tbuckley/cabot-search huggingface dataset:
Sodium-Coupled Glucose Transporter as a Functional Glucose Sensor of Retinal Microvascular Circulation
Authors: Masanori Wakisaka, Takanari Kitazono, Masako Kato, Udai Nakamura, Maki Yoshioka, Yuji Uchizono, Mototaka Yoshinari
Journal: Circulation Research (2001)

To clarify the function of the Na(+)-coupled glucose transporter in the regulation of cellular tone of cultured retinal pericytes, we investigated the effects of extracellular glucose concentration on cell size. The surface area and diameter of cultured bovine retinal pericytes under different glucose concentrations were measured by using a light microscope with a digital camera. We also examined the effects of extracellular Na(+) and Ca(2+), inhibitors of the Na(+)-coupled glucose transporter and Na(+)-Ca(2+) exchanger, a Ca(2+) channel blocker, and nonmetabolizable sugars on cell size. The surface area and diameter of the cells changed according to extracellular glucose concentrations. alpha-Methyl glucoside, which enters the cell through the Na(+)-coupled glucose transporter, induced cellular contraction. However, the cells did not contract in response to 2-deoxyglucose, which enters the cell through a facilitated glucose transporter. Glucose-induced cellular contraction was abolished in the absence of extracellular Na(+) and Ca(2+). Moreover, phlorizin, an inhibitor of the Na(+)-coupled glucose transporter, and 2',4'-dichlorobenzamil-HCl, an inhibitor of the Na(+)-Ca(2+) exchanger, also abolished glucose-induced cellular contraction, whereas nicardipine, a Ca(2+) channel blocker, did not. Our results indicate that high extracellular glucose concentrations induce contraction of bovine retinal pericytes via Na(+) entry through a Na(+)-coupled glucose transporter, suggesting that the Na(+)-coupled glucose transporter may act as a functional glucose sensor of retinal microvascular circulation.>
Phase 1 Study of AMG 386, a Selective Angiopoietin 1/2–Neutralizing Peptibody, in Combination with Chemotherapy in Adults with Advanced Solid Tumors
Authors: Alain C. Mita, Chris H. Takimoto, Monica Mita, Anthony Tolcher, Kamalesh Sankhala, John Sarantopoulos, Manuel Valdivieso, Leslie Wood, Erik Rasmussen, Yu-Nien Sun, Z. Don Zhong, Michael B. Bass, NgocDiep Le, Patricia LoRusso
Journal: Clinical Cancer Research (2010)

To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors.Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed.Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease > or =8 weeks (n = 13), and progressive disease (n = 1).Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations.
Epigenetic changes within the promoter region of the HLA-G gene in ovarian tumors
Authors: Laura Menendez, L DeEtte Walker, Lilya V Matyunina, Kimberly A Totten, Benedict B Benigno, John F McDonald
Journal: Molecular Cancer (2008)

Abstract Background Previous findings have suggested that epigenetic-mediated HLA-G expression in tumor cells may be associated with resistance to host immunosurveillance. To explore the potential role of DNA methylation on HLA-G expression in ovarian cancer, we correlated differences in HLA-G expression with methylation changes within the HLA-G regulatory region in an ovarian cancer cell line treated with 5-aza-deoxycytidine (5-aza-dC) and in malignant and benign ovarian tumor samples and ovarian surface epithelial cells (OSE) isolated from patients with normal ovaries. Results A region containing an intact hypoxia response element (HRE) remained completely methylated in the cell line after treatment with 5-aza-dC and was completely methylated in all of the ovarian tumor (malignant and benign) samples examined, but only variably methylated in normal OSE samples. HLA-G expression was significantly increased in the 5-aza-dC treated cell line but no significant difference was detected between the tumor and OSE samples examined. Conclusion Since HRE is the binding site of a known repressor of HLA-G expression (HIF-1), we hypothesize that methylation of the region surrounding the HRE may help maintain the potential for expression of HLA-G in ovarian tumors. The fact that no correlation exists between methylation and HLA-G gene expression between ovarian tumor samples and OSE, suggests that changes in methylation may be necessary but not sufficient for HLA-G expression in ovarian cancer.
Improving Patient Safety in Clinical Oncology
Authors: Bhishamjit S. Chera, Lukasz Mazur, Ian Buchanan, Hong Jin Kim, John Rockwell, Matthew I. Milowsky, Lawrence B. Marks
Journal: JAMA Oncology (2015)

Concerns for patient safety persist in clinical oncology. Within several nonmedical areas (eg, aviation, nuclear power), concepts from Normal Accident Theory (NAT), a framework for analyzing failure potential within and between systems, have been successfully applied to better understand system performance and improve system safety. Clinical oncology practice is interprofessional and interdisciplinary, and our therapies often have narrow therapeutic windows. Thus, many of our processes are, in NAT terms,<i>interactively complex</i>and<i>tightly coupled</i>within and across systems and are therefore prone to unexpected behaviors that can result in substantial patient harm. To improve safety at the University of North Carolina, we have applied the concepts of NAT to our practice to better understand our systems’ behavior and adopted strategies to reduce complexity and coupling. Furthermore, recognizing that we cannot eliminate all risks, we have stressed safety mindfulness among our staff to further promote safety. Many specific examples are provided herein. The lessons from NAT are translatable to clinical oncology and may help to promote safety.
Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232
Authors: Michael J. Borowitz, Brent L. Wood, Meenakshi Devidas, Mignon L. Loh, Elizabeth A. Raetz, Wanda L. Salzer, James B. Nachman, Andrew J. Carroll, Nyla A. Heerema, Julie M. Gastier-Foster, Cheryl L. Willman, Yunfeng Dai, Naomi J. Winick, Stephen P. Hunger, William L. Carroll, Eric Larsen
Journal: Blood (2015)
ASK1 promotes maladaptive remodeling in a rodent model of pulmonary hypertension
Authors: John Liles, Grant Budas, Faquan Liang, Dillon Phan, Sarah Fernandes, Jessie Jia, Jason Oliver, Lina Yao, Liguo Chi, Arvinder Dhalla, Luiz Belardinelli
Journal: European Respiratory Journal (2014)

Background: Apoptosis Signal-regulating Kinase 1 (ASK1) is a redox-sensitive kinase that stimulates inflammatory and fibrotic pathways via activation of p38 and c-Jun N-terminal kinase (JNK). Patients with pulmonary hypertension (PH) have increased oxidative stress and p38 activation, which are believed to drive maladaptive remodeling of the right ventricle (RV) and the pulmonary vasculature.

Aim: Evaluate efficacy of a selective ASK1 inhibitor on RV and pulmonary vascular remodeling in a model of PH.

Methods: Monocrotaline (MCT, 60 mg/kg) was injected in rats to induce PH and 1 week later a small molecule inhibitor of ASK1 (GS-444217) was administered orally to achieve EC50 or EC90 levels (n=8-10). 1-4 weeks following MCT, ASK1 signaling (p-ASK1, p-p38 and p-JNK), gene expression (CTGF, TIMP-1, MCP-1), pulmonary hemodynamics, RV hypertrophy (RVH) and function, and pulmonary vascular endpoints (vessel wall thickness and endothelium-dependent vasodilator response) were evaluated.

Results: p-ASK1 increased and correlated with progression of PH and RVH. GS-444217 dose-dependently reduced PH, RVH, and maladaptive gene expression in the RV; and reduced plasma biomarkers (BNP, TIMP-1). RV ejection fraction decreased in rats with PH and was attenuated by 50% with GS-444217. GS-444217 also decreased vascular wall hypertrophy by 50%, and restored the maximal relaxation to acetylcholine (46 vs. 24%) compared to PH. Exposures >15-fold above EC90 had no effect on pulmonary or systemic hemodynamics in normal animals.

Conclusion: An orally administered ASK1 inhibitor dose-dependently reduced maladaptive remodeling of the RV and pulmonary vasculature, with corresponding increases in RV function and vasoreactivity.
Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis
Authors: C.E. Brightling, R. Ward, A.j Wardlaw, I.d Pavord
Journal: European Respiratory Journal (2000)

Eosinophilic bronchitis is a common cause of chronic cough, characterized by sputum eosinophilia similar to that seen in asthma, but unlike asthma the patients have no objective evidence of variable airflow obstruction or airway hyperresponsiveness. The reason for the different functional associations is unclear. The authors have tested the hypothesis that in eosinophilic bronchitis the inflammation is mainly localized in the upper airway. In an open study the authors measured the lower (provocative concentration causing a 20% fall in forced expiratory volume in one second (PC20)) and upper (PC25 MIF50) airway responsiveness to histamine, lower and upper airway inflammation using induced sputum and nasal lavage, in II patients with eosinophilic bronchitis. The authors assessed changes in these measures and in cough reflex sensitivity to capsaicin and cough severity after 400 microg of inhaled budesonide for 4 weeks. A nasal eosinophilia was present in only three patients with one having upper airway hyperresponsiveness. Following treatment with inhaled corticosteroids the geometric mean sputum eosinophil count decreased from 12.8% to 2.9% (mean difference 4.4-fold, 95% confidence interval (CI) 2.14-10.02), the mean +/- sem cough visual analogue score on a 100 mm scale decreased from 27.2 +/- 6.6 mm to 12.6 +/- 5.7 mm (mean difference 14.6, 95% CI 9.1-20.1) and the cough sensitivity assessed as the capsaicin concentration required to cause two coughs (C2) and five coughs (C5) improved (C2 mean difference 0.75 doubling concentrations, 95% CI 0.36-1.1; C5 mean difference 1.3 doubling concentration, 95% CI 0.6-2.1). There was a significant positive correlation between the fold change in sputum eosinophil count and doubling dose change in C5 after inhaled budesonide (r=0.61). It is concluded that upper airway inflammation is not prominent in eosinophilic bronchitis and that inhaled budesonide improves the sputum eosinophilia, cough severity and sensitivity suggesting a causal link between the inflammation and cough.
The Availability of Web Sites Offering to Sell Opioid Medications Without Prescriptions
Authors: Robert Forman
Journal: American Journal of Psychiatry (2006)

Objective: This study was designed to determine the availability of web sites offering to sell opioid medications without prescriptions. Method: Forty-seven Internet searches were conducted with a variety of opioid medication terms, including "codeine," "no prescription Vicodin," and "OxyContin." Two independent raters examined the links generated in each search and resolved any coding disagreements. The resulting links were coded as "no prescription web sites" (NPWs) if they offered to sell opioid medications without prescriptions. Results: In searches with terms such as "no prescription codeine" and "Vicodin," over 50% of the links obtained were coded as "NPWs." The proportion of links yielding NPWs was greater when the phrase "no prescription" was added to the opioid term. More than 300 opioid NPWs were identified and entered into a database. Conclusions: Three national drug-use monitoring studies have cited significant increases in prescription opioid use over the past 5 years, particularly among young people. The emergence of NPWs introduces a new vector for unregulated access to opioids. Research is needed to determine the effect of NPWs on prescription opioid use initiation, misuse, and dependence.
Genetic Control Of Natural Killing and In Vivo Tumor Elimination by the Chok Locus
Authors: Azza H. Idris, Koho Iizuka, Hamish R.C. Smith, Anthony A. Scalzo, Wayne M. Yokoyama
Journal: The Journal of Experimental Medicine (1998)

The molecular mechanisms underlying target recognition during natural killing are not well understood. One approach to dissect the complexities of natural killer (NK) cell recognition is through exploitation of genetic differences among inbred mouse strains. In this study, we determined that interleukin 2–activated BALB/c-derived NK cells could not lyse Chinese hamster ovary (CHO) cells as efficiently as C57BL/6-derived NK cells, despite equivalent capacity to kill other targets. This strain-determined difference was also exhibited by freshly isolated NK cells, and was determined to be independent of host major histocompatibility haplotype. Furthermore, CHO killing did not correlate with expression of NK1.1 or 2B4 activation molecules. Genetic mapping studies revealed linkage between the locus influencing CHO killing, termed Chok, and loci encoded within the NK gene complex (NKC), suggesting that Chok encodes an NK cell receptor specific for CHO cells. In vivo assays recapitulated the in vitro data, and both studies determined that Chok regulates an NK perforin–dependent cytotoxic process. These results may have implications for the role of NK cells in xenograft rejection. Our genetic analysis suggests Chok is a single locus that affects NK cell–mediated cytotoxicity similar to other NKC loci that also regulate the complex activity of NK cells.
Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy
Authors: Long Shuang Huang, Evgeny V Berdyshev, John T Tran, Lishi Xie, Jiwang Chen, David L Ebenezer, Biji Mathew, Irina Gorshkova, Wei Zhang, Sekhar P Reddy, Anantha Harijith, Gang Wang, Carol Feghali-Bostwick, Imre Noth, Shwu-Fan Ma, Tong Zhou, Wenli Ma, Joe G N Garcia, Viswanathan Natarajan
Journal: Thorax (2015)

<h3>Introduction</h3> Idiopathic pulmonary fibrosis (IPF) is characterised by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. Sphingosine-1-phosphate (S1P) signalling plays a critical role in pulmonary fibrosis. <h3>Methods</h3> S1P lyase (S1PL) expression in peripheral blood mononuclear cells (PBMCs) was correlated with pulmonary functions and overall survival; used a murine model to check the role of S1PL on the fibrogenesis and a cell culture system to study the effect of S1PL expression on transforming growth factor (TGF)-β- and S1P-induced fibroblast differentiation. <h3>Results</h3> S1PL expression was upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with IPF and bleomycin-challenged mice. TGF-β increased the expression of S1PL in human lung fibroblasts via activation and binding of Smad3 transcription factor to Sgpl1 promoter. Overexpression of S1PL attenuated TGF-β-induced and S1P-induced differentiation of human lung fibroblasts through regulation of the expression of LC3 and beclin 1. Knockdown of S1PL (<i>Sgpl1<sup>+/−</sup></i>) in mice augmented bleomycin-induced pulmonary fibrosis, and patients with IPF reduced <i>Sgpl1</i> mRNA expression in PBMCs exhibited higher severity of fibrosis and lower survival rate. <h3>Conclusion</h3> These studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.
Shoulder laxity and traumatic shoulder instability in professional rugby players
Authors: Ziali Sivardeen, Shih Chung Cheng, Donald Buchanan, David Hulse, K Julia Fairbairn, Simon Patrick Thomas Kemp, John Huw Meirion Brooks, William Angus Wallace
Journal: British Journal of Sports Medicine (2011)

Objective This study aimed to see whether the risk of shoulder dislocation is associated with innate shoulder laxity, in professional rugby players. Methodology We performed a pilot study where we validated techniques we used in the study and subsequently gained ethics committee approval. We visited all the premiership rugby clubs in England and assessed 169 professional rugby players with no history of shoulder instability and 46 players with clinical instability symptoms in one shoulder. We assessed shoulder laxity by means of clinical evaluation, questionnaires and ultrasound. Previous studies have shown no difference in shoulder laxity in left and right shoulders in normal individuals. We therefore compared the laxity in the uninjured shoulder of players with a previous history of dislocation, with the shoulders of players with no history of shoulder injury. Data was analysed by unpaired t tests. Results The results showed there was no significant difference between the left and right shoulders in players with no history of instability (p&gt;0.05). Players with a history of instability had a significantly higher shoulder translation in their normal shoulder than uninjured players (p&lt;0.05). Players with an anterior laxity of at least 4 mm had a 50% chance of sustaining a dislocation. There was no correlation between, the age of the player, dominant hand or position played and the incidence of increased laxity. Conclusions This is the first study looking at laxity and the risk of shoulder dislocations in sportsmen involved in a high contact sport. These results support the hypothesis that rugby players with ‘lax’ shoulders are more likely to sustain a dislocation or subluxation injury to one of these lax shoulders in their sport. We believe preseason screening and targeted training may play a role in identifying those at risk and may decrease the incidence of dislocations.
Biochemical Basis of Malignant Hyperpyrexia
Authors: R. F. W. Moulds, M. A. Denborough
Journal: BMJ (1974)

Pharmacologically-induced muscle contracture in vitro has been used as a model to study the biochemical basis of malignant hyperpyrexia. In 15 susceptible subjects halothane, succinylcholine, and potassium chloride all produced an abnormal muscle contracture, and the caffeine-induced contracture was greater than normal. The contractures were reproducible only in the presence of extracellular calcium ions. The fact that such dissimilar pharmacological stimuli all induced contracture in the affected muscle suggests that the essential abnormality in the muscle cell in malignant hyperpyrexia is an impaired binding of calcium ions to the membranes of the sarcoplasmic reticulum and the sarcolemma. Exposure of these membranes to halothane, succinylcholine, and other anaesthetic agents then leads to a rapid and abnormally large release of calcium into the myoplasm, which in turn gives rise to all the clinical features of the syndrome.
Brainstem Control of Saccadic Eye Movements
Authors: A. F. Fuchs, C. R. S. Kaneko, C. A. Scudder
Journal: Annual Review of Neuroscience (1985)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Discussing randomised clinical trials of cancer therapy: evaluation of a Cancer Research UK training programme
Authors: V Jenkins, L Fallowfield, I Solis-Trapala, C Langridge, V Farewell
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To evaluate a training intervention aimed at improving healthcare professionals9 communication with cancer patients about randomised clinical trials. <b>Design</b> Before and after evaluation of training programme. <b>Setting</b> Members of the National Cancer Research Network, Scottish Trials Network, and the Welsh Cancer Trials Network <b>Participants</b> 101 healthcare professionals (33 clinicians and 68 research nurses). <b>Intervention</b> Four modules delivered by a trained facilitator using videotapes and interactive exercises to cover general issues about discussing randomised clinical trials with patients, problems specific to adjuvant trials, trials with palliation as the goal, and trials where patients had a strong preference for one treatment arm. <b>Main outcome measures</b> Before and after the intervention, participants were videotaped discussing a trial with an actor portraying a patient. These consultations were assessed for presence of information required by good clinical practice guidelines. The actor patients gave an assessment after each interview. Participants reported their self confidence about key aspects of trial discussion. <b>Results</b> Analysis of the videotaped consultations showed that, after intervention, significantly more participants displayed key communication behaviours such as explaining randomisation (69 <i>v</i> 81, odds ratio 2.33, P = 0.033), checking patients9 understanding (11 <i>v</i> 31, odds ratio 3.22, P = 0.002), and discussing standard treatment (73 <i>v</i> 88, odds ratio 4.75, P = 0.005) and side effects (69 <i>v</i> 85, odds ratio 3.29, P = 0.006). Participants9 self confidence increased significantly (P &lt; 0.001) across all areas. Actor patients9 ratings of participants9 communication showed significant improvements for 12/15 key items. <b>Conclusion</b> This intensive 8 hour intervention significantly improved participants9 confidence and competence when communicating about randomised clinical trials.
Talk that works: the rise of cognitive behaviour therapy
Authors: G. Andrews
Journal: BMJ (1996)

I look at wealth trends from 1962 to 2013, particularly for the middle class. Asset prices plunged between 2007 and 2010 but then rebounded from 2010 to 2013. The most telling finding is that median wealth plummeted by 44 percent between 2007 and 2010, almost double the drop in housing prices. Wealth inequality, after almost two decades of little movement, was up sharply from 2007 to 2010. This sharp fall in median net worth and rise in overall wealth inequality are traceable primarily to the high leverage of middle-class families, the high share of homes in their portfolio, and the plunge in house prices. Rather remarkably, median (and mean) wealth did not essentially change from 2010 to 2013 despite the rebound in asset prices. The proximate cause was the high dissavings of the middle class. Wealth inequality also remained largely unchanged.