tbuckley/cabot-search huggingface dataset:
Daily Oral Everolimus Activity in Patients With Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial
Authors: James C. Yao, Catherine Lombard-Bohas, Eric Baudin, Larry K. Kvols, Philippe Rougier, Philippe Ruszniewski, Sakina Hoosen, Jessica St. Peter, Tomas Haas, David Lebwohl, Eric Van Cutsem, Matthew H. Kulke, Timothy J. Hobday, Thomas M. O'Dorisio, Manisha H. Shah, Guillaume Cadiot, Gabriele Luppi, James A. Posey, Bertram Wiedenmann
Journal: Journal of Clinical Oncology (2009)

PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.
Multi-process models in social psychology provide a more balanced view of social thought and action
Authors: Richard E. Petty
Journal: Behavioral and Brain Sciences (2004)

Krueger &amp; Funder (K&amp;F) describe social psychology as overly consumed with maladaptive heuristics and biases. This characterization fails to consider multi-process models of social thought and action. Such models, especially with respect to attitudes, have outlined the situational and individual difference variables responsible for determining when thoughts and actions are relatively thoughtful versus when they are more reliant on mental shortcuts.
Feasibility of a walking workstation to increase daily walking
Authors: W G Thompson, R C Foster, D S Eide, J A Levine
Journal: British Journal of Sports Medicine (2007)

Objective: The number of calories expended in the workplace has declined significantly in the past 75 years. A walking workstation that allows workers to walk while they work has the potential to increase caloric expenditure. We evaluated whether employees can and will use walking workstations while performing their jobs. Methods and procedures: We studied nurses, clinical assistants, secretaries and appointment secretaries using the StepWatch Activity Monitor System (which accurately measures steps taken at slow speeds) while performing their job functions in their usual fashion and while using the walking workstation. Results: Subjects increased the number of steps taken during the workday by 2000 steps per day (p&lt;0.05). This was equivalent to an increase in caloric expenditure of 100 kcal/day. Subjects reported that they enjoyed using the workstation, that it could be used in the actual work arena and that, if available, they would use it. Discussion: Walking workstations have the potential for promoting physical activity and facilitating weight loss. Several subjects in this study expended more than 200 extra calories daily using such a system. Further trials are indicated.
Ventricular Remodeling Does Not Accompany the Development of Heart Failure in Diabetic Patients After Myocardial Infarction
Authors: Scott D. Solomon, Martin St John Sutton, Gervasio A. Lamas, Ted Plappert, Jean L. Rouleau, Hicham Skali, Lemuel Moyé, Eugene Braunwald, Marc A. Pfeffer
Journal: Circulation (2002)

Background— Diabetic patients are at increased risk for heart failure (HF) and other adverse events after myocardial infarction (MI). Left ventricular (LV) enlargement after MI is also associated with the same increased risk. We used data from the Survival and Ventricular Enlargement (SAVE) echocardiographic substudy to test the hypothesis that diabetes was associated with increased LV enlargement after MI. Methods and Results— Four hundred twelve nondiabetic and 100 diabetic patients underwent echocardiographic assessment at baseline and 3 months, 1 year, and 2 years after MI. HF developed in 30% of diabetic and 17% of nondiabetic patients during follow-up ( P &lt;0.001). Baseline LV diastolic size, ejection fraction, and infarct segment length were similar between diabetic and nondiabetic patients. Diabetic patients demonstrated less LV enlargement between baseline and 2 years than nondiabetic patients (0.9±11.1 cm 2 versus 3.8±10.9 cm 2 , P =0.047). In patients who developed HF, LV diastolic dilatation (10.0±12.4 cm 2 versus 3.7±13.1 cm 2 , P =0.06) and systolic dilatation (4.6±11.8 versus 0.91±12.1, P =0.017) were greater in nondiabetic than in diabetic patients. LV dilatation between baseline and 2 years was a predictor of HF in nondiabetic patients, but not in diabetic patients, even after excluding patients with recurrent MI and adjusting for history of hypertension, prior MI, age, treatment group, and smoking. Diabetes modified the relationship between ventricular enlargement and the risk of HF ( P =0.011). Conclusions— The increased incidence of HF after MI in diabetic patients is not explained by a greater propensity for LV remodeling.
Fluorescent Imaging of a Dual-Pathway Atrioventricular-Nodal Conduction System
Authors: Vladimir Nikolski, Igor R. Efimov
Journal: Circulation Research (2001)

A dual-pathway theory to explain atrioventricular-nodal (AVN) reentry has been proposed previously. However, the exact anatomical and functional correlates of the fast pathway (FP) and slow pathway (SP) have not yet been elucidated. We used optical mapping to reconstruct patterns of activation during retrograde conduction through the AVN and during AVN reentry in the triangles of Koch of 12 rabbits. Reentry was inducible by a premature stimulation of the bundle of His in 6 preparations (50%). A functional FP and SP appear to be anatomically correlated with posterior and posterolateral extensions of the AVN, which were recently described. Retrograde breakthrough points in 6 noninducible preparations were clustered near the apex of the triangle of Koch (FP), whereas 6 inducible preparations had either cycle length-dependent FP and SP exits (n=3) or only SP exits located near the coronary sinus orifice. The shift of breakthrough points from FP to SP during progressive shortening of the coupling interval was accompanied by a discontinuity in the conduction curve. We observed a transmural reentrant circuit involving the AVN, FP, SP, and the superficial endocardial layer of atrial and transitional cells. The presence of a functional SP during retrograde conduction was associated with inducibility of AVN reentry. The full text of this article is available at http://www.circresaha.org.
Nitric Oxide Regulates Shear Stress–Induced Early Growth Response-1
Authors: J. J. Chiu, B. S. Wung, H. J. Hsieh, L. W. Lo, D. L. Wang
Journal: Circulation Research (1999)

Abstract —Endothelial cells (ECs) subjected to shear stress constantly release nitric oxide (NO). The effect of NO on shear stress–induced endothelial responses was examined. ECs subjected to shear stress induced a transient and shear force–dependent increase in early growth response-1 (Egr-1) mRNA levels. Treatment of ECs with an NO donor, S -nitroso- N -acetylpenicillamine (SNAP) or 3-morpholinosydnonimine (SIN-1), inhibited this shear stress–induced Egr-1 expression. Conversely, an NO synthase inhibitor to ECs, N G -monomethyl- l -arginine, augmented this Egr-1 expression. NO modulation of Egr-1 expression was demonstrated by functional analysis of Egr-1 promoter activity using a chimera containing the Egr-1 promoter region (–698 bp) and reporter gene luciferase. In contrast to the enhanced promoter activity after N G -monomethyl- l -arginine treatment, shear stress–induced Egr-1 promoter activity was attenuated after ECs were treated with an NO donor. ECs cotransfected with a dominant negative mutant of Ras (RasN17), Raf-1 (Raf301), or a catalytically inactive mutant of extracellular signal–regulated kinase (ERK)–2 (mERK) inhibited shear stress–induced Egr-1 promoter activity. NO modulation of the signaling pathway was shown by its inhibitory effect on shear stress–induced ERK1/ERK2 phosphorylation and activity. This inhibitory effect was further substantiated by the inhibition of NO on both the shear stress–induced transcriptional activity of Elk-1 (an ERK substrate) and the promoter activity of a reporter construct containing serum response element. NO-treated ECs resulted in a reduction of binding of nuclear proteins to the Egr-1 binding sequences in the platelet-derived growth factor-A promoter region. These results indicate that shear stress–induced Egr-1 expression is modulated by NO via the ERK signaling pathway in ECs. Our findings support the importance of NO as a negative regulator in endothelial responses to hemodynamic forces.
Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects
Authors: C L M Krieckaert, S C Nair, M T Nurmohamed, C J J van Dongen, W F Lems, F P J G Lafeber, J W J Bijlsma, H Koffijberg, G Wolbink, P M J Welsing
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To evaluate the cost-effectiveness of personalised treatment for rheumatoid arthritis (RA) using clinical response and serum adalimumab levels. <h3>Methods</h3> A personalised treatment algorithm defined, based on clinical (European League Against Rheumatism) response and drug levels at 6 months, whether adalimumab treatment should be continued in a specific dose or discontinued and/or switched to a next biological. Outcomes were simulated using a patient level Markov model, with 3 months cycles, based on a cohort of 272 adalimumab-treated patients with RA for 3 years and data of patients from the Utrecht Rheumatoid Arthritis Cohort. Costs, clinical effectiveness and quality adjusted life years (QALYs) were compared with outcomes as observed in usual care and incremental cost-effectiveness ratios were calculated. Analyses were performed probabilistically. <h3>Results</h3> Clinical effectiveness was higher for the cohort simulated to receive personalised care compared with usual care; the average difference in QALYs was 3.84 (95 percentile range −8.39 to 16.20). Costs were saved on drugs: €2 314 354. Testing costs amounted to €10 872. Mean total savings were €2 561 648 (95 percentile range −3 252 529 to −1 898 087), resulting in an incremental cost-effectiveness ratio of €666 500 or €646 266 saved per QALY gained from a societal or healthcare perspective, respectively. In 72% of simulations personalised care saved costs and resulted in more QALYs, in 28% it was cost saving with lower QALYs. Scenario analyses showed cost saving along with QALYs gain or limited loss. <h3>Conclusions</h3> Tailoring biological treatment to individual patients with RA starting adalimumab using drug levels and short-term outcome is cost-effective. Results underscore the potential merit of personalised biological treatment in RA.
Prospective Study of Incidence and Severity of Epiphora and Canalicular Stenosis in Patients With Metastatic Breast Cancer Receiving Docetaxel
Authors: Bita Esmaeli, Sapna Amin, Vicente Valero, Rosnie Adinin, Rebecca Arbuckle, Roberto Banay, Kim-Anh Do, Edgardo Rivera
Journal: Journal of Clinical Oncology (2006)

To determine the incidence and severity of epiphora and canalicular stenosis in patients receiving docetaxel weekly or every 3 weeks.In this prospective trial, each patient underwent an ophthalmologic examination and probing and irrigation of the lacrimal drainage apparatus at baseline and every 4 to 6 weeks after initiation of docetaxel. During each visit, epiphora and canalicular stenosis were graded. Patients with epiphora were treated with tobramycin and dexamethasone drops. If epiphora worsened or if findings on probing and irrigation suggested further canalicular narrowing, silicone intubation was offered.Twenty-eight patients received docetaxel weekly, and 28 patients received docetaxel every 3 weeks. Eighteen patients (64%) who received weekly docetaxel developed epiphora. Epiphora was mild in seven patients, moderate in five, and severe in six. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Nine patients had worsened canalicular stenosis; six underwent surgery. The median cumulative docetaxel dose was 496.5 mg at onset of epiphora and 889.5 mg at surgery. Eleven patients (39%) who received docetaxel every 3 weeks developed epiphora. The median cumulative docetaxel dose at onset of epiphora in this group was 420 mg. Epiphora was mild in nine patients, moderate in one, and severe in one. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Two patients underwent surgery.Epiphora occurred in 64% of patients in the weekly group and in 39% of patients in the every-3-weeks group. Moderate or severe canalicular stenosis was seen in about one-third of patients in the weekly group and in none of the patients in the every-3-weeks group.
Intergenerational genomic DNA methylation patterns in mouse hybrid strains
Authors: Luz D Orozco, Liudmilla Rubbi, Lisa J Martin, Fang Fang, Farhad Hormozdiari, Nam Che, Andrew D Smith, Aldons J Lusis, Matteo Pellegrini
Journal: Genome biology (2014)

DNA methylation is a contributing factor to both rare and common human diseases, and plays a major role in development and gene silencing. While the variation of DNA methylation among individuals has been partially characterized, the degree to which methylation patterns are preserved across generations is still poorly understood. To determine the extent of methylation differences between two generations of mice we examined DNA methylation patterns in the livers of eight parental and F1 mice from C57BL/6J and DBA/2J mouse strains using bisulfite sequencing. We find a large proportion of reproducible methylation differences between C57BL/6J and DBA/2J chromosomes in CpGs, which are highly heritable between parent and F1 mice. We also find sex differences in methylation levels in 396 genes, and 11% of these are differentially expressed between females and males. Using a recently developed approach to identify allelically methylated regions independently of genotypic differences, we identify 112 novel putative imprinted genes and microRNAs, and validate imprinting at the RNA level in 10 of these genes. The majority of DNA methylation differences among individuals are associated with genetic differences, and a much smaller proportion of these epigenetic differences are due to sex, imprinting or stochastic intergenerational effects. Epigenetic differences can be a determining factor in heritable traits and should be considered in association studies for molecular and clinical traits, as we observed that methylation differences in the mouse model are highly heritable and can have functional consequences on molecular traits such as gene expression.
Tracheal damage after endotracheal intubation: comparison of two types of endotracheal tubes.
Authors: D Honeybourne, J C Costello, C Barham
Journal: Thorax (1982)

Twenty-eight patients who required endotracheal intubation for open-heart surgery were randomly allocated to one of two types of endotracheal tube.The tracheal mucosa was examined with a fibreoptic bronchoscope at the time of extubation, usually 24 hours after opera- tion.The degree of oedema, inflammation, and ulceration was scored by the bronchoscopist, who also photographed the whole length of the trachea.An independent observer subsequently scored any tracheal damage from these photographs.Both observers found significantly less mucosal damage with the low-pressure, high-volume type of cuff than with the traditional high- pressure, low-volume type.This difference may be related to the differences in lateral wall pressures exerted by the two types of cuff.The low-pressure type of cuff may be preferable in patients requiring prolonged endotracheal intubation.
Preclinical <i>In vivo</i> Study of New Insulin-Like Growth Factor-I Receptor–Specific Inhibitor in Ewing's Sarcoma
Authors: Maria C. Manara, Lorena Landuzzi, Patrizia Nanni, Giordano Nicoletti, Diana Zambelli, Pier Luigi Lollini, Cristina Nanni, Francesco Hofmann, Carlos García-Echeverría, Piero Picci, Katia Scotlandi
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Small-molecule insulin-like growth factor-I receptor (IGF-IR)-specific tyrosine kinase inhibitors have been recently proposed as clinically viable approaches to impair IGF-IR functions. NVP-AEW541 seems one of the most promising agents. In this article, we point out its effects against migration, metastasis, vasculogenicity, and angiogenesis of Ewing's sarcoma cells. Experimental Design: In vivo NVP-AEW541 effectiveness was analyzed against TC-71 Ewing's sarcoma growth and bone metastasis after cell inoculation in athymic mice. Activity of the compound against angiogenesis as well as vasculogenesis properties was also considered both in vitro and in xenografts. Serum glucose, urea, transaminase levels, as well as other signs of distress were checked in mice treated with the IGF-IR inhibitor. Results: Significant inhibition of migration, metastasis, vasculogenicity, and angiogenesis was recorded after treatment of Ewing's sarcoma cells with NVP-AEW541. In view of its application and the similarity of insulin receptor and IGF-IR, diabetogenic side effects were considered. We observed a significant decrease of glucose blood serum due to increased glucose uptake at cellular level and an increase in urea concentration. Moreover, an initial weight loss was observed in mice bearing tumors. All these side effects were similarly detected in mice treated with vincristine. After the first days of treatment, all the animals started to grow again. Conclusions: Our results globally reinforce the idea that IGF-IR inhibitor NVP-AEW541 could have a role in future combined therapies and suggest to pursue a thorough molecular analysis of the metabolic activity of IGF-IR to avoid possible side effects of these inhibitors.
Aspirin Use and the Risk of Prostate Cancer Mortality in Men Treated With Prostatectomy or Radiotherapy
Authors: Kevin S. Choe, Janet E. Cowan, June M. Chan, Peter R. Carroll, Anthony V. D'Amico, Stanley L. Liauw
Journal: Journal of Clinical Oncology (2012)

Purpose Experimental evidence suggests that anticoagulants (ACs) may inhibit cancer growth and metastasis, but clinical data have been limited. We investigated whether use of ACs was associated with the risk of death from prostate cancer. Patients and Methods This study comprised 5,955 men in the Cancer of the Prostate Strategic Urologic Research Endeavor database with localized adenocarcinoma of the prostate treated with radical prostatectomy (RP) or radiotherapy (RT). Of them, 2,175 (37%) were receiving ACs (warfarin, clopidogrel, enoxaparin, and/or aspirin). The risk of prostate cancer–specific mortality (PCSM) was compared between the AC and non-AC groups. Results After a median follow-up of 70 months, risk of PCSM was significantly lower in the AC group compared with the non-AC group (3% v 8% at 10 years; P &lt; .01). The risks of disease recurrence and bone metastasis were also significantly lower. In a subgroup analysis by clinical risk category, the reduction in PCSM was most prominent in patients with high-risk disease (4% v 19% at 10 years; P &lt; .01). The benefit from AC was present across treatment modalities (RT or RP). Analysis by type of AC medication suggested that the PCSM reduction was primarily associated with aspirin. Multivariable analysis indicated that aspirin use was independently associated with a lower risk of PCSM (adjusted hazard ratio, 0.43; 95% CI, 0.21 to 0.87; P = .02). Conclusion AC therapy, particularly aspirin, was associated with a reduced risk of PCSM in men treated with RT or RP for prostate cancer. The association was most prominent in patients with high-risk disease.
Prevention of Azoxymethane-Induced Colon Cancer by Combination of Low Doses of Atorvastatin, Aspirin, and Celecoxib in F 344 Rats
Authors: Bandaru S. Reddy, Chung Xiou Wang, Ah-Ng Kong, Tin Oo Khor, Xi Zheng, Vernon E. Steele, Levy Kopelovich, Chinthalapally V. Rao
Journal: Cancer Research (2006)

Abstract Preclinical and clinical studies have provided evidence that aspirin, celecoxib, (cyclooxygenase-2 inhibitor), and statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) inhibit colon carcinogenesis. Chronic use of high doses of these agents may induce side effects in ostensibly normal individuals. Combining low doses of agents may be an effective way to increase their efficacy and minimize toxicity. We assessed the efficacy of atorvastatin (lipitor), celecoxib, and aspirin, given individually at high dose levels and in combination at lower doses against azoxymethane-induced colon carcinogenesis, in male F 344 rats. One day after the last azoxymethane treatment (15 mg/kg body weight, s.c., once weekly for 2 weeks), groups of male F 344 rats were fed the AIN-76A diet or AIN-76A diet containing 150 ppm atorvastatin, 600 ppm celecoxib, and 400 ppm aspirin, 100 ppm atorvastatin + 300 ppm celecoxib, and 100 ppm atorvastatin + 200 ppm aspirin. Rats were killed 42 weeks later, and colon tumors were processed histopathologically and analyzed for cell proliferation and apoptosis immunohistochemically. Administration of these agents individually and in combination significantly suppressed the incidence and multiplicity of colon adenocarcinomas. Low doses of these agents in combination inhibited colon carcinogenesis more effectively than when they were given individually at higher doses. Inhibition of colon carcinogenesis by these agents is associated with the inhibition of cell proliferation and increase in apoptosis in colon tumors. These observations are of clinical significance because this can pave the way for the use of combinations of these agents in small doses against colon cancer. (Cancer Res 2006; 66(8): 4542-6)