tbuckley/cabot-search huggingface dataset:
Whole-Body Protein Turnover in Humans—Past, Present, and Future
Authors: J. C. Waterlow
Journal: Annual Review of Nutrition (1995)

Protein turnover is a fundamental biological process in all living organisms. The study of protein turnover in human subjects, and in the body as a whole, is of relatively recent origin. In this review, I summarize briefly how this field of work has expanded over the past 25 years, with emphasis on conceptual problems and controversies, particularly those related to methods of measurement. We cannot be certain that our estimates are accurate because no method of verification exists, but progress will be made through successive approximations. Some of the applications are described in different physiological and pathological states such as growth and trauma, and possible directions for fruitful future research are indicated.
A Systematic Survey of an Intragenic Epistatic Landscape
Authors: Claudia Bank, Ryan T. Hietpas, Jeffrey D. Jensen, Daniel N.A. Bolon
Journal: Molecular Biology and Evolution (2014)

Mutations are the source of evolutionary variation. The interactions of multiple mutations can have important effects on fitness and evolutionary trajectories. We have recently described the distribution of fitness effects of all single mutations for a nine-amino-acid region of yeast Hsp90 (Hsp82) implicated in substrate binding. Here, we report and discuss the distribution of intragenic epistatic effects within this region in seven Hsp90 point mutant backgrounds of neutral to slightly deleterious effect, resulting in an analysis of more than 1,000 double mutants. We find negative epistasis between substitutions to be common, and positive epistasis to be rare—resulting in a pattern that indicates a drastic change in the distribution of fitness effects one step away from the wild type. This can be well explained by a concave relationship between phenotype and genotype (i.e., a concave shape of the local fitness landscape), suggesting mutational robustness intrinsic to the local sequence space. Structural analyses indicate that, in this region, epistatic effects are most pronounced when a solvent-inaccessible position is involved in the interaction. In contrast, all 18 observations of positive epistasis involved at least one mutation at a solvent-exposed position. By combining the analysis of evolutionary and biophysical properties of an epistatic landscape, these results contribute to a more detailed understanding of the complexity of protein evolution.
O6-benzylguanine in humans: metabolic, pharmacokinetic, and pharmacodynamic findings.
Authors: M E Dolan, S K Roy, A A Fasanmade, P R Paras, R L Schilsky, M J Ratain
Journal: Journal of Clinical Oncology (1998)

PURPOSE O6-Benzylguanine is a potent inactivator of the DNA-repair protein, O6-alkylguanine-DNA alkyl-transferase (AGT), that enhances sensitivity to nitrosoureas in tumor-cell lines and tumor-bearing animals. The objective of this study was to determine the pharmacokinetics and metabolic fate of O6-Benzylguanine in humans and its effect on AGT activity in peripheral-blood mononuclear cells (PBMCs). PATIENTS AND METHODS Twenty-five cancer patients were treated with O6-Benzylguanine at a dose level of 10, 20, 40, and 80 mg/m2 intravenously (IV) over 1 hour. Plasma and urine samples were collected and analyzed for O6-Benzylguanine and O6-Benzyl-8-oxoguanine concentrations. AGT activity in PBMCs was determined up to 2 weeks postinfusion. RESULTS There was no toxicity attributable to O6-Benzylguanine alone at all doses tested. O6-Benzylguanine rapidly disappeared from plasma and was converted to a major metabolite, O6-Benzyl-8-oxoguanine. The half-life of O6-Benzyl-8-oxoguanine increased with dose from 2.8 to 9.2 hours at doses of 10 and 80 mg/m2, respectively. The maximum concentration Cmax and area under the concentration-time curve (AUC) for O6-Benzyl-8-oxoguanine were, respectively, 2.2- and 12- to 29-fold greater than those of O6-Benzylguanine. At all doses, depletion of AGT activity was observed in lymphocytes with a return to baseline by 1 week posttreatment. CONCLUSION This study demonstrates that administration of O6-Benzylguanine to humans results in a rapid conversion to O6-Benzyl-8-oxoguanine, which follows nonlinear kinetics. Both compounds contribute to an effective depletion of AGT activity in lymphocytes; however, prolonged depletion of AGT activity is likely due primarily to the effect of O6-Benzyl-8-oxoguanine.
High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study
Authors: Anoop S V Shah, Atul Anand, Yader Sandoval, Kuan Ken Lee, Stephen W Smith, Philip D Adamson, Andrew R Chapman, Timothy Langdon, Dennis Sandeman, Amar Vaswani, Fiona E Strachan, Amy Ferry, Alexandra G Stirzaker, Alan Reid, Alasdair J Gray, Paul O Collinson, David A McAllister, Fred S Apple, David E Newby, Nicholas L Mills
Journal: The Lancet (2015)

Suspected acute coronary syndrome is the commonest reason for emergency admission to hospital and is a large burden on health-care resources. Strategies to identify low-risk patients suitable for immediate discharge would have major benefits.We did a prospective cohort study of 6304 consecutively enrolled patients with suspected acute coronary syndrome presenting to four secondary and tertiary care hospitals in Scotland. We measured plasma troponin concentrations at presentation using a high-sensitivity cardiac troponin I assay. In derivation and validation cohorts, we evaluated the negative predictive value of a range of troponin concentrations for the primary outcome of index myocardial infarction, or subsequent myocardial infarction or cardiac death at 30 days. This trial is registered with ClinicalTrials.gov (number NCT01852123).782 (16%) of 4870 patients in the derivation cohort had index myocardial infarction, with a further 32 (1%) re-presenting with myocardial infarction and 75 (2%) cardiac deaths at 30 days. In patients without myocardial infarction at presentation, troponin concentrations were less than 5 ng/L in 2311 (61%) of 3799 patients, with a negative predictive value of 99·6% (95% CI 99·3-99·8) for the primary outcome. The negative predictive value was consistent across groups stratified by age, sex, risk factors, and previous cardiovascular disease. In two independent validation cohorts, troponin concentrations were less than 5 ng/L in 594 (56%) of 1061 patients, with an overall negative predictive value of 99·4% (98·8-99·9). At 1 year, these patients had a lower risk of myocardial infarction and cardiac death than did those with a troponin concentration of 5 ng/L or more (0·6% vs 3·3%; adjusted hazard ratio 0·41, 95% CI 0·21-0·80; p<0·0001).Low plasma troponin concentrations identify two-thirds of patients at very low risk of cardiac events who could be discharged from hospital. Implementation of this approach could substantially reduce hospital admissions and have major benefits for both patients and health-care providers.British Heart Foundation and Chief Scientist Office (Scotland).
Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial
Authors: Diamant Thaçi, Eric L Simpson, Lisa A Beck, Thomas Bieber, Andrew Blauvelt, Kim Papp, Weily Soong, Margitta Worm, Jacek C Szepietowski, Howard Sofen, Makoto Kawashima, Richard Wu, Steven P Weinstein, Neil M H Graham, Gianluca Pirozzi, Ariel Teper, E Rand Sutherland, Vera Mastey, Neil Stahl, George D Yancopoulos, Marius Ardeleanu
Journal: The Lancet (2015)
The results of chemotherapy for extragonadal germ-cell tumors in the cisplatin era: the Memorial Sloan-Kettering Cancer Center experience (1975 to 1982).
Authors: A Israel, G J Bosl, R B Golbey, W Whitmore, N Martini
Journal: Journal of Clinical Oncology (1985)

Thirty-eight patients with extragonadal germ-cell tumors treated at Memorial Sloan-Kettering Cancer Center (New York) between 1975 and 1982 received high-dose cisplatin-based chemotherapy. Complete response was achieved in 89% of patients with pure seminoma and all complete responders are alive without evidence of disease (median follow-up time, 29+ months). Complete response was achieved in only 41% (12 of 29) of patients with extragonadal nonseminomatous germ-cell tumors; only four patients are alive and free of disease (median survival time, 18 months). Although patients with extragonadal seminoma respond well with current cisplatin-based chemotherapy, minimal improvement in CR rates has been achieved in patients with extragonadal nonseminomatous tumors. Patients with extragonadal nonseminomatous germ-cell tumors have a relatively poor prognosis when compared to patients with primary testicular tumors and investigational trials of innovative therapy should be considered.
NHS in England missed all key targets in September
Authors: G. Iacobucci
Journal: BMJ (2015)

The NHS in England missed all of its key performance targets in September, as an increasing number of patients were delayed in being discharged from hospital.

New figures from NHS England showed that the service missed its target to see, treat, or discharge 95% of patients in hospital emergency departments within four hours, with only 93.4% of patients seen.1 This was the worst September performance against the target since the government started publishing monthly figures in 2010 and suggests that the NHS is set for a …
What kinds of conservatives does social psychology lack, and why?
Authors: Lee Ross
Journal: Behavioral and Brain Sciences (2015)

Abstract Although Duarte et al.'s claims about the potential benefits of greater political diversity in the ranks of social psychology are apt, their discussion of the decline in such diversity, the role played by self-selection, and the specific domains they cite in discussing an anti-conservative bias raise issues that merit closer examination. The claim that sound research and analysis challenging liberal orthodoxies fails to receive a fair hearing in our journals and professional discourse is also disputed.
An animal model of hypersensitivity pneumonitis in the rabbit.
Authors: V L Moore, G T Hensley, J N Fink
Journal: Journal of Clinical Investigation (1975)

This study was devised to produce an animal model of hypersensitivity pneumonitis in order to study both the induction and the elicitation of the disease. Rabbits exposed by aerosol to large quantities of pigeon antigens developed a humoral, but not cellular, immunologic response. Moreover, their lungs were essentially normal histologically. A single i.v. injection of killed BCG in oil permitted the induction of pulmonary cell-medid hypersensitivity to the inhaled antigen, as well as the development of pulmonary lesions which were more severe than that caused by the administration of BCG alone. The humoral immunologic response to the inhaled antigen was not increased after BCG injection. Since many individuals are exposed to the etiologic agents of hypersensitivity pneumonitis for extended periods without developing the disease, these findings in animals suggest that some event may occur to induce cell mediated hypersensitivity in order to initiate the disease process. In addition, we have shown that animals with normal lung histology and circulating complement-fixing antibodies undergo serum complement (CH50) depression after an aerosol challenge with the specific antigen. Animals with circulating, complement-fixing antibodies, and inflamed lungs (BCG-induced failed to undergo a complement depression subsequent to an aerosol challenge with specific antigens. These results re consistent with those seen in symptomatic and asymptomatic pigeon breeders and suggest that antigen distribution through the lung is important in the pathogenesis of hypersensitivity pneumonitis.
Changes in Bone Mineral Density in the Year after Critical Illness
Authors: Neil R. Orford, Stephen E. Lane, Michael Bailey, Julie A. Pasco, Claire Cattigan, Tania Elderkin, Sharon L. Brennan-Olsen, Rinaldo Bellomo, David J. Cooper, Mark A. Kotowicz
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Critical illness may be associated with increased bone turnover and loss of bone mineral density (BMD). Prospective evidence describing long-term changes in BMD after critical illness is needed to further define this relationship.To measure the change in BMD and bone turnover markers (BTMs) in subjects 1 year after critical illness compared with population-based control subjects.We studied adult patients admitted to a tertiary intensive care unit (ICU) who required mechanical ventilation for at least 24 hours. We measured clinical characteristics, BTMs, and BMD during admission and 1 year after ICU discharge. We compared change in BMD to age- and sex-matched control subjects from the Geelong Osteoporosis Study.Sixty-six patients completed BMD testing. BMD decreased significantly in the year after critical illness at both femoral neck and anterior-posterior spine sites. The annual decrease was significantly greater in the ICU cohort compared with matched control subjects (anterior-posterior spine, -1.59%; 95% confidence interval, -2.18 to -1.01; P < 0.001; femoral neck, -1.20%; 95% confidence interval, -1.69 to -0.70; P < 0.001). There was a significant increase in 10-year fracture risk for major fractures (4.85 ± 5.25 vs. 5.50 ± 5.52; P < 0.001) and hip fractures (1.57 ± 2.40 vs. 1.79 ± 2.69; P = 0.001). The pattern of bone resorption markers was consistent with accelerated bone turnover.Critically ill individuals experience a significantly greater decrease in BMD in the year after admission compared with population-based control subjects. Their bone turnover biomarker pattern is consistent with an increased rate of bone loss.
Abstract 15925: Localization of Nav1.5 at the Intercellular Junctions Resolved by Diffraction-Unlimited Microscopy in Three Dimensions and by Correlative Light-Electron Microscopy
Authors: Alejandra Leo-Macias, Esperanza Agullo-Pascual, Eli Rothenberg, Mario Delmar
Journal: Circulation (2014)

Sodium current amplitude, kinetics and regulation depend on the properties of the pore-forming protein (mostly NaV1.5 in adult heart) and on the specific molecular partners with which the channel protein associates. The composition of the voltage-gated sodium channel macromolecular complex is location-specific; yet, the exact position of NaV1.5 in the subcellular landscape of the intercalated disc (ID), remains unclear. We implemented diffraction unlimited microscopy (direct stochastic optical reconstruction microscopy, or “dSTORM”) to localize the pore-forming subunit of the cardiac sodium channel NaV1.5 with a resolution of 20nm on the XY plane. In isolated adult ventricular myocytes, NaV1.5 was found in distinct semi-circular clusters. When the entire population of clusters within a 500 nm window from the ID was considered (more than 350 individual clusters analyzed), 75% of them localized to N-cadherin rich sites. NaV1.5-distal clusters were found at an average 313±15 nm from the cell end. Introducing an astigmatic lens in the light path allowed us to solve cluster location in three dimensions, at resolutions of 20 nm in XY and 40 nm in the z plane. Three-dimensional images confirmed the preferential localization at or near N-cadherin plaques, and further suggested that NaV1.5 arrives to the membrane via N-cadherin-anchored paths, most likely microtubules. In additional experiments, we developed a novel approach to correlate the image of NaV1.5 clusters by dSTORM with the cellular ultrastructure as resolved by electron microscopy on the same sample. This “correlative light-electron microscopy” method confirmed the preference of NaV1.5 clusters at sites of mechanical coupling. Overall, we provide the first ultrastructural description of NaV1.5 at the cardiac ID and its relation with the major electron-dense domains of the adult heart. Our data support a model by which microtubule-mediated delivery of NaV1.5 anchors at N-cadherin-rich sites, likely “mixed junctions” also containing desmosomal molecules (such as plakophilin-2; see Cerrone et al; Circulation 129:1092-1103, 2014) and connexin43. These findings have major implications to the understanding of sodium current disruption in diseases affecting the integrity of the ID.
Rational design and physiological selection of a RAF pathway inhibitor that disrupts angiogenesis and tumor growth
Authors: Eric Murphy, Wolfgang Wrasidlo, Konstantin Stoletov, Elena Dneprovskaia, Michele McElroy, Jeff Lindquist, Bharat Majeti, Lisette Acevedo, Milan Makale, Joshua Greenberg, Leo Barnes, Michael Martin, Richard Soll, George Davis, Robert Hoffman, Michael Bouvet, Richard Klemke, David Cheresh
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2490 

Identification of therapeutic kinase inhibitors via high throughput screening using recombinant catalytic kinase domains at low ATP concentration often yields high affinity ATP mimetics that lack specificity, thereby producing unwanted side effects. We identified an inhibitor of endothelial cell RAF signaling by applying a rational design approach using a novel amino-triazole scaffold designed to stabilize B-RAF in the inactive state. We selected RAF pathway inhibitors in an endothelial cell-based model followed by further selection in a Tg( fli1-EGFP) zebrafish embryogenesis model, allowing us to identify potent anti-angiogenic compounds. Our lead compound, KG5, disrupts the association of B- and C-RAF in endothelial cells and prevents endothelial cell lumen formation during angiogenesis. In addition to RAF, KG5 inhibited PDGFRbeta in smooth muscle cells but failed to interfere with a wide variety of other kinases. While structurally similar to the multikinase inhibitor Sorafenib, KG5 does not compete for ATP yet it readily disrupts RAF signaling in tumor cells and endothelial cells. Evidence is provided that KG5 is an orally-active RAF pathway inhibitor that blocks angiogenesis and tumor growth in orthotopic models of pancreatic carcinoma and renal cell carcinoma, as well as a V600E BRAF expressing melanoma.
Diet, Body Build, and Breast Cancer
Authors: D J Hunter, W C Willett
Journal: Annual Review of Nutrition (1994)

INTRODUCTION       ,   ',',      ,  ,             , 393 TOTAL ENERGY INTAKE, BODY SIZE, AND RISK OF BREAST CANCER  ' , ' 394 Animal Studies          ,    ,     ,   '       '   ,     ,    394 Height ,       ,  ,    ,      ,   ,     ,        ,  ,',   ,   ,   394 Body Mass Index (BMI) • • • • • •  •  • , , , • , , • • • • • • • • • • • • • • • , •   • • • • , ,  •  • •  • • 395 DIETARY FAT AND BREAST CANCER .                , ' 397 Animal Studies '    ,                      ',  ,   ', ,     ,  ,' 397 Ecologic Studies, , , , • , , , , , , , • , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,  , , , ,  397 Temporal Trends     .....  .......  , ...    .. ,.,., ,., .. ,., 400 Special Populations  ,       ,  ,     ,',   ,  ,  ,   '   ,  ,  , 401 Case-Control Studies ,   ,  , , , ,     ,  , , ,   ,  , , , , , ,    , , , , , ,     , ,  , , , ,   , 401 Cohort Studies ...       ,     '       ,       ,   ,   ,    ,     ,   402 Type of Fat   , ,  ,  , , ,  ,  ,  , , ,    , , , , , , • , , , , , , , • ,  , , , , , ,   ,  , , , , , ,  , ,  , 405 DIETARY FIBER AND BREAST CANCER  ,  ,',.      ,     ,,  ,   405 MICRONUTRIENTS , , ,    ,  , , , ,  , , , , , , , , , ,  , , , • ,  , , , , , , , , ,  , , , , ,  , ,  , , , , , 406 Vitamin A  ,  ..... ,    ....   , ..    ...  , ... , 406 Vitamin E     , .. ,     ,.,.,   ',., , , , , , 409 Vitamin C ,    ,               ,          ,','     ',',     ,' 410 Selenium, ,  , , , , , ,   , , , , • • , , , , , , ,   , , , , , ,  , , , , ,  ,  , , , , , ,     , , , ,     , , 410 OTHER DIETARY CONSTITUENTS  ..    ,                    41 1 Alcohol       ,. ,         ,  ,   ',. ,  ,       ,  ,    41 1 Caffeine .. ,  , • ,   , , , , ,    , , , ,     , , ,  ,  , , , , , ,  , , , , , , ,   , , , , , •  ,  ,  , , , , 411 Anticarcinogenic Phytochemicais               ,       ,',    ,       412 CONCLUSIONS              ,   .,        ,      412
Is Caffeine Abstention Necessary Before Adenosine-Induced Fractional Flow Reserve Measurement?
Authors: Hidenari Matsumoto, Shunpei Ushimaru, Tetsuya Matsuda, Toshihiko Shimada, Mikiko Mikuri, Haruya Takahashi, Nobuyuki Takahashi, Teruo Kawada, Taketoshi Yamazaki
Journal: Journal of the American College of Cardiology (2015)
Localization of Metabolic Activation and Deactivation Systems in the Lung: Significance to the Pulmonary Toxicity of Xenobiotics
Authors: R F Minchin, M R Boyd
Journal: The Annual Review of Pharmacology and Toxicology (1983)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
MesobanK UK: an international mesothelioma bioresource
Authors: Robert C Rintoul, Doris M Rassl, Jacki Gittins, Stefan J Marciniak
Journal: Thorax (2015)

Malignant pleural mesothelioma causes the greatest societal burden of all the asbestos-related diseases. Progress in better understanding tumour biology will be facilitated by the availability of quality-assured annotated tissue. MesobanK has been created to establish a bioresource of pleural mesothelioma tissue linked to detailed anonymised clinical data. When complete, the bioresource will comprise a 750-patient tissue microarray and prospectively collected tissue, blood and pleural fluid from 300 patients with mesothelioma. Twenty-six new cell lines have also been developed. MesobanK meets all appropriate ethical and regulatory procedures and has recently opened to requests for tissue and data.
Pdgfrβ+ Mural Preadipocytes Contribute to Adipocyte Hyperplasia Induced by High-Fat-Diet Feeding and Prolonged Cold Exposure in Adult Mice
Authors: Lavanya Vishvanath, Karen A. MacPherson, Chelsea Hepler, Qiong A. Wang, Mengle Shao, Stephen B. Spurgin, Margaret Y. Wang, Christine M. Kusminski, Thomas S. Morley, Rana K. Gupta
Journal: Cell Metabolism (2015)
Next-generation metabolic imaging in pancreatic cancer
Authors: Rickmer F Braren, Jens T Siveke
Journal: Gut (2015)

In pancreatic ductal adenocarcinoma (PDAC), the lack of specific symptoms or diagnostic markers, the highly aggressive nature of the disease and high intrinsic and acquired therapy resistance all result in a virtually unchanged overall 5-year survival rate of around 5%.1 Thus, early detection of PDAC is a major task for improvement of prognosis and management of this fatal disease as surgery currently presents the only option for long-term survival.2 Conventional imaging techniques, including CT, proton-based MRI and endoscopic ultrasound, differentiate tumour tissue based on morphological and physiological (eg, reduced perfusion) changes, often not present in precursor lesions and early-stage tumours. Consequently, emerging innovative imaging technologies include molecular and metabolic approaches that allow the assessment of tumour biology.

Cancer phenotypes result from a host of mutational events, including signalling pathways that adapt tumour cell metabolism to support growth. One of these metabolic phenotypes observed in tumour cells is the Warburg effect, that is, ATP generation from glycolysis even under normal oxygen condition, converting most incoming glucose to lactate. Key pathways involved include phosphoinositide 3-kinase, hypoxia-inducible factor, p53, MYC and AMP-activated protein kinase. These alterations in glucose metabolism have been used in positron emission tomography (PET) imaging, in which the glucose analogue 18F-labelled fluorodeoxyglucose (18F-FDG) has been extensively applied in many cancer entities including PDAC. However, …