85 years-old patients had NIHSS≥11 compared with 22.0% in the younger age group. Adjusted rates of in-hospital complications [OR (95% CI=1.7 (1.3–2.2)] and severe disability or death (mRS&gt;3) [1.4 (1.0–1.9)] were increased for very elderly patients. In the analysis of trends by registry period, rates of dyslipidemia increased from 25.4% in 2004 to 63.7% in 2010 (p for trend&lt;0.0001) and hypertension increased from 74.8% in 2004 to 90.5% in 2010 (p for trend=0.0004). A significant decrease in the rate of in-hospital mortality among the very old patients is evident: rates decreased from 18.7% in 2004 to 5.7% in 2010 (p for trend=0.0005). Conclusions: There is an increasing proportion of very elderly subjects, mostly women, among first-ever ischemic stroke patients. Current information on age specific aspects of stroke in the very elderly is crucial to set up successful prevention pathways and implementing well-organized stroke care for this population.
Abstract 5472: Expression Of TCTP Antisense In CD4+CD25High Regulatory T Cells Weakens The Cell Survival And Aggravates Vascular Inflammation
Authors: Yan Yan, Zeyu Xiong, Jian Song, Ying Yin, Alan Cowan, Hong Wang, Xiao-Feng Yang
Journal: Circulation (2008)

Suppression of atherosclerosis and adaptive immune responses by CD4+CD25 high  regulatory T cells (Tregs) has been reported. However, the role of Tregs in suppressing adaptive immunity-independent acute vascular inflammation remains poorly defined. In addition, the question of whether signaling pathways in regulating Treg apoptosis can be modulated for regulation of inflammation is less well known. We examined our hypotheses that anti-apoptotic protein translationally controlled tumor protein (TCTP) expression in Tregs is critical for Treg survival and homeostasis, and that modulation of Treg apoptosis pathway affects development of vascular inflammation. We found that lower TCTP expression in Tregs than in CD4+CD25-T cells was associated with the higher susceptibility of Tregs to apoptosis induced by interleukin-2 (IL-2, a Treg survival cytokine) withdrawal. To determine whether the expression of TCTP in Tregs is critical for Treg generation and survival, we established a Tregs-specific TCTP antisense transgenic mouse model. Overexpression of TCTP antisense in Tregs in TCTP transgenic mice led to decreased positive selection of CD25 high  thymic Tregs and reduced survival of peripheral Tregs. In addition, TCTP antisense transgene conferred higher susceptibility of Tregs to apoptosis induced by IL-2 withdrawal than wild-type Tregs, which was suppressed by exogenous supply of IL-2, suggesting that IL-2 promotes Treg survival at least partially due to promoting TCTP expression. Finally, decreased expression of TCTP in Tregs aggravated experimental vascular inflammation, presumably due to increased Treg apoptosis and failure of decreased Tregs in suppressing inflammatory cells and immune cells. The result is correlated to our previous reports that the overexpression of TCTP antisense cDNA knocks down the expression of anti-apoptotic TCTP protein and promotes T cell apoptosis, and that higher expression of pro-apoptotic protein Bax in Tregs increases vascular inflammation. These results suggest that Tregs suppress acute vascular inflammation, and that the modulation of Tregs apoptosis/survival may be used as a new therapeutic approach for treating inflammatory cardiovascular diseases.
Abstract 19724: Hypertriglyceridemia and Low HDL-C Predicts Fenofibrate Response in The ACCORD-Lipid Trial
Authors: Marshall B Elam, Laura C Lovato, Robert P Byington, Denise Bonds, Lawrence Leiter, John R Crouse, Peter Linz, Santica Marcovina, Patrick J O'Connor, Henry N Ginsberg
Journal: Circulation (2010)

Background: The ACCORD-Lipid trial assessed effects of combination fenofibrate and simvastatin therapy on cardiovascular disease (CVD) in Type 2 Diabetes (T2DM). CVD events were not significantly r...
Long-Term Results After Simple Versus Complex Stenting of Coronary Artery Bifurcation Lesions
Authors: Michael Maeng, Niels R. Holm, Andrejs Erglis, Indulis Kumsars, Matti Niemelä, Kari Kervinen, Jan S. Jensen, Anders Galløe, Terje K. Steigen, Rune Wiseth, Inga Narbute, Pål Gunnes, Jan Mannsverk, Oliver Meyerdierks, Svein Rotevatn, Kjell Nikus, Saila Vikman, Jan Ravkilde, Stefan James, Jens Aarøe, Antti Ylitalo, Steffen Helqvist, Iwar Sjögren, Per Thayssen, Kari Virtanen, Mikko Puhakka, Juhani Airaksinen, Evald H. Christiansen, Jens F. Lassen, Leif Thuesen
Journal: Journal of the American College of Cardiology (2013)
Ultrasonography During Liver Surgery
Authors: Guido Torzilli
Journal: Liver Cancer (2009)

Since the late 1980s, it has been evident that hepatic surgery performed using the conventional approach, carries a very high risk for patients' survivals due to the high rate of postoperative liver failure (Lin, 1979). In particular, the coexistence of liver cirrhosis in most cases with hepato-cellular carcinoma (HCC) has a considerable adverse effect on the surgical results with 6% postoperative mortality, which is not negligible (Liu et al., 2004). For this reason and for the broadening of ultrasound-guided percutaneous therapies, the surgical treatment of HCC has loosen its role of first choice treatment. Furthermore, the good results with interstitial therapies in the treatment of HCC has induced the extension of their use also for those patients with colorectal cancer (CRC) liver metas-tases (Solbiati et al., 2001). However, the imaging techniques have been introduced also as aids for surgeons in performing liver resection. In fact, at the end of the 1970s, intraoperative ultrasonography (IOUS) in hepatic surgery in the case of liver cirrhosis started (Makuuchi et al., 1980, 1998). Now, liver resections can be carried out with no mortality even if cirrhosis is associated (Torzilli et al., 1999a), combining the needs for oncological radicality and liver parenchyma sparing, and this goal is mainly achievable because of IOUS (Torzilli et al., 2005a, 2006). Recently, the demonstration of feasibility and efficacy of contrast-enhanced ultrasonography performed intraoperatively (CE-IOUS) has furthermore stressed the relevance of IOUS guidance during liver surgery (Torzilli et al., 2004a, b, 2005b).
Using experimental data and analysis in EEG modelling
Authors: Donald L. Rowe, James Wright
Journal: Behavioral and Brain Sciences (2001)

We question the falsifiability of Tsuda's theory and emphasise the need for physiologically based, quantitative models of large scale cortical function that can be validated through experimental data. We outline such a model emphasising its verification through experimental data and possible avenues for testing Tsuda's predictions about nonlinearities in neural behaviour.
Abstract 10381: Improved Left Ventricular Mass Quantification with Partial Voxel Interpolation - in vivo and Necropsy Validation of a Novel Algorithm for Automated Analysis of Cardiac Magnetic Resonance (CMR)
Authors: Noel C Codella, Hae Yeoun Lee, David S Fieno, Debbie W Chen, Minisha Kochar, John P Finn, Robert Judd, Parag Goyal, Jesse Schenendorf, Matthew D Cham, Richard B Devereux, Martin Prince, Yi Wang, Jonathan W Weinsaft
Journal: Circulation (2011)

Background Partial voxel analysis, a new segmentation method for LV mass (LVM), accounts for myocardium admixed with blood in a single voxel. This differs from conventional full voxel analysis, whi...
Abstract 3367: Prospective Testing of Isoproterenol and Adenosine After Pulmonary Vein Isolation: Acute Results
Authors: Thomas D Callahan, John S Zakaib, John Meulet, Conor Barrett, Karen Phillips, Sanjeev Wasson, Claude Elayi, Chi Keong Ching, Thomas Dresing, Robert Schweikert, David Martin, J D Burkhardt, Jennifer Cummings, Ousama Wazni, Mohamed Kanj, Walid Saliba, Andrea Natale
Journal: Circulation (2007)

Background: Pulmonary vein isolation (PVI) offers an estimated cure rate from atrial fibrillation (AF) of 60 to 80% after the first procedure. While some data suggest that lack of inducibility of AF by electrical stimulation after atrial fibrillation ablation may predict improved outcomes, chemical induction of AF during PVI has not been well-studied. In an on-going prospective study, we seek to determine if chemical induction of AF after PVI with subsequent ablation of elicited triggers improves overall success. Herein, we report acute results of attempted re-induction of AF using adenosine and isoproterenol in patients undergoing PVI. Methods: Fourty-three consecutive patients with symptomatic AF presented for PVI. Following initial isolation and while catheters were still in place in the left atrium, 18 to 24 mg of IV adenosine was administered as a single bolus. Subsequently, infusion of isoproterenol was administered at up to 20 mcg/min. After administration of each drug, patients were observed for induction of AF or other atrial arrhythmias, focal firing including frequent monomorphic PAC’s or focal atrial tachycardias or evidence of recovery of conduction from the pulmonary veins. Results: Adenosine administration induced atrial fibrillation in 3 of 43 patients. Notably, no arrhythmias or focal firing were seen with isoproterenol in these three patients. Adenosine did not uncover recovery of conduction from the pulmonary veins in any patient or induce focal firing. Isoproterenol administration induced atrial fibrillation in 3 patients. Focal firing was induced in 18 patients. Recovery of conduction into pulmonary veins was observed after isoproterenol in 6 of 43 patients resulting in application of additional lesions to achieve re-isolation in each case. Conclusions: Our initial data suggests atrial fibrillation may be chemically re-induced with adenosine and isoproterenol administration in a minority of patients undergoing PVI. Focal firing may also be induced with isoproterenol. Isoproterenol but not adenosine uncovered recovery of conduction into the pulmonary veins in several patients. The mechanism by which arrhythmias and AF initiate may differ with adenosine versus isoproterenol.
Abstract 1052: 26S Proteasome: Intracellular Localization and Regulation by Nitric Oxide
Authors: Muneera R Kapadia, Jason W Eng, Jozef Murar, Qun Jiang, Melina R Kibbe
Journal: Circulation (2007)

Introduction: Nitric oxide (NO) is known to inhibit vascular smooth muscle cell (VSMC) proliferation by modulating cell cycle proteins. The 26S proteasome tightly regulates the degradation of most cell cycle proteins. Therefore, we previously studied the relationship between NO and the 26S proteasome, and found that NO directly inhibits 26S proteasome catalytic activity. The purpose of this study was two-fold: to determine the effect of NO on 26S proteasome subunit expression, and to determine the intracellular localization of these subunits. Methods: Protein expression was examined using western blot analysis conducted on rat aortic VSMC exposed to varying concentrations of the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 125–1000 μM) for 24 hours. Intracellular localization was conducted with immunofluorescent staining of VSMC ± exposure to SNAP (500 μM). VSMC were also fractionated into their nuclear and cytoplasmic components and western blot analysis was conducted to confirm localization. Results: Of the 26S proteasome subunits examined, the α5, α6, β1, and inducible β1 subunits demonstrated increased protein expression with increasing concentrations of NO. However, β2, inducible β2, β5, and inducible β5 protein expression did not change with NO exposure. Immunofluorescent staining of VSMC for these subunits confirmed these results. Additionally, each of these subunits showed a distinct pattern of staining: the α5 subunit was mostly perinuclear, the α6 subunit appeared mostly nuclear, and the β1 and inducible β1 subunits were mostly cytoplasmic. Western blot analysis following nuclear and cytoplasmic separation confirmed that α5, β1, and inducible β1 subunits were mostly in the cytoplasmic fraction. Interestingly, while the α6 subunit localizes to the nucleus by immunofluorescent staining, western blotting showed it to be mostly in the cytoplasmic fraction, indicating that its cellular distribution is perinuclear. Conclusion: Our data indicate that the 26S proteasome subunits have distinct patterns of intracellular localization, and are differentially regulated by NO. Understanding the relationship between NO and the 26S proteasome provides insight into the mechanism by which NO inhibits VSMC proliferation.
Abstract 6006: Comparison of the Safety and Efficacy of Zotarolimus-Eluting Stent versus Sirolimus-Eluting Stent versus Paclitaxel-Eluting Stent for Primary Percutaneous Coronary Intervention in ST-Elevation Acute Myocardial Infarction
Authors: Tae Hoon Ahn, Woong Chul Kang, Myung Ho Jeong, Seung Woon Rha, Jang Ho Bae, Jong Soon Park, Seung Ho Hur, Doo Il Kim, Seok Kyu Oh, Jung Han Yoon, Yang Soo Jang, Byung Ok Kim, Jae Woong Choi
Journal: Circulation (2008)

Background: Data regarding the safety of using drug-eluting stents(DES) in ST-elevation acute myocardial infarction(STEMI) are limited with small, randomized clinical trials. Further, there were no...
Abstract 16861: Reduction in Inappropriate Utilization of Myocardial Perfusion SPECT, Stress Echocardiography, and Coronary CT Angiography Using a Point-of-Order Automated Decision Support Tool: The Prospective Multicenter ENCOURAGE study
Authors: Fay Y Lin, Dan Gebow, Troy M Labounty, Millie J Gomez, Allison M Dunning, Leslee J Shaw, James K Min
Journal: Circulation (2011)

Background. The appropriate use rates for myocardial perfusion SPECT (MPS), stress echocardiography (STE) and coronary CT angiography (CCTA) in the community are unknown. Methods. We prospectively collected American College of Cardiology appropriate use criteria (AUC) ratings on consecutive MPS, STE and CCTA studies among single specialty cardiology practices in one large metro area that submitted claims to United Health Care. Physician groups used online appropriate use decision support tools for determination of appropriateness. Results. 4 physician groups comprised of 101 cardiologists rated indications for 612 patients over 8 months (43±25 years, 35% female, 18% diabetic, 40% prior CAD). Imaging studies comprised 431 (70%) MPS, 152 (25%) STE and 29 (5%) CCTA. On average, it took 133+322 seconds to obtain an appropriate use rating using the calculator. Appropriate studies constituted 56%, 47%, and 52% of all MPS, STE and CCTA respectively, while indications not covered by AUC guidelines constituted 7%, 18% and 17% respectively. There were no significant differences in the proportions of appropriate, uncertain, inappropriate and non-addressed indications by MPS, STE or CCTA (p=0.16). There was a secular trend towards decreased inappropriate studies over time (23% in 1st quarter vs 11% in last (4th) quarter, p = 0.002) Conclusion. In a consecutive cohort of imaging studies in a large metro area, the distribution of appropriateness ratings does not differ significantly between modalities. An appropriate use decision support tool reduces inappropriate testing over time.
The Melbourne Family Grief Study, I: Perceptions of family functioning in bereavement
Authors: David W. Kissane, Sidney Bloch, David L. Dowe, Ray D. Snyder, Patrick Onghena, Dean P. McKenzie, Christopher S. Wallace
Journal: American Journal of Psychiatry (1996)

The aim of this study was to identify patterns of family functioning in adult families after the death of a parent.One hundred fifteen families completed measures of family functioning, grief, psychological state, and social adjustment 6 weeks (time 1), 6 months (time 2), and 13 months (time 3) after the death of a parent (a total of 670 individual responses). Cluster analytic methods were applied to develop a typology of perceptions of family functioning during bereavement.Five types of families emerged from dimensions of cohesiveness, conflict, and expressiveness on the Family Environment Scale. Thirty-six percent of the families were considered supportive because of their high cohesiveness, and another 23% resolved conflict effectively. Two types were dysfunctional: hostile families, distinguished by high conflict, low cohesiveness, and poor expressiveness, and sullen families, who had more moderate limitations in these three areas; they declined in frequency from 30% at time 1 to 15% at time 3. The remaining type (26%), termed intermediate, exhibited midrange cohesiveness, low control, and low achievement orientation. The typology at time 1 predicted typologies at time 2 and time 3. There were no age or gender differences among the family types, but offspring, as compared with spouses, were overrepresented in the hostile families.Family types can be identified, allowing at-risk families to be helped to prevent complications of grief. Screening with the family relationship index of the Family Environment Scale would facilitate such a family-centered approach.