tbuckley/cabot-search huggingface dataset:
A Novel Role for Human Sulfiredoxin in the Reversal of Glutathionylation
Authors: Victoria J. Findlay, Danyelle M. Townsend, Taylor E. Morris, Jacob P. Fraser, Lin He, Kenneth D. Tew
Journal: Cancer Research (2006)

Abstract Modification of protein cysteine residues by disulfide formation with glutathione (glutathionylation) is a reversible posttranslational modification of critical importance in controlling cell signaling events following oxidative and/or nitrosative stress. Here, we show that human sulfiredoxin, a small redox protein conserved in eukaryotes, can act as a novel regulator of the redox-activated thiol switch in cells by catalyzing deglutathionylation of a number of distinct proteins in response to oxidative and/or nitrosative stress. Actin and protein tyrosine phosphatase 1B were identified in vitro as targets of sulfiredoxin 1 (Srx1)–dependent deglutathionylation and confirmed in vivo by two-dimensional gel electrophoresis analysis. In addition, we show that Srx1-dependent deglutathionylation is functionally relevant through restoration of phosphatase activity. Human sulfiredoxin contains one cysteine residue (Cys99) that is conserved in all family members. Mutation of the cysteine residue inhibits deglutathionylation but did not affect its capacity to bind intracellular proteins. Furthermore, sulfiredoxin is not an acceptor molecule for the GS− moiety during the reaction process. Using two-dimensional gel electrophoresis, we identified multiple protein targets in vivo that are deglutathionylated by sulfiredoxin following oxidative and/or nitrosative stress. This novel deglutathionylation function of sulfiredoxin suggests it has a central role in redox control with potential implications in cell signaling. (Cancer Res 2006; 66(13): 6800-6)
Estimating <i>CDKN2A</i> Carrier Probability and Personalizing Cancer Risk Assessments in Hereditary Melanoma Using MelaPRO
Authors: Wenyi Wang, Kristin B. Niendorf, Devanshi Patel, Amanda Blackford, Fabio Marroni, Arthur J. Sober, Giovanni Parmigiani, Hensin Tsao
Journal: Cancer Research (2010)

Abstract Personalized cancer risk assessment remains an essential imperative in postgenomic cancer medicine. In hereditary melanoma, germline CDKN2A mutations have been reproducibly identified in melanoma-prone kindreds worldwide. However, genetic risk counseling for hereditary melanoma remains clinically challenging. To address this challenge, we developed and validated MelaPRO, an algorithm that provides germline CDKN2A mutation probabilities and melanoma risk to individuals from melanoma-prone families. MelaPRO builds on comprehensive genetic information, and uses Mendelian modeling to provide fine resolution and high accuracy. In an independent validation of 195 individuals from 167 families, MelaPRO exhibited good discrimination with a concordance index (C) of 0.86 [95% confidence intervals (95% CI), 0.75–0.97] and good calibration, with no significant difference between observed and predicted carriers (26; 95% CI, 20–35, as compared with 22 observed). In cross-validation, MelaPRO outperformed the existing predictive model MELPREDICT (C, 0.82; 95% CI, 0.61–0.93), with a difference of 0.05 (95% CI, 0.007–0.17). MelaPRO is a clinically accessible tool that can effectively provide personalized risk counseling for all members of hereditary melanoma families. Cancer Res; 70(2); 552–9
Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998
Authors: S D Taylor-Robinson, M B Toledano, S Arora, T J Keegan, S Hargreaves, A Beck, S A Khan, P Elliott, H C Thomas
Journal: Gut (2001)

BACKGROUND The age standardised mortality rate per 100 000 population for all causes of liver tumours (International Classification of Disease 9 (ICD-9) 155) has almost doubled in England and Wales during the period 1979–1996. We further analysed the mortality statistics to determine which anatomical subcategories were involved. METHODS Mortality statistics for liver tumours of ICD-9 155, 156, and subcategories, and for tumours of the pancreas (ICD-9 157), in England and Wales were investigated from the Office for National Statistics, London, from 1968 to 1996 inclusive. Data for 1997 and 1998 were also available on intrahepatic cholangiocarcinomas. RESULTS There has been a marked rise in age standardised mortality rates for intrahepatic cholangiocarcinoma. Since 1993, it represents the commonest recorded cause of liver tumour related death in England and Wales. This is evident in age groups older than 45 years. In contrast, mortality trends from other primary liver tumours, including hepatocellular carcinoma, were unremarkable. CONCLUSIONS The observed increase in mortality from intrahepatic cholangiocarcinoma may represent better case ascertainment and diagnosis due to improved diagnostic imaging, use of image guided biopsies, or increased use of ERCP. However, the trend started before ERCP was introduced nationally, mortality rates have continued to increase steadily thereafter, and there is no clear evidence that diagnostic transfers easily explains the findings. Alternatively, these observations may represent a true increase in intrahepatic bile duct tumours. Epidemiological studies are required to determine whether there is any geographical clustering of cases around the UK.
Anti-inflammatory drugs modulate histamine release from mast cells induced by fibrinogen degradation products.
Authors: E Wojtecka-Lukasik, J Stachurska, M Kopec, S Maslinski
Journal: Annals of the Rheumatic Diseases (1988)

The products resulting from proteolytic degradation of human fibrinogen (FDP) were found to induce the release of histamine from rat peritoneal mast cells. Low molecular weight, dialysable peptides (FDP) showed the highest dose dependent, histamine releasing activity. Histamine release induced by FDP was effectively inhibited by the gold compound auranofin at a concentration of 10(-5)-10(-7) mol/l and also by the non-steroidal anti-inflammatory drugs BW 755c, timegadine, medosan, naproxen, and aspirin at the higher concentration range of 10(-4)-10(-6) mol/l. It is concluded that the release of histamine from mast cells may be modulated to some extent by anti-inflammatory drugs, especially auranofin, BW 755c and timegadine, a functional property which may be beneficial in the management of joint disease.
The Relationships Among MicroRNA Regulation, Intrinsically Disordered Regions, and Other Indicators of Protein Evolutionary Rate
Authors: S. C.-C. Chen, T.-J. Chuang, W.-H. Li
Journal: Molecular Biology and Evolution (2011)

Many indicators of protein evolutionary rate have been proposed, but some of them are interrelated. The purpose of this study is to disentangle their correlations. We assess the strength of each indicator by controlling for the other indicators under study. We find that the number of microRNA (miRNA) types that regulate a gene is the strongest rate indicator (a negative correlation), followed by disorder content (the percentage of disordered regions in a protein, a positive correlation); the strength of disorder content as a rate indicator is substantially increased after controlling for the number of miRNA types. By dividing proteins into lowly and highly intrinsically disordered proteins (L-IDPs and H-IDPs), we find that proteins interacting with more H-IDPs tend to evolve more slowly, which largely explains the previous observation of a negative correlation between the number of protein–protein interactions and evolutionary rate. Moreover, all of the indicators examined here, except for the number of miRNA types, have different strengths in L-IDPs and in H-IDPs. Finally, the number of phosphorylation sites is weakly correlated with the number of miRNA types, and its strength as a rate indicator is substantially reduced when other indicators are considered. Our study reveals the relative strength of each rate indicator and increases our understanding of protein evolution.
Regulation of Cardiac Output Through Stroke Volume
Authors: HOMER R. WARNER, ALAN F. TORONTO
Journal: Circulation Research (1960)

Heart rate was controlled by direct stimulation of the right ventricle of a dog previously subjected to complete A-V block in order to study the effect of this variable on cardiac output. Measurements of cardiac output were made at various heart rates in unanesthetized dogs, both at rest and walking on a treadmill. Except at the extremes, cardiac output was independent of heart rate at rest and during mild exercise. This finding emphasizes the fact that cardiac output may be regulated to provide required flow through changes in stroke volume alone, even though adjustment of heart rate is the usual means for obtaining this end.
Positive neonatal screening for cystic fibrosis in neonates with renal failure
Authors: M. J. S. Oosterveld, J. V. Schilperoort, M. R. Lilien, H. G. M. Arets
Journal: Thorax (2010)

Screening for cystic fibrosis (CF) was recently added to the neonatal screening programme in the Netherlands. Four patients with renal failure whose heel prick tests were positive for CF as defined by raised levels of immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) are described. Both cystic fibrosis transmembrane conductance regulator (CFTR) DNA analysis and sweat tests were negative. Limited renal function can be a cause of false positive neonatal screening for CF using IRT and PAP.
Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data
Authors: Monique Maas, Patty J Nelemans, Vincenzo Valentini, Prajnan Das, Claus Rödel, Li-Jen Kuo, Felipe A Calvo, Julio García-Aguilar, Rob Glynne-Jones, Karin Haustermans, Mohammed Mohiuddin, Salvatore Pucciarelli, William Small, Javier Suárez, George Theodoropoulos, Sebastiano Biondo, Regina GH Beets-Tan, Geerard L Beets
Journal: The Lancet Oncology (2010)
Measures of Thyroid Function among Belarusian Children and Adolescents Exposed to Iodine-131 from the Accident at the Chernobyl Nuclear Plant
Authors: Evgenia Ostroumova, Alexander Rozhko, Maureen Hatch, Kyoji Furukawa, Olga Polyanskaya, Robert J. McConnell, Eldar Nadyrov, Sergey Petrenko, George Romanov, Vasilina Yauseyenka, Vladimir Drozdovitch, Viktor Minenko, Alexander Prokopovich, Irina Savasteeva, Lydia B. Zablotska, Kiyohiko Mabuchi, Alina V. Brenner
Journal: Environmental Health Perspectives (2013)

Thyroid dysfunction after exposure to low or moderate doses of radioactive iodine-131 (131I) at a young age is a public health concern. However, quantitative data are sparse concerning 131I-related risk of these common diseases.Our goal was to assess the prevalence of thyroid dysfunction in association with 131I exposure during childhood (≤ 18 years) due to fallout from the Chernobyl accident.We conducted a cross-sectional analysis of hypothyroidism, hyperthyroidism, autoimmune thyroiditis (AIT), serum concentrations of thyroid-stimulating hormone (TSH), and autoantibodies to thyroperoxidase (ATPO) in relation to measurement-based 131I dose estimates in a Belarusian cohort of 10,827 individuals screened for various thyroid diseases.Mean age at exposure (± SD) was 8.2 ± 5.0 years. Mean (median) estimated 131I thyroid dose was 0.54 (0.23) Gy (range, 0.001-26.6 Gy). We found significant positive associations of 131I dose with hypothyroidism (mainly subclinical and antibody-negative) and serum TSH concentration. The excess odds ratio per 1 Gy for hypothyroidism was 0.34 (95% CI: 0.15, 0.62) and varied significantly by age at exposure and at examination, presence of goiter, and urban/rural residency. We found no evidence of positive associations with antibody-positive hypothyroidism, hyperthyroidism, AIT, or elevated ATPO.The association between 131I dose and hypothyroidism in the Belarusian cohort is consistent with that previously reported for a Ukrainian cohort and strengthens evidence of the effect of environmental 131I exposure during childhood on hypothyroidism, but not other thyroid outcomes.
Microcephalin Regulates BRCA2 and Rad51-Associated DNA Double-Strand Break Repair
Authors: Xianglin Wu, Gourish Mondal, Xianshu Wang, Jianmin Wu, Lin Yang, Vernon S. Pankratz, Matthew Rowley, Fergus J. Couch
Journal: Cancer Research (2009)

Abstract Microcephalin (MCPH1) is a BRCA1 COOH terminal (BRCT) domain containing protein involved in the cellular response to DNA damage that has been implicated in autosomal recessive primary microcephaly. MCPH1 is recruited to sites of DNA double-strand breaks by phosphorylated histone H2AX (γH2AX), but the mechanism by which MCPH1 contributes to the repair process remains to be determined. Here, we show that MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. The interaction occurs through the NH2 terminus of BRCA2 and the COOH terminal BRCT domains of MCPH1. Disruption of the interaction between MCPH1 and BRCA2 has no effect on the ability of BRCA2 to form a complex with Rad51 but is associated with substantially reduced levels of both BRCA2 and Rad51 at sites of DNA double-strand breaks. Uncoupling of MCPH1 from BRCA2 also interferes with Rad51-dependent and BRCA2-dependent homologous recombination repair activity. These results suggest that the role of MCPH1 in the DNA damage response is in part associated with the ability to localize BRCA2 to sites of DNA double-stand breaks. [Cancer Res 2009;69(13):5531–6]
Sorafenib in patients with locally advanced and metastatic chordomas: a phase II trial of the French Sarcoma Group (GSF/GETO)
Authors: E. Bompas, A. Le Cesne, E. Tresch-Bruneel, L. Lebellec, V. Laurence, O. Collard, E. Saada-Bouzid, N. Isambert, J.Y. Blay, E.Y. Amela, S. Salas, C. Chevreau, F. Bertucci, A. Italiano, S. Clisant, N. Penel
Journal: Annals of Oncology (2015)

There is no consensual treatment of locally advanced or metastatic chordomas.We conducted a multicenter, open-label, uncontrolled phase II trial of sorafenib (800 mg/day). The primary end point was the 9-month progression-free rate according to RECIST 1.1. All patients had documented progressive disease at the time of study entry.Twenty-seven patients were enrolled between May 2011 and January 2014. The median age was 64 (range, 30-86) years. There were 17 men and 10 women. Twelve patients had been previously treated with chemotherapy and molecularly targeted agents. The maximum toxicity grade per patient was grade 3 in 21 cases (77.8%) and grade 4 in 4 cases (14.8%). Sorafenib provided an intent-to-treat best objective response of 1/27 [3.7%; 95% confidence interval (CI) 0.1% to 19.0%], a 9-month progression-free rate of 73.0% (95% CI 46.1-88.0) and a 12-month overall survival rate of 86.5% (95% CI 55.8-96.5). Survival curves were similar in pretreated and not pretreated patients.Additional clinical trials further exploring sorafenib as a treatment of locally advanced or metastatic chordomas are warranted.
Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell–depleted SCT
Authors: Joost W. J. van Esser, Bronno van der Holt, Ellen Meijer, Hubert G. M. Niesters, Rudolf Trenschel, Steven F. T. Thijsen, Anton M. van Loon, Francesco Frassoni, Andrea Bacigalupo, Ulrich W. Schaefer, Albert D. M. E. Osterhaus, Jan Willem Gratama, Bob Löwenberg, Leo F. Verdonck, Jan J. Cornelissen
Journal: Blood (2001)
P173 The role of transcutaneous carbon dioxide monitoring in acute non-invasive ventilation
Authors: J Van Oppen, P Daniel, M Sovani
Journal: Thorax (2013)

<h3>Background</h3> Transcutaneous carbon dioxide monitoring is rarely used in the acute hospital setting, where samples of arterial blood are used to measure pCO2. This is a pilot observational study to assess the role of transcutaneous (p<sub>tc</sub>CO<sub>2</sub>) versus arterial (p<sub>a</sub>CO<sub>2</sub>) monitoring during acute NIV, both to calculate pH and to guide therapy. <h3>Methods</h3> Ten patients with acute hypercapnic respiratory failure were recruited. All had arterial lines placed for guiding acute NIV therapy. p<sub>tc</sub>CO<sub>2</sub> was monitored for 12 hours (Radiometer TOSCA TCM4) and compared to measures of p<sub>a</sub>CO<sub>2 </sub>from samples taken from the arterial lines. Non-invasive pH<sub>tc</sub> was calculated from p<sub>tc</sub>CO<sub>2</sub>. Agreements between pCO<sub>2</sub> and pH methods were assessed using Bland-Altman analysis and regression. The potential for guiding acute NIV therapy based on transcutaneous data was assessed and pain scores for each method were compared using the Wilcoxon signed rank test. <h3>Results</h3> Mean bias between p<sub>a</sub>CO<sub>2</sub> and p<sub>tc</sub>CO<sub>2</sub> was -0.31 (95% CI 0.98) kPa, R<sup>2</sup> = 0.79 (p &lt; 0.0001). p<sub>tc</sub>CO<sub>2</sub> followed the same time trend as p<sub>a</sub>CO<sub>2</sub>. Mean pH bias was not statistically significant at 0.006 (95% CI 0.116), R<sup>2</sup> = 0.64 (p &lt; 0.0001). If based on transcutaneous data only, clinical decisions would have been unchanged in nine out of ten patients. Transcutaneous readings were also less painful (p &lt; 0.001) and preferred by patients. <h3>Conclusion</h3> This pilot study demonstrates the potential for using transcutaneous pCO<sub>2</sub> monitoring to calculate pH and guide therapy, in the acute care setting. p<sub>tc</sub>CO<sub>2 </sub>shows promise in replacing arterial blood gases, in acute hypercapnic respiratory failure.
Effect of the Affordable Care Act’s Young Adult Insurance Expansions on Hospital-Based Mental Health Care
Authors: Ezra Golberstein, Susan H. Busch, Rebecca Zaha, Shelly F. Greenfield, William R. Beardslee, Ellen Meara
Journal: American Journal of Psychiatry (2014)

Insurance coverage for young adults has increased since 2010, when the Affordable Care Act (ACA) required insurers to permit children to remain on parental policies until age 26 as dependents. This study estimated the association between the dependent coverage provision and changes in young adults' use of hospital-based services for substance use disorders and non-substance use psychiatric disorders.The authors conducted a quasi-experimental comparison of a national sample of non-childbirth-related inpatient admissions to general hospitals (a total of 2,670,463 admissions, 430,583 of which had primary psychiatric diagnoses) and California emergency department visits with psychiatric diagnoses (N=11,139,689), using data spanning 2005 to 2011. Analyses compared young adults who were targeted by the ACA dependent coverage provision (19- to 25-year-olds) and those who were not (26- to 29-year-olds), estimating changes in utilization before and after implementation of the dependent coverage provision. Primary outcome measures included quarterly inpatient admissions for primary diagnoses of any psychiatric disorder per 1,000 population; emergency department visits with any psychiatric diagnosis per 1,000 population; and payer source.Dependent coverage expansion was associated with 0.14 more inpatient admissions for psychiatric diagnoses per 1,000 for 19- to 25-year-olds (targeted by the ACA) than for 26- to 29-year-olds (not targeted by the ACA). The coverage expansion was associated with 0.45 fewer psychiatric emergency department visits per 1,000 in California. The probability that inpatient admissions nationally and emergency department visits in California were uninsured decreased significantly.ACA dependent coverage provisions produced modest increases in general hospital psychiatric inpatient admissions and higher rates of insurance coverage for young adults nationally. Lower rates of emergency department visits were observed in California.
PULMONARY EDEMA IN INFLUENZAL PNEUMONIA OF THE MOUSE AND THE RELATION OF FLUID IN THE LUNG TO THE INCEPTION OF PNEUMOCOCCAL PNEUMONIA
Authors: Carl G. Harford, Mary Hara
Journal: The Journal of Experimental Medicine (1950)

Pulmonary edema is a component of the fully developed influenza viral lesion in the mouse. Mice with experimental pulmonary fluid have an increased susceptibility to inhaled pneumococci and under these circumstances the organisms grow in the lung and produce the lesion of bacterial pneumonia. The presence of pulmonary edema in the lesion due to the influenza virus in the lung of the mouse appears to account adequately for the previous observation that inhaled pneumococci grow in the influenza viral lesion. Mice dying of pneumococcal septicemia after inhaling fine droplets containing this organism do not have pneumonia. The delay in migration of polymorphonuclear leucocytes into the lung after injection of pneumococci suspended in serum is an important factor in susceptibility to infection since it allows ample time for pneumococci to grow in the pulmonary fluid. The slow phagocytic action of pulmonary macrophages likewise permits growth of pneumococci. Conditions in human beings that are known to be complicated by pulmonary edema are also known to be associated with increased susceptibility to secondary bacterial pneumonia.
A Genetically Defined Model for Human Ovarian Cancer
Authors: Jinsong Liu, Gong Yang, Jennifer A. Thompson-Lanza, Armand Glassman, Kimberly Hayes, Andrea Patterson, Rebecca T. Marquez, Nelly Auersperg, Yinhua Yu, William C. Hahn, Gordon B. Mills, Robert C. Bast
Journal: Cancer Research (2004)

Disruptions of the p53, retinoblastoma (Rb), and RAS signaling pathways and activation of human telomerase reverse transcriptase (hTERT) are common in human ovarian cancer; however, their precise role in ovarian cancer development is not clear. We thus introduced the catalytic subunit of hTERT, the SV40 early genomic region, and the oncogenic alleles of human HRAS or KRAS into human ovarian surface epithelial cells and examined the phenotype and gene expression profile of those cells. Disruption of p53 and Rb pathway by SV40 early genomic region and hTERT immortalized but did not transform the cells. Introduction of HRAS(V12) or KRAS(V12) into the immortalized cells, however, allowed them to form s.c. tumors after injection into immunocompromised mice. Peritoneal injection of the transformed cells produced undifferentiated carcinoma or malignant mixed Mullerian tumor and developed ascites; the tumor cells are focally positive for CA125 and mesothelin. Gene expression profile analysis of transformed cells revealed elevated expression of several cytokines, including interleukin (IL)-1beta, IL-6, and IL-8, that are up-regulated by the nuclear factor-kappaB pathway, which is known to contribute to the tumor growth of naturally ovarian cancer cells. Incubation with antibodies to IL-1beta or IL-8 led to apoptosis in the ras-transformed cells and ovarian cancer cells but not in immortalized cells that had not been transformed. Thus, the transformed human ovarian surface epithelial cells recapitulated many features of natural ovarian cancer including a subtype of ovarian cancer histology, formation of ascites, CA125 expression, and nuclear factor-kappaB-mediated cytokine activation. These cells provide a novel model system to study human ovarian cancer.