tbuckley/cabot-search huggingface dataset:
Identification and Selective Degradation of Neopeptide-Containing Truncated Mutant Proteins in the Tumors with High Microsatellite Instability
Authors: Won Kyu Kim, Misun Park, Minhee Park, Yun Ji Kim, Nara Shin, Hyun Ki Kim, Kwon Tae You, Hoguen Kim
Journal: Clinical Cancer Research (2013)

Frameshift mutations in coding mononucleotide repeats (cMNR) are common in tumors with high microsatellite instability (MSI-H). These mutations generate mRNAs containing abnormal coding sequences and premature termination codons (PTC). Normally, mRNAs containing PTCs are degraded by nonsense-mediated mRNA decay (NMD). However, mRNAs containing PTCs located in the last exon are not subject to degradation by NMD (NMD-irrelevant). This study aimed to discover whether genes with frameshift mutations in the last exon generate truncated mutant proteins.We identified 66 genes containing cMNRs in the last exon by bioinformatic analysis. We found frequent insertion/deletion mutations in the cMNRs of 29 genes in 10 MSI-H cancer cell lines and in the cMNRs of 3 genes in 19 MSI-H cancer tissues. We selected 7 genes (TTK, TCF7L2, MARCKS, ASTE1, INO80E, CYHR1, and EBPL) for mutant mRNA expression analysis and 3 genes (TTK, TCF7L2, and MARCKS) for mutant protein expression analysis.The PTC-containing NMD-irrelevant mRNAs from mutated genes were not degraded. However, only faint amounts of endogenous mutant TTK and TCF7L2 were detected, and we failed to detect endogenous mutant MARCKS. By polysome analysis, we showed that mRNAs from genomic mutant MARCKS constructs are normally translated. After inhibiting 3 protein degradation pathways, we found that only inhibition of the proteasomal pathway facilitated the rescue of endogenous mutant TTK, TCF7L2, and MARCKS.Our findings indicate that cancer cells scavenge potentially harmful neopeptide-containing mutant proteins derived from NMD-irrelevant abnormal mRNAs via the ubiquitin-proteasome system, and these mutant proteins may be important substrates for tumor-specific antigens.
Noninvasive In Vivo Imaging of Monocyte Trafficking to Atherosclerotic Lesions
Authors: Moritz F. Kircher, Jan Grimm, Filip K. Swirski, Peter Libby, Robert E. Gerszten, Jennifer R. Allport, Ralph Weissleder
Journal: Circulation (2008)

Monocytes play a key role in atherogenesis, but their participation has been discerned largely via ex vivo analyses of atherosclerotic lesions. We sought to establish a noninvasive technique to determine monocyte trafficking to atherosclerotic lesions in live animals.Using a micro-single-photon emission computed tomography small-animal imaging system and a Food and Drug Administration-approved radiotracer ([indium 111] oxyquinoline, (111)In-oxine), we demonstrate here that monocyte recruitment to atherosclerotic lesions can be visualized in a noninvasive, dynamic, and 3-dimensional fashion in live animals. We show in vivo that monocytes are recruited avidly to plaques within days of adoptive transfer. Using micro-single-photon emission computed tomography imaging as a screening tool, we were able to investigate modulatory effects on monocyte recruitment in live animals. We found that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors rapidly and substantially reduce monocyte recruitment to existing atherosclerotic lesions, as imaged here in vivo.This novel approach to track monocytes to atherosclerotic plaques in vivo should have broad applications and create new insights into the pathogenesis of atherosclerosis and other inflammatory diseases.
Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system
Authors: E. Mergia
Journal: Journal of Clinical Investigation (2006)

In the vascular system, the receptor for the signaling molecule NO, guanylyl cyclase (GC), mediates smooth muscle relaxation and inhibition of platelet aggregation by increasing intracellular cyclic GMP (cGMP) concentration. The heterodimeric GC exists in 2 isoforms (alpha1-GC, alpha2-GC) with indistinguishable regulatory properties. Here, we used mice deficient in either alpha1- or alpha2-GC to dissect their biological functions. In platelets, alpha1-GC, the only isoform present, was responsible for NO-induced inhibition of aggregation. In aortic tissue, alpha1-GC, as the major isoform (94%), mediated vasodilation. Unexpectedly, alpha2-GC, representing only 6% of the total GC content in WT, also completely relaxed alpha1-deficient vessels albeit higher NO concentrations were needed. The functional impact of the low cGMP levels produced by alpha2-GC in vivo was underlined by pronounced blood pressure increases upon NO synthase inhibition. As a fractional amount of GC was sufficient to mediate vasorelaxation at higher NO concentrations, we conclude that the majority of NO-sensitive GC is not required for cGMP-forming activity but as NO receptor reserve to increase sensitivity toward the labile messenger NO in vivo.
Association between psychosocial work characteristics and health functioning in American women: prospective study
Authors: Y. Cheng
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objective:</b> To examine prospectively the relation between psychosocial work characteristics and changes in health related quality of life over four years in a cohort of working women in the United States. <b>Design:</b> Longitudinal cohort study. <b>Setting:</b> United States. <b>Participants:</b> 21 290 female registered nurses who completed the Karasek9s job content questionnaire and a modified version of the short form 36 questionnaire (SF-36) as used for a survey of health status by the medical outcomes study. <b>Main outcome measures:</b> Seven dimensions of health status: physical functioning, role limitations due to physical health problems, bodily pain, vitality, social functioning, role limitations due to emotional problems, and mental health. <b>Results:</b> Examined separately low job control, high job demands, and low work related social support were associated with poor health status at baseline as well as greater functional declines over the four year follow up period. Examined in combination, women with low job control, high job demands, and low work related social support (“iso-strain” jobs) had the greatest functional declines. These associations could not be explained by age, body mass index, comorbid disease status, alcohol consumption, smoking status, education level, exercise level, employment status, marital status, or presence of a confidant. <b>Conclusions:</b> Adverse psychosocial work conditions are important predictors of poor functional status and its decline over time.
Estimated Radiation Exposure from Medical Imaging in Hemodialysis Patients
Authors: Andreana De Mauri, Marco Brambilla, Doriana Chiarinotti, Roberta Matheoud, Alessandro Carriero, Martino De Leo
Journal: Journal of the American Society of Nephrology (2011)

Radiation exposure accompanying medical imaging associates with cancer risk. Patients with recurrent or chronic diseases may be especially at risk, because they may undergo more of these procedures. The aim of this study was to assess the individual cumulative effective doses (CEDs), which quantify radiation from medical imaging procedures, in a cohort of 106 hemodialysis patients during a median follow-up of 3 years. We retrospectively calculated individual radiation exposures by collecting the number and type of radiologic procedures from hospital records. We also estimated organ doses for computed tomography procedures. The mean and median annual CEDs were 21.9 and 11.7 mSv per patient-year, respectively. The mean and median total CEDs per patient during the study period were 57.7 and 27.3 mSv, respectively. By radiation dose group, we classified 22 patients as low (<3 mSv/yr), 51 as moderate (3 to <20 mSv/yr), 22 as high (20 to <50 mSv/yr), and 11 as very high (≥50 mSv/yr). Seventeen patients had a total CED >100 mSv, a value associated with a substantial increase in risk for cancer-related mortality. Of the total CED,s 76% was a result of CT scanning. The annual CED significantly associated with age and transplant waitlist status. In summary, this study shows that a significant fraction of surviving hemodialysis patients during a 3-year period receives estimated radiation doses that may put them at an increased risk for cancer.
Factors influencing atopic dermatitis-a questionnaire survey of schoolchildren's perceptions
Authors: J.R. Williams, M.L. Burr, H.C. Williams
Journal: British Journal of Dermatology (2004)

Journal Article Factors influencing atopic dermatitis—a questionnaire survey of schoolchildren's perceptions Get access J.R. Williams, J.R. Williams Department of Epidemiology, Statistics and Public Health, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, U.K., and Department of Dermatology, School of Medical and Surgical Sciences, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, U.K Search for other works by this author on: Oxford Academic Google Scholar M.L. Burr, M.L. Burr Department of Epidemiology, Statistics and Public Health, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, U.K., and Department of Dermatology, School of Medical and Surgical Sciences, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, U.K Dr M. L. Burr. E‐mail: BurrML@Cardiff.ac.uk Search for other works by this author on: Oxford Academic Google Scholar H.C. Williams H.C. Williams Department of Epidemiology, Statistics and Public Health, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, U.K., and Department of Dermatology, School of Medical and Surgical Sciences, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 150, Issue 6, 1 June 2004, Pages 1154–1161, https://doi.org/10.1111/j.1365-2133.2004.05869.x Published: 01 June 2004 Article history Accepted: 28 September 2003 Published: 01 June 2004
Association of a Full-Day vs Part-Day Preschool Intervention With School Readiness, Attendance, and Parent Involvement
Authors: Arthur J. Reynolds, Brandt A. Richardson, Momoko Hayakawa, Erin M. Lease, Mallory Warner-Richter, Michelle M. Englund, Suh-Ruu Ou, Molly Sullivan
Journal: JAMA (2014)

Early childhood interventions have demonstrated positive effects on well-being. Whether full-day vs part-day attendance improves outcomes is unknown.To evaluate the association between a full- vs part-day early childhood program and school readiness, attendance, and parent involvement.End-of-preschool follow-up of a nonrandomized, matched-group cohort of predominantly low-income, ethnic minority children enrolled in the Child-Parent Centers (CPC) for the full day (7 hours; n = 409) or part day (3 hours on average; n = 573) in the 2012-2013 school year in 11 schools in Chicago, Illinois.The Midwest CPC Education Program provides comprehensive instruction, family-support, and health services from preschool to third grade.School readiness skills at the end of preschool, attendance and chronic absences, and parental involvement. The readiness domains in the Teaching Strategies GOLD Assessment System include a total of 49 items with a score range of 105-418. The specific domains are socioemotional with 9 items (score range, 20-81), language with 6 items (score range, 15-54), literacy with 12 items (score range, 9-104), math with 7 items (score, 8-60), physical health with 5 items (score range, 14-45), and cognitive development with 10 items (score range, 18-90).Full-day preschool participants had higher scores than part-day peers on socioemotional development (58.6 vs 54.5; difference, 4.1; 95% CI, 0.5-7.6; P = .03), language (39.9 vs 37.3; difference, 2.6; 95% CI, 0.6-4.6; P = .01), math (40.0 vs 36.4; difference, 3.6; 95% CI, 0.5-6.7; P = .02), physical health (35.5 vs 33.6; difference, 1.9; 95% CI, 0.5-3.2; P = .006), and the total score (298.1 vs 278.2; difference, 19.9; 95% CI, 1.2-38.4; P = .04). Literacy (64.5 vs 58.6; difference, 5.9; 95% CI, -0.07 to 12.4; P = .08) and cognitive development (59.7 vs 57.7; difference, 2.0; 95% CI, -2.4 to 6.3; P = .38) were not significant. Full-day preschool graduates also had higher rates of attendance (85.9% vs 80.4%; difference, 5.5; 95% CI, 2.6-8.4; P = .001) and lower rates of chronic absences (≥10% days missed; 53.0% vs 71.6%; difference, -18.6; 95% CI, -28.5 to -8.7; P = .001; ≥20% days missed; 21.2% vs 38.8%; difference -17.6%; 95% CI, -25.6 to -9.7; P < .001) but no differences in parental involvement.In an expansion of the CPCs in Chicago, a full-day preschool intervention was associated with increased school readiness skills in 4 of 6 domains, attendance, and reduced chronic absences compared with a part-day program. These findings should be replicated in other programs and contexts.
Phase II Study of the Halichondrin B Analog Eribulin Mesylate in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline, a Taxane, and Capecitabine
Authors: Javier Cortes, Linda Vahdat, Joanne L. Blum, Chris Twelves, Mario Campone, Henri Roché, Thomas Bachelot, Ahmad Awada, Robert Paridaens, Anthony Goncalves, Dale E. Shuster, Jantien Wanders, Fang Fang, Renuka Gurnani, Elaine Richmond, Patricia E. Cole, Simon Ashworth, Mary Ann Allison
Journal: Journal of Clinical Oncology (2010)

The activity and safety of eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, were evaluated in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, taxane, and capecitabine.Eligible patients in this single-arm, open-label phase II study received eribulin mesylate (1.4 mg/m(2)) administered as a 2- to 5-minute intravenous infusion on days 1 and 8 of a 21-day cycle. The primary end point was objective response rate (ORR) assessed by independent review.Of 299 enrolled patients who had received a median of four prior chemotherapy regimens, 291 received eribulin (for a median of four cycles). Of these, 269 patients met key inclusion criteria for the primary efficacy analysis. The primary end point of ORR by independent review was 9.3% (95% CI, 6.1% to 13.4%; all partial responses [PRs]), the stable disease (SD) rate was 46.5%, and clinical benefit rate (complete response + PR + SD > or = 6 months) was 17.1%. The investigator-reported ORR was 14.1% (95% CI, 10.2% to 18.9%). Median duration of response was 4.1 months, and progression-free survival was 2.6 months. Median overall survival was 10.4 months. The most common treatment-related grade 3 or 4 toxicities were neutropenia (54%; febrile neutropenia, 5.5%), leukopenia (14%), and asthenia/fatigue (10%; no grade 4); grade 3 neuropathy occurred in 6.9% of patients (no grade 4).Eribulin demonstrated antitumor activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine, with a manageable tolerability profile.
MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4
Authors: Rintaro Shimazu, Sachiko Akashi, Hirotaka Ogata, Yoshinori Nagai, Kenji Fukudome, Kensuke Miyake, Masao Kimoto
Journal: The Journal of Experimental Medicine (1999)

Toll-like receptor 4 (TLR4) is a mammalian homologue of Drosophila Toll, a leucine-rich repeat molecule that can trigger innate responses against pathogens. The TLR4 gene has recently been shown to be mutated in C3H/HeJ and C57BL/10ScCr mice, both of which are low responders to lipopolysaccharide (LPS). TLR4 may be a long-sought receptor for LPS. However, transfection of TLR4 does not confer LPS responsiveness on a recipient cell line, suggesting a requirement for an additional molecule. Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. MD-2 is thus a link between TLR4 and LPS signaling. Identification of this new receptor complex has potential implications for understanding host defense, as well as pathophysiologic, mechanisms.
Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo-controlled study (SPINE)
Authors: M. Dougados, J. Braun, S. Szanto, B. Combe, M. Elbaz, P. Geher, G. Thabut, V. Leblanc, I. Logeart
Journal: Annals of the Rheumatic Diseases (2011)

Patients with advanced ankylosing spondylitis (AS) experience disability because of reduced spinal mobility and pulmonary function impairment. This placebo-controlled study evaluated the effect of etanercept (ETN) in patients with advanced AS.A multicentre randomised double-blind placebo-controlled trial of 12 weeks' duration was performed. Patients had definite (modified New York criteria), active (Bath AS Disease Activity Index (BASDAI) ≥40), severe (radiological intervertebral bridges) AS refractory to non-steroidal anti-inflammatory drugs and were antitumour necrosis factor naive. They were treated with ETN 50 mg once weekly or identical placebo (PBO).Of the 95 patients screened, 82 were randomised to receive ETN (n=39) or PBO (n=43). At baseline the disease was active (mean BASDAI 61.0±13.4, C reactive protein (CRP) 20.7±25.5 mg/l) and severe (mean Bath AS Metrology Index (BASMI) 5.7±1.3, mSASSS 36.5±20.5); forced pulmonary vital capacity (FVC) was 3.3±0.7 l. Improvement in BASDAI (normalised net incremental area under the curve between baseline and week 12, primary end point) was significantly greater in the ETN group than in the PBO group (-19.8±16.5 vs -11.0±16.4, p=0.019). Moreover, at week 12, ETN gave better results than PBO for the BASDAI (-26.4±19.7 vs -14.4±19.7; p=0.008), total back pain (-29.2±24.0 vs -14.9±24.0; p=0.010), BASFI (-21.7±17.6 vs -10.1±17.6; p=0.004), BASMI (-0.6±0.6 vs -0.2±0.6; p=0.011), CRP level (-15.7±14.2 vs -1.3±14.2; p<0.001) and FVC (+160±280 ml vs -20±280 ml; p=0.006).ETN has short-term efficacy for patients with advanced AS, as was previously reported for less advanced disease. The efficacy is observed for the main symptoms (pain) and on markers of inflammation (CRP), as well as disease severity in terms of spinal mobility and pulmonary function.
Rhabdomyosarcoma in Children: Epidemiologic Study and Identification of a Familial Caneer Syndrome
Authors: Frederick P. Li, Joseph F. Fraumeni
Journal: JNCI Journal of the National Cancer Institute (1969)

Journal Article Rhabdomyosarcoma in Children: Epidemiologic Study and Identification of a Familial Caneer Syndrome Get access Frederick P. Li, M.D., Frederick P. Li, M.D. Epidemiology Branch, National Cancer Institute,5Bethesda, Maryland 20014 Search for other works by this author on: Oxford Academic PubMed Google Scholar Joseph F. Fraumeni, Jr., M.D. Joseph F. Fraumeni, Jr., M.D. Epidemiology Branch, National Cancer Institute,5Bethesda, Maryland 20014 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 43, Issue 6, December 1969, Pages 1365–1373, https://doi.org/10.1093/jnci/43.6.1365 Published: 01 December 1969 Article history Received: 05 August 1969 Accepted: 02 September 1969 Published: 01 December 1969
Severe pulmonary embolism decreases plasma L-arginine
Authors: Jeffrey A. Kline, John Watts, Daniel Courtney, Yong Yook Lee, Sunil Hwang
Journal: European Respiratory Journal (2013)

To the Editor: 

Measurements from humans and animal models with pulmonary embolism (PE) have demonstrated increases in multiple vasoconstrictive molecules, including prostaglandins, platelet-activating factor and leukotrienes [1]. Nitric oxide (NO), produced tonically by vascular endothelial nitric oxide synthase (eNOS), plays a pivotal role in maintaining a normal pulmonary vascular resistance under these conditions [2]. These facts underlie the construct hypothesis that in different subjects, PE can obstruct the same degree of pulmonary vasculature but manifest widely different pulmonary arterial resistances.

Preliminary evidence from animal models and humans suggests that acute PE is associated with intravascular haemolysis, related to the severity of PE [3–8]. Intravascular haemolysis liberates haemoglobin and diffusible haem, both of which directly bind NO. Ruptured erythrocytes also release large amounts of the enzyme arginase-1, which cleaves the eNOS substrate l-arginine, producing urea and l-ornithine.

We hypothesised that patients with acute PE that causes significant tricuspid regurgitation (TR) will have acutely increased plasma concentrations of arginase-1, decreased l-arginine and increased asymmetric dimethylarginine (aDMA) compared with patients who have mild PE without TR as well as patients without PE.

This was a secondary analysis of a four-centre prospective study of diagnostic accuracy conducted in patients with suspected PE (www.clinicaltrials.gov identifier NCT00368836) [9]. The enrolment and diagnostic criteria have been described previously [9]. Acute PE was considered present if two independent board-certified radiologists interpreted a filling defect consistent with acute PE on computed tomographic pulmonary angiography. Echocardiography was performed using techniques as previously described, …
Abstract 16154: Soluble Urokinase Plasminogen Activator Receptor (suPAR) is Associated with Presence and Severity of Coronary Disease and is an Independent Predictor of Adverse Cardiovascular Outcomes
Authors: Danny J Eapen, Pankaj Manocha, Riyaz S Patel, Hatem Al Kassem, Muhammad Hammadah, Ayman Samman Tahhan, Nima Ghasemzadeh, Mohammad Tarek Kabbany, Mohammad M Asfari, Neal K Bhatia, Mohamed Khayata, Suliman Alradawi, Emir Veledar, Tomasz Pielak, Christian W Thorball, Kobina A Wilmot, Revanth S Yendamuri, Michael M Halista, Ngoc-Anh Le, Stamatios Lerakis, Laurence Sperling, Arshed Quyyumi
Journal: Circulation (2012)

Introduction: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging inflammatory and immune biomarker. Recent studies have demonstrated a positive association of suPAR with incide...
Isoform-specific regulation of mood behavior and pancreatic β cell and cardiovascular function by L-type Ca2+ channels
Authors: Martina J. Sinnegger-Brauns, Alfred Hetzenauer, Irene G. Huber, Erik Renström, Georg Wietzorrek, Stanislav Berjukov, Maurizio Cavalli, Doris Walter, Alexandra Koschak, Ralph Waldschütz, Steffen Hering, Sergio Bova, Patrik Rorsman, Olaf Pongs, Nicolas Singewald, Jörg Striessnig
Journal: Journal of Clinical Investigation (2004)

Cav1.2 and Cav1.3 L-type Ca2+ channels (LTCCs) are believed to underlie Ca2+ currents in brain, pancreatic β cells, and the cardiovascular system. In the CNS, neuronal LTCCs control excitation-transcription coupling and neuronal plasticity. However, the pharmacotherapeutic implications of CNS LTCC modulation are difficult to study because LTCC modulators cause card iovascular (activators and blockers) and neurotoxic (activators) effects. We selectively eliminated high dihydropyridine (DHP) sensitivity from Cav1.2 α1 subunits (Cav1.2DHP–/–) without affecting function and expression. This allowed separation of the DHP effects of Cav1.2 from those of Cav1.3 and other LTCCs. DHP effects on pancreatic β cell LTCC currents, insulin secretion, cardiac inotropy, and arterial smooth muscle contractility were lost in Cav1.2DHP–/– mice, which rules out a direct role of Cav1.3 for these physiological processes. Using Cav1.2DHP–/– mice, we established DHPs as mood-modifying agents: LTCC activator–induced neurotoxicity was abolished and disclosed a depression-like behavioral effect without affecting spontaneous locomotor activity. LTCC activator BayK 8644 (BayK) activated only a specific set of brain areas. In the ventral striatum, BayK-induced release of glutamate and 5-HT, but not dopamine and noradrenaline, was abolished. This animal model provides a useful tool to elucidate whether Cav1.3-selective channel modulation represents a novel pharmacological approach to modify CNS function without major peripheral effects.