tbuckley/cabot-search huggingface dataset:
The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation
Authors: Ming Yan, Marie Claude Gingras, Elaine A. Dunlop, Yann Nouët, Fanny Dupuy, Zahra Jalali, Elite Possik, Barry J. Coull, Dmitri Kharitidi, Anders Bondo Dydensborg, Brandon Faubert, Miriam Kamps, Sylvie Sabourin, Rachael S. Preston, David Mark Davies, Taren Roughead, Laëtitia Chotard, Maurice A.M. Van Steensel, Russell Jones, Andrew R. Tee, Arnim Pause
Journal: Journal of Clinical Investigation (2014)

The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK-dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.
Robert Phillipson Warin and Barbara Anne Warin
Authors: J.L. Burton
Journal: British Journal of Dermatology (1993)

Journal Article Robert Phillipson Warin and Barbara Anne Warin Get access J.L. Burton J.L. Burton Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 128, Issue 2, 1 February 1993, Pages 223–224, https://doi.org/10.1111/j.1365-2133.1993.tb15157.x Published: 01 February 1993
The role of lipid droplets in metabolic disease in rodents and humans
Authors: Andrew S. Greenberg, Rosalind A. Coleman, Fredric B. Kraemer, James L. McManaman, Martin S. Obin, Vishwajeet Puri, Qing-Wu Yan, Hideaki Miyoshi, Douglas G. Mashek
Journal: Journal of Clinical Investigation (2011)

Lipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in parallel, our understanding of the role of LDs in health and disease. In its simplest form, the LD regulates the storage and hydrolysis of neutral lipids, including triacylglycerol and/or cholesterol esters. It is becoming increasingly evident that alterations in the regulation of LD physiology and metabolism influence the risk of developing metabolic diseases such as diabetes. In this review we provide an update on the role of LD-associated proteins and LDs in metabolic disease.
Effect of Food on Lapatinib Pharmacokinetics
Authors: Andrea Messori
Journal: Journal of Clinical Oncology (2007)

The Commentary also contained a suggestion that even greater cost savings might be achieved by drinking grapefruit juice with food to further boost bioavailability.This suggestion is particularly worrisome, because there is a large body of literature indicating that the effect of grapefruit juice is highly variable and can alter bioavailability in either direction due to multiple effects on metabolic enzymes and intestinal and hepatic drug transport proteins. 3,4More importantly, this would increase the risk of serious toxicity from other drugs prescribed concomitantly for these patients, such as calcium channel blockers 5 and benzodiazepines. 6 In addition to cost savings, a potential benefit was proposed in that dosing with food could increase absorption, leaving less unabsorbed drug in the gut, and thereby decrease diarrhea.Food certainly increases the bioavailability of lapatinib, but the data suggest that this is not solely due to increased absorption.In fact, the data presented at the ASCPT meeting suggested no decrease in the incidence or severity of diarrhea when lapatinib was administered with food (Table 2).Based on this clinical experience, the proposed benefit appears unlikely.Near the end of their proposed off-label dosing regimen, the authors strongly recommend against implementing the proposal in practice.This is appropriate advice, given that they had not reviewed all of the data on which the dosing recommendation was based.Like many patients who, in response to the Commentary, called the sponsor to ask if dosing with food would improve efficacy, we are all seeking ways to improve their therapy.So we welcome the scientific debate and the public reaction that reminds us of our obligation to patients who look to us for guidance in their struggle with disease.We hope that this brief discussion of the data, underlying one of the many decisions made in the course of developing a new drug, is helpful to both patients and practitioners.Development of new drugs with complex pharmacokinetic properties is a challenge we continue to take on long after they become available to patients, as we continue to examine ways in which to make dosing easier.However, until a safer and more effective regimen is demonstrated to treat patients with this drug, the dosing instructions in the US Food and Drug Administration-approved label represent the best and most reliable method to deliver lapatinib therapy to patients with breast cancer.
Hypoxaemia in chronic obstructive bronchitis.
Authors: H C Middleton, M D Peake, P Howard
Journal: Thorax (1979)

Arterial blood gas tensions were studied for six years in 85 patients (59 men, 26 women, mean age 58.8 years) with hypoxaemia associated with chronic bronchitis. All patients who died had a precipitous fall of arterial oxygen tension (PaO2) breathing air. In patients dying within two years of the first appearance of ankle oedema the mean rate of fall of PaO2 was 0.11 kPa/month. Patients who survived two years appeared to deteriorate more slowly (0.017 kPa/month) until some months before death, when they too deteriorated rapidly. Hypoxaemic patients with obstructive airways disease suffer a terminal rapid decline in arterial oxygen tension, which probably indicates real pathological change in the lungs and has important implications for long-term domiciliary oxygen treatment.
Role of kinase suppressor of Ras-1 in<i>Pseudomonas aeruginosa</i>infections
Authors: Syed Huq
Journal: Thorax (2011)

Respiratory infection with Pseudomonas aeruginosa can have serious implications, particularly on a background of immunodeficiency, cystic fibrosis and mechanical ventilation. In this study, by conducting a series of experiments on mice, the authors identified the key role of the kinase suppressor …
Antiangiogenic and Antitumoral Activity of Phenyl-3-(2-Chloroethyl)Ureas
Authors: Éric Petitclerc, Réna G. Deschesnes, Marie-France Côté, Claude Marquis, Richard Janvier, Jacques Lacroix, Élisabeth Miot-Noirault, Jean Legault, Emmanuelle Mounetou, Jean-Claude Madelmont, René C.-Gaudreault
Journal: Cancer Research (2004)

Abstract The development of new anticancer agents with lower toxicity, higher therapeutic index, and weaker tendency to induce resistant phenotypes in tumor cells is a continuous challenge for the scientific community. Toward that end, we showed previously that a new class of soft alkylating agents designed as phenyl-3-(2-chloroethyl)ureas (CEUs) inhibits tumor cell growth in vitro and that their efficiency is not altered by clinically relevant mechanisms of resistance such as overexpression of multidrug resistance proteins, increase in intracellular concentration of glutathione and/or glutathione S-transferase activity, alteration of topoisomerase II, and increased DNA repair. Mechanistic studies have showed recently that the cytotoxic activity of several CEUs was mainly related to the disruption of microtubules. Here, we present results supporting our assumption that 4-tert-butyl-[3-(2-chloroethyl)ureido]phenyl (tBCEU) (and its bioisosteric derivative 4-iodo-[3-(2-chloroethyl)ureido]phenyl (ICEU) are potent antimicrotubule agents both in vitro and in vivo. They covalently bind to β-tubulin, leading to a microtubule depolymerization phenotype, consequently disrupting the actin cytoskeleton and altering the nuclear morphology. Accordingly, tBCEU and ICEU also inhibited the migration and proliferation of endothelial and tumor cells in vitro in a dose-dependent manner. It is noteworthy that ICEU efficiently blocked angiogenesis and tumor growth in three distinct animal models: (a) the Matrigel plug angiogenesis assay; (b) the CT-26 tumor growth assay in mice; and (c) the chick chorioallantoic membrane tumor assay. In addition, we present evidence that CEU cytotoxicity is unaffected by additional resistance mechanisms impeding tumor response to DNA alkylating agents such as cisplatin, namely the cell adhesion mediated-drug resistance mechanism, which failed to influence the cytocidal activity of CEUs. On the basis of the apparent innocuousness of CEUs, on their ability to circumvent many classical and recently described tumor cell resistance mechanisms, and on their specific biodistribution to organs of the gastrointestinal tract, our results suggest that CEUs represent a promising new class of anticancer agents.
Statistics of Divergence Times
Authors: Bernhard Haubold, Thomas Wiehe
Journal: Molecular Biology and Evolution (2001)

Given the number of nucleotide substitutions between two species (K) and the substitution rate ν, the expectation of the corresponding divergence time is usually calculated as K/(2ν). This is strictly true only if ν is regarded as a constant because the ratio of two random variables, such as K/(2ν), has distributional properties different from those of the distribution of K. Therefore, both the mean and any confidence interval for divergence times are unknown in this situation. We model the distribution of K and ν using the Gamma distribution and calculate the mean and 95% confidence interval for the corresponding divergence time. These calculations are compared with results obtained by bootstrapping sequence data from the model plant Arabidopsis thaliana and its relatives. We show that for nonoverlapping pairs of phylogenetic distances, our method approaches the bootstrap results very closely. In contrast, regarding the mutation rate as a constant leads to strong underestimation of the confidence interval. An implementation of our method of computing divergence times is accessible through a web interface at http://www.soft.ice.mpg.de/cite.
The Mitochondrial Permeability Transition Pore Regulates Endothelial Bioenergetics and Angiogenesis
Authors: Raluca Marcu, Surya Kotha, Zhongwei Zhi, Wan Qin, Christopher K. Neeley, Ruikang K. Wang, Ying Zheng, Brian J. Hawkins
Journal: Circulation Research (2015)

The mitochondrial permeability transition pore is a well-known initiator of cell death that is increasingly recognized as a physiological modulator of cellular metabolism.We sought to identify how the genetic deletion of a key regulatory subunit of the mitochondrial permeability transition pore, cyclophilin D (CypD), influenced endothelial metabolism and intracellular signaling.In cultured primary human endothelial cells, genetic targeting of CypD using siRNA or shRNA resulted in a constitutive increase in mitochondrial matrix Ca(2+) and reduced nicotinamide adenine dinucleotide (NADH). Elevated matrix NADH, in turn, diminished the cytosolic NAD(+)/NADH ratio and triggered a subsequent downregulation of the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1). Downstream of SIRT1, CypD-deficient endothelial cells exhibited reduced phosphatase and tensin homolog expression and a constitutive rise in the phosphorylation of angiogenic Akt. Similar changes in SIRT1, phosphatase and tensin homolog, and Akt were also noted in the aorta and lungs of CypD knockout mice. Functionally, CypD-deficient endothelial cells and aortic tissue from CypD knockout mice exhibited a dramatic increase in angiogenesis at baseline and when exposed to vascular endothelial growth factor. The NAD(+) precursor nicotinamide mononucleotide restored the cellular NAD(+)/NADH ratio and normalized the CypD-deficient phenotype. CypD knockout mice also presented accelerated wound healing and increased neovascularization on tissue injury as monitored by optical microangiography.Our study reveals the importance of the mitochondrial permeability transition pore in the regulation of endothelial mitochondrial metabolism and vascular function. The mitochondrial regulation of SIRT1 has broad implications in the epigenetic regulation of endothelial phenotype.
Dietary Acculturation, Obesity, and Diabetes Among Chinese Immigrants in New York City
Authors: Ady Oster, Janette Yung
Journal: Diabetes Care (2010)

Only limited data are available regarding East Asians, one of the fastest growing immigrant populations in the U.S. (1–4). We conducted a cross-sectional study of the association between sociodemographic factors, Western acculturation, BMI, physical activity, and fasting glucose among Chinese immigrants attending free cardiovascular risk screening at a New York City community health center.

We obtained randomly selected venous samples from 300 of a total of 622 self-identified Chinese participants, age 18 years or older. Sociodemographic details and time since immigration were obtained. Dietary acculturation was measured using a previously validated scale relying on self-recollected consumption of Western and Chinese foods (5). Cronbach α was 0.747 for the Western and 0.338 for the Chinese scale. Age was categorized as ≤39, 40–55, …
How can we reduce the number of coroner autopsies? Lessons from Scotland and the Dundee initiative
Authors: Derrick Pounder, Matthew Jones, Heiko Peschel
Journal: Journal of the Royal Society of Medicine (2011)

Summary Currently the medicolegal dissection rate for England and Wales is 22% (110,000 coronial autopsies for 500,000 deaths per annum), yet there is a general lack of evidence about the utility of and justification for such a high level of activity, which is between double and triple the rate in other jurisdictions. The government is currently consulting on how to reduce the numbers, and the Coroners and Justice Act 2009 is permissive of external examinations as an alternative to dissections. We describe the philosophy and practice of the Scottish system of postmortem external examinations, and the 20-year experience of a local initiative to maximize use of such external examinations. Currently our regional medicolegal dissection rate is 6%, which if applied to England and Wales would reduce the number of dissections from 110,000 to 30,000 per annum, with all of the social, resource and management implications. While the autopsy is an important tool in modern death investigation, an almost automatic recourse to it is inappropriate. In our view external examinations are not only cost-effective but also a necessary element in any death investigative system which wishes to strike an appropriate balance between intrusion by the state and the rights of the bereaved.
Interpreting small differences in functional status: the Six Minute Walk test in chronic lung disease patients.
Authors: D A Redelmeier, A M Bayoumi, R S Goldstein, G H Guyatt
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Functional status measurements are often difficult to interpret because small differences may be statistically significant but not clinically significant. How much does the Six Minute Walk test (6MW) need to differ to signify a noticeable difference in walking ability for patients with chronic obstructive pulmonary disease (COPD)? We studied individuals with stable COPD (n = 112, mean age = 67 yr, mean FEV1 = 975 ml) and estimated the smallest difference in 6MW distances that was associated with a noticeable difference in patients' subjective comparison ratings of their walking ability. We found that the 6MW was significantly correlated with patients' ratings of their walking ability relative to other patients (r = 0.59, 95% confidence interval [CI]: 0.54 to 0.63). Distances needed to differ by 54 m for the average patient to stop rating themselves as "about the same" and start rating themselves as either "a little bit better" or "a little bit worse" (95% CI: 37 to 71 m). We suggest that differences in functional status can be statistically significant but below the threshold at which patients notice a difference in themselves relative to others; an awareness of the smallest difference in walking distance that is noticeable to patients may help clinicians interpret the effectiveness of symptomatic treatments for COPD.
Identification of hazelnut major allergens in sensitive patients with positive double-blind, placebo-controlled food challenge results
Authors: Elide A. Pastorello, Stefan Vieths, Valerio Pravettoni, Laura Farioli, Chiara Trambaioli, Donatella Fortunato, Dirk Lüttkopf, Marianna Calamari, Raffaella Ansaloni, Joseph Scibilia, Barbara K. Ballmer-Weber, Lars K. Poulsen, Brunello Wütrich, Kirsten Skamstrup Hansen, Anna Maria Robino, Claudio Ortolani, Amedeo Conti
Journal: Journal of Allergy and Clinical Immunology (2002)
Paclitaxel in combination with carboplatin as salvage treatment in refractory small-cell lung cancer (SCLC): A multicenter phase II study
Authors: S. Kakolyris, D. Mavroudis, N. Tsavaris, J. Souglakos, P. Tsiafaki, K. Kalbakis, S. Agelaki, N. Androulakis, V. Georgoulias
Journal: Annals of Oncology (2001)

The activity and toxicity of paclitaxel plus carboplatin combination in patients with disease progression after initial chemotherapy for small-cell lung cancer (SCLC) was investigated in a multicenter phase II study.Thirty-two patients (twenty-seven men) with extensive stage refractory SCLC after EP or CAV front-line chemotherapy were treated with paclitaxel 200 mg/m2 on day 1 and carboplatin 6 AUC on day 2 in a four-week schedule. The patients' median age was 60 years and the performance status (WHO) was 0 for 9, 1 for 20 and 2 for 3 patients. All patients were evaluable for toxicity and 29 for response.Complete response was observed in one (3%) and partial response in seven (22%) for an overall response rate of 25% (95% confidence interval (CI): 10%-40%). Seven (22%) patients had stable disease and seventeen (53%) progressive disease. All but one of the responders had been previously treated with EP combination and three of them had failed to respond. The median duration of response and the median TTP were 3 and 5.5 months, respectively. The median overall survival was seven months. Grade 3-4 neutropenia was observed in 12 (37%) patients and in 2 of these it was associated with infection. There were no toxic deaths. Grade 4 anaemia was observed in one (3%) patient and grade 3 thrombocytopenia in three (9.4%). Non-hematologic toxicity was very mild with grade 2-3 asthenia occurring in 10 (25%) patients; asthenia was the reason for treatment discontinuation in 3 patients.The combination of paclitaxel and carboplatin is a relatively active and well-tolerated regimen as salvage treatment in patients with refractory SCLC.
Adjuvant Therapy with Small Hairpin RNA Interference Prevents Non–Small Cell Lung Cancer Metastasis Development in Mice
Authors: Etmar Bulk, Antje Hascher, Ruediger Liersch, Rolf M. Mesters, Sven Diederichs, Bülent Sargin, Volker Gerke, Marc Hotfilder, Josef Vormoor, Wolfgang E. Berdel, Hubert Serve, Carsten Müller-Tidow
Journal: Cancer Research (2008)

Abstract Development of distant metastasis is the major reason for cancer-related deaths worldwide. Adjuvant therapy approaches after local therapies are most effective when specific targets are inhibited. Recently, we identified S100P overexpression as a strong predictor for metastasis development in early-stage non–small cell lung cancer (NSCLC) patients. Here, we show that S100P overexpression increased angiogenesis in and metastasis formation from s.c. xenotransplants of NSCLC cells. Plasmid-derived short hairpin RNAs (shRNA) were developed as specific adjuvant therapy. I.v. injected shRNA against S100P significantly decreased S100P protein expression in xenograft tumors and inhibited tumor angiogenesis in vivo. Metastasis formation 8 weeks after primary tumor resection was significantly reduced. Lung metastases developed in 31% of mice treated with S100P-targeting shRNAs compared with 64% in control shRNA–treated mice (P &amp;lt; 0.05). These findings suggest that RNA interference–based therapy approaches can be highly effective in the adjuvant setting. [Cancer Res 2008;68(6):1896–904]
Monoclonal Gammopathy of Undetermined Significance
Authors: Joan Bladé
Journal: New England Journal of Medicine (2006)

A 58-year-old man with no significant medical history is found to have an elevated total protein concentration (8.1 g per deciliter) on a routine blood chemical study. He is asymptomatic, and his physical examination is normal. Serum protein electrophoresis reveals a monoclonal spike of 2.1 g per deciliter at the gamma region; immunofixation shows a monoclonal IgG kappa protein. What further evaluation is warranted, and assuming the diagnosis of monoclonal gammopathy of undetermined significance is made, how should the patient be followed?
704 OVEREXPRESSION OF PD-1 DURING CHRONIC HCV (CHC) INFECTION IMPAIRS THE ANTIVIRAL FUNCTION OF CD8+ T LYMPHOCYTES
Authors: M.C. Choudhary, B. Saha, K. Dongre, S. Baweja, V. Singh, N. Trehanpati, M. Sharma, S.K. Sarin
Journal: Journal of Hepatology (2010)
Pain pressure threshold, a new way to assess dyspnea-pain counter-irritation?
Authors: Laurence Dangers, Louis Laviolette, Thomas Similowski, Capucine Morélot-Panzini
Journal: European Respiratory Journal (2013)

Introduction.Counter-irritation is the attenuation of a painful sensation by a newly occurring heterotopic stimulus that must be noxious in nature. Dyspnea-pain counter-irritation has been described with experimental dyspnea of the work/effort type, with dyspnea inhibiting laser evoked cortical potentials and RIII flexion reflex. Pain pressure threshold (PPT) using algometry is an easy to use and reliable model to induce acute experimental pain.  Objectives. Assess the effects of experimental work/effort dyspnea on PPT.  Methods. Inspiratory threshold loading was used to induce experimental dyspnea (work/effort) in 14 young and healthy volunteers. PPT were obtained using a pressure algometer at baseline and at two different intensities of dyspnea; visual analogic scale (VAS) ratings ≥ 6 and ≥ 8 cm. Force was applied incrementally on non-dominant trapeze, biceps and deltoid muscles of the subjects during 3 conditions: baseline, VAS dyspnea ≥ 6 and VAS dyspnea ≥ 8.  Results. PPT increased significantly with increasing dyspnea ratings; trapeze (35.3 N to 44.2 N to 46.3 N ; F = 8.3, p = 0.01), biceps (29.2 N to 33.7 N to 42.0 N ; F = 13, p = 0.001) and deltoid (41 N to 50.1 N to 52.9 N ; F = 8.7, p = 0,01) for baseline, VAS dyspnea ≥ 6 and VAS dyspnea ≥ 8 respectively. Dunn’s multiple comparison test showed that VAS dyspnea ≥ 6 significantly increased PPT for the deltoid only, while VAS dyspnea ≥ 8 increased PPT for all 3 muscle sites.  Conclusion. Work/effort dyspnea signifcantly increases PPT, with an apparent dose-response relationship. PPT is an easy to use method for assessing dyspnea-pain counter-irritation, that could be used to indirectly but more objectively measure dyspnea in clinical populations.