tbuckley/cabot-search huggingface dataset:
Disease-Free Survival in Colon Cancer: Still Relevant After All These Years!
Authors: Axel Grothey, Aimery de Gramont, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2013)

We congratulate Tournigand et al 1 on the publication of the results of the post hoc exploratory study of patients with stage II disease and elderly patients in the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC).However, we would like to make some comments on certain aspects of the article.First and foremost, we are intrigued at the relevant delay in the publication of the results in 2012, taking into account that the cutoff date for analysis of survival was January 16, 2007.This suggests a follow-up that was not updated when compared to the previous publication. 2In fact, the publications 1,2 present median follow-ups of 81.9 months and 80 months, respectively.Furthermore, when examining the 2010 American Society of Clinical Oncology meeting abstracts (abstracts 3522 and 3524) 3,4 in detail, both the number of patients alive with relapse and the number of second cancers are identical to the data that were provided in the current report. 1 Therefore, one could interpret that the current results were already available, at least when the 2009 article was published, and probably even before.Interestingly, in their report, 1 the authors raise a relevant concern regarding chemotherapy-induced secondary neoplasms.To supplement this evidence, we want to add our personal experience with 139 patients with stage II or III disease who received adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) at our institution.With a median follow-up of 36 months, eight patients developed a second neoplasm.One of them, a 56-year-old man, developed an aggressive acute myeloblastic leukemia (therapy related [monosomy 7] 5 ), 18 months after initiation of FOLFOX4 as adjuvant chemotherapy.Another point of discussion is to what extent the change in age rangesisjustifiedintheauthors'mostrecentreport. 1 Wethinkthattheage classification should have been the same as it appears in the two previously published articles. 2,6As was shown, the survival hazard ratio was approximately 1.0 in patients with stage III disease and patients older than age 64 years in both articles.Thus, if data from the 2009 publication did not show a benefit from FOLFOX4 in patients older than age 65 years, and the
Association of Brain DNA Methylation in<i>SORL1</i>,<i>ABCA7</i>,<i>HLA-DRB5</i>,<i>SLC24A4</i>, and<i>BIN1</i>With Pathological Diagnosis of Alzheimer Disease
Authors: Lei Yu, Lori B. Chibnik, Gyan P. Srivastava, Nathalie Pochet, Jingyun Yang, Jishu Xu, James Kozubek, Nikolaus Obholzer, Sue E. Leurgans, Julie A. Schneider, Alexander Meissner, Philip L. De Jager, David A. Bennett
Journal: JAMA Neurology (2014)

Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown.To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies.Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old.DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay.Pathological diagnosis of AD by National Institute on Aging-Reagan criteria following a standard postmortem examination.Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and paired helical filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with paired helical filament tau tangle density, and the expression of BIN1 was associated with Aβ load.Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.
Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation
Authors: T. Thenappan, S. J. Shah, S. Rich, L. Tian, S. L. Archer, M. Gomberg-Maitland
Journal: European Respiratory Journal (2009)

The aim of the present study was to determine contemporary survival in pulmonary arterial hypertension (PAH), and to investigate whether or not the National Institutes of Health (NIH) equation remains an accurate predictor of survival. In 576 patients with PAH referred during 1991–2007, observed survival was described using the Kaplan–Meier method. In patients with idiopathic, familial and anorexigen-associated PAH (n = 247), observed versus NIH equation predicted survival was compared. A new survival prediction equation was developed using exponential regression analysis. The observed 1-, 3- and 5-yr survival in the total cohort were 86, 69 and 61%, respectively. In patients with idiopathic, familial and anorexigen-associated PAH, the observed 1-, 3- and 5-yr survival (92, 75 and 66%, respectively) were significantly higher than the predicted survival (65, 43 and 32%, respectively). The new equation (P( t ) = e -A( x , y , z ) t , where P( t ) is probability of survival, t the time interval in years, A( x , y , z ) = e (−1.270–0.0148 x +0.0402 y –0.361 z ) , x the mean pulmonary artery pressure, y the mean right atrial pressure and z the cardiac index) performed well when applied to published contemporary studies of survival in PAH. Contemporary survival in the PAH cohort was better than that predicted by the NIH registry equation. The NIH equation underestimated survival in idiopathic, familial and anorexigen-associated PAH. Once prospectively validated, the new equation may be used to determine prognosis.
Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis
Authors: T. Senoo, N. Hattori, T. Tanimoto, M. Furonaka, N. Ishikawa, K. Fujitaka, Y. Haruta, H. Murai, A. Yokoyama, N. Kohno
Journal: Thorax (2010)

Background and aim There is a growing body of evidence demonstrating that plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. In fact, PAI-1 knockout mice are protected from bleomycin-induced pulmonary fibrosis. This study was conducted to determine whether the intrapulmonary administration of small interfering RNA (siRNA) targeting PAI-1 (PAI-1-siRNA) limits the development of bleomycin-induced pulmonary fibrosis. Methods Lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) were stained for PAI-1. The distribution of siRNA in the lung, the PAI-1 level in bronchoalveolar (BAL) fluid and the extent of fibrotic changes in the lung were evaluated following the intranasal administration of PAI-1-siRNA in a mouse model of bleomycin-induced pulmonary fibrosis. The effect of PAI-1-siRNA on the epithelial to mesenchymal transition (EMT) was also evaluated using a mouse lung epithelial cell line, LA-4. Results PAI-1 was overexpressed in the hyperplastic type 2 pneumocytes lining the honeycomb lesions of patients with IPF. The single intranasal instillation of PAI-1-siRNA resulted in the diffuse uptake of siRNA into the epithelial cells lining the dense fibrotic lesions. The repeated administration of PAI-1-siRNA initiated during either the inflammatory or the fibrotic phase into bleomycin-injured mice reduced the PAI-1 level in BAL fluid and limited the accumulation of collagen in the lungs. EMT induced by transforming growth factor β (TGFβ) in LA-4 cells was inhibited by transfection with PAI-1-siRNA. Conclusions The direct suppression of PAI-1 in the lung by the intrapulmonary administration of PAI-1-siRNA attenuated the development and progression of pulmonary fibrosis. The inhibition of EMT may be, at least in part, involved in this effect.
Association between baseline radiographic damage and improvement in physical function after treatment of patients with rheumatoid arthritis
Authors: F C Breedveld
Journal: Annals of the Rheumatic Diseases (2004)

To identify factors associated with poor physical function in rheumatoid arthritis and to assess whether baseline joint damage has an impact on improvement in physical function during infliximab treatment.428 patients with active rheumatoid arthritis despite methotrexate treatment received methotrexate alone or with infliximab (3 mg/kg or 10 mg/kg every four or eight weeks) for 54 weeks (the ATTRACT trial). Data on clinical outcomes and physical function (assessed by the health assessment questionnaire (HAQ)) were collected. Structural damage was assessed using the van der Heijde modification of the Sharp score. Odds ratios (OR) for factors associated with severe functional disability (HAQ > or =2.0) at baseline were estimated using multiple logistic regression analyses, and baseline factors related to the change in physical function after treatment at week 54 were determined.Baseline radiographic scores were correlated with baseline HAQ scores. After adjustment for demographic characteristics in the logistic regression model, baseline disease activity scores, radiological joint damage, fatigue, and morning stiffness were found to be associated with severe functional disability (HAQ >2.0), with OR values of 2.00 (1.53 to 2.63), 1.82 (1.15 to 2.87), 1.19 (1.05 to 1.34), and 1.07 (1.01 to 1.13), respectively. In multiple linear regression analysis, physical disability, joint damage, and fatigue at baseline were correlated with less improvement in physical function after treatment. Infliximab treatment was associated with greater improvement in physical function.Greater joint damage at baseline was associated with poorer physical function at baseline and less improvement in physical function after treatment, underlining the importance of early intervention to slow the progression of joint destruction.
Phase II, Open-Label, Single-Arm Trial of Imatinib Mesylate in Patients With Metastatic Melanoma Harboring <i>c-Kit</i> Mutation or Amplification
Authors: Jun Guo, Lu Si, Yan Kong, Keith T. Flaherty, Xiaowei Xu, Yanyan Zhu, Christopher L. Corless, Li Li, Haifu Li, Xinan Sheng, Chuanliang Cui, Zhihong Chi, Siming Li, Mei Han, Lili Mao, Xuede Lin, Nan Du, Xiaoshi Zhang, Junling Li, Baocheng Wang, Shukui Qin
Journal: Journal of Clinical Oncology (2011)

Melanomas harbor aberrations in the c-Kit gene. We tested the efficiency of the tyrosine kinase inhibitor imatinib in selected patients with metastatic melanoma harboring c-Kit mutations or amplifications.Forty-three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial. Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or disease progression occurred. Fifteen patients who experienced progression of disease were allowed to escalate the dose to 800 mg/d.Forty-three patients were eligible for evaluation, and the median follow-up time was 12.0 months. The median progression-free survival (PFS) was 3.5 months, and the 6-month PFS rate was 36.6%. Rate of total disease control was 53.5%: 10 patients (23.3%; 95% CI, 10.2% to 36.4%) and 13 patients (30.2%; 95% CI, 16.0% to 44.4%) achieved partial response (PR) and stable disease (SD), respectively. Eighteen patients (41.9%) demonstrated regression of tumor mass. Notably, nine of the 10 PRs were observed in patients with mutations in exons 11 or 13. The 1-year overall survival (OS) rate was 51.0%. The median PFS and OS times for patients who had PR or SD versus disease progression were 9.0 months versus 1.5 months (P < .001) and 15.0 months versus 9.0 months (P = .036), respectively. Imatinib 400 mg/d was well tolerated, and only one of the 15 patients who received dose escalation to 800 mg/d achieved SD.Imatinib demonstrated significant activity in patients with metastatic melanoma harboring genetic c-Kit aberrations, with an overall response rate of 23.3%. Escalation to 800 mg/d could not restore disease control.
Systematic review on cashew nut allergy
Authors: J. P. M. van der Valk, A. E. J. Dubois, R. Gerth van Wijk, H. J. Wichers, N. W. de Jong
Journal: Allergy (2014)

Recent studies on cashew nut allergy suggest that the prevalence of cashew nut allergy is increasing. Cashew nut consumption by allergic patients can cause severe reactions, including anaphylaxis. This review summarizes current knowledge on cashew nut allergy to facilitate timely clinical recognition and to promote awareness of this emerging food allergy amongst clinicians. The goal of this study is to present a systematic review focused on the clinical aspects of allergy to cashew nut including the characteristics of cashew nut, the prevalence, allergenic components, cross-reactivity, diagnosis and management of cashew nut allergy. The literature search yielded 255 articles of which 40 met our selection criteria and were considered to be relevant for this review. The 40 articles included one prospective study, six retrospective studies and seven case reports. The remaining 26 papers were not directly related to cashew nut allergy. The literature suggests that the prevalence of cashew nut allergy is increasing, although the level of evidence for this is low. A minimal amount of cashew nut allergen may cause a severe allergic reaction, suggesting high potency comparable with other tree nuts and peanuts. Cashew allergy is clearly an underestimated important healthcare problem, especially in children.
Continuous positive-pressure ventilation decreases right and left ventricular end-diastolic volumes in the dog.
Authors: J E Fewell, D R Abendschein, C J Carlson, J F Murray, E Rapaport
Journal: Circulation Research (1980)

We investigated the mechanism(s) responsible for the decreased cardiac output during continuous positive-pressure ventilation (CPPV). Seven dogs were anesthetized with chloralose-urethane, intubated, and ventilated using a volume ventilator. We measured heart rate, stroke volume, and the determinants of stroke volume: left and right ventricular end-diastolic volumes, isovolumic and ejection phase indices of myocardial contractility, and pulmonary and systemic arterial pressures. Myocardial blood flow was estimated using radioactive microspheres. Variables were measured during a control period of intermittent positive-pressure ventilation (IPPV), 8-20 minutes after the initiation of CPPV using 12 cm H2O positive end-expiratory pressure (PEEP), and 8-20 minutes after the removal of PEEP. CPPV decreased cardiac output but did not affect total or regional myocardial blood flow or the ratio of subendocardial to subepicardial blood flow. Isovolumic and ejection phase indices of myocardial cointractility, heart rate, and systemic arterial pressure did not change during CPPV. Right and left ventricular end-diastolic and end-systolic volumes decreased markedly during CPPV. We conclude that CPPV decreases cardiac output in accordance with Starling's law by decreasing preload.
Pulmonary Interstitial Glycogenosis
Authors: Anne-Marie Canakis, Ernest Cutz, David Manson, Hugh O'Brodovich
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

We present the clinical, radiologic, and pathologic findings in lung biopsies from seven infants with atypical neonatal lung disease. All seven infants presented with tachypnea, hypoxemia, and diffuse interstitial infiltrates with overinflated lungs on chest radiographs in the first month of life. Lung biopsies from all cases showed similar pathology, with expansion of the interstitium by spindle-shaped cells containing periodic acid-Schiff positive diastase labile material consistent with glycogen. Immunohistochemical staining showed these cells to be vimentin positive but negative for leucocyte common antigen, lysozyme, and other macrophage markers. Electron microscopy revealed primitive interstitial mesenchymal cells with few cytoplasmic organelles and abundant monoparticulate glycogen. Minimal or no glycogen was seen in the alveolar lining cells. Five cases were treated with pulse corticosteroids; hydroxychloroquine was added in one case. Six of seven infants have shown a favorable clinical outcome. One infant died from complications of extreme prematurity and bronchopulmonary dysplasia. Three cases that have been followed for at least 6 years have shown clinical resolution and radiographic improvement. We propose the term "pulmonary interstitial glycogenosis" of the neonate for this new entity to be differentiated from other forms of interstitial lung disease. Because abundant glycogen is not normally found in pulmonary interstitial cells, we postulate an abnormality in lung cytodifferentiation involving interstitial mesenchymal cells.
Small RNA Sequencing and Functional Characterization Reveals MicroRNA-143 Tumor Suppressor Activity in Liposarcoma
Authors: Stacy Ugras, Elliott Brill, Anders Jacobsen, Markus Hafner, Nicholas D. Socci, Penelope L. DeCarolis, Raya Khanin, Rachael O'Connor, Aleksandra Mihailovic, Barry S. Taylor, Robert Sheridan, Jeffrey M. Gimble, Agnes Viale, Aimee Crago, Cristina R. Antonescu, Chris Sander, Thomas Tuschl, Samuel Singer
Journal: Cancer Research (2011)

Liposarcoma remains the most common mesenchymal cancer, with a mortality rate of 60% among patients with this disease. To address the present lack of therapeutic options, we embarked upon a study of microRNA (miRNA) expression alterations associated with liposarcomagenesis with the goal of exploiting differentially expressed miRNAs and the gene products they regulate as potential therapeutic targets. MicroRNA expression was profiled in samples of normal adipose tissue, well-differentiated liposarcoma, and dedifferentiated liposarcoma by both deep sequencing of small RNA libraries and hybridization-based Agilent microarrays. The expression profiles discriminated liposarcoma from normal adipose tissue and well differentiated from dedifferentiated disease. We defined over 40 miRNAs that were dysregulated in dedifferentiated liposarcomas in both the sequencing and the microarray analysis. The upregulated miRNAs included two cancer-associated species (miR-21 and miR-26a), and the downregulated miRNAs included two species that were highly abundant in adipose tissue (miR-143 and miR-145). Restoring miR-143 expression in dedifferentiated liposarcoma cells inhibited proliferation, induced apoptosis, and decreased expression of BCL2, topoisomerase 2A, protein regulator of cytokinesis 1 (PRC1), and polo-like kinase 1 (PLK1). The downregulation of PRC1 and its docking partner PLK1 suggests that miR-143 inhibits cytokinesis in these cells. In support of this idea, treatment with a PLK1 inhibitor potently induced G(2)-M growth arrest and apoptosis in liposarcoma cells. Taken together, our findings suggest that miR-143 re-expression vectors or selective agents directed at miR-143 or its targets may have therapeutic value in dedifferentiated liposarcoma.
Predisposition to essential hypertension and renal hemodynamics in recent-onset insulin-dependent diabetic patients.
Authors: T P Hannedouche, L P Marques, P Guicheney, B Lacour, C Boitard, J P Grünfeld
Journal: Journal of the American Society of Nephrology (1992)

The offspring of essential hypertensive parents have been found to exhibit abnormalities in renal hemodynamics and sodium handling before the eventual occurrence of hypertension. The reported abnormalities represent a wide spectrum of changes including increased GFR, normal or decreased RPF, slight increase in blood pressure (although within the normal range), and an exaggerated natriuresis response to a sodium load. The heterogeneity of these abnormalities may reflect the specific conditions of the studies, the lability of the changes, or different subgroups of subjects with genetic predisposition to essential hypertension. Several lines of evidence have suggested a relationship between hypertension and the development of diabetic nephropathy in insulin-dependent diabetics. This laboratory has found that recent-onset insulin-dependent diabetics can exhibit renal hemodynamics abnormalities very early in the course of diabetes according to a positive or negative family history of essential hypertension. These changes include increased GFR and mean arterial pressure, but no differences in renal sodium and lithium handling in diabetics with a genetic predisposition to essential hypertension. In addition, diabetics with a positive family history of essential hypertension exhibited a more-marked vasodilative response to an acute interruption of the renin-angiotensin system, further suggesting inadequate angiotensin modulation of renal vascular tone. The significance of these abnormalities in relation to the development of diabetic nephropathy requires further investigation.
Endothelium-Dependent Cerebral Artery Dilation Mediated by TRPA1 and Ca <sup>2+</sup> -Activated K <sup>+</sup> Channels
Authors: Scott Earley, Albert L. Gonzales, Rachael Crnich
Journal: Circulation Research (2009)

Although it is well established that changes in endothelial intracellular [Ca(2+)] regulate endothelium-dependent vasodilatory pathways, the molecular identities of the ion channels responsible for Ca(2+) influx in these cells are not clearly defined. The sole member of the ankyrin (A) transient receptor potential (TRP) subfamily, TRPA1, is a Ca(2+)-permeable nonselective cation channel activated by electrophilic compounds such as acrolein (tear gas), allicin (garlic), and allyl isothiocyanate (AITC) (mustard oil). The present study examines the hypothesis that Ca(2+) influx via TRPA1 causes endothelium-dependent vasodilation. The effects of TRPA1 activity on vascular tone were examined using isolated, pressurized cerebral arteries. AITC induced concentration-dependent dilation of pressurized vessels with myogenic tone that was accompanied by a corresponding decrease in smooth muscle intracellular [Ca(2+)]. AITC-induced dilation was attenuated by disruption of the endothelium and when the TRPA1 channel blocker HC-030031 was present in the arterial lumen. TRPA1 channels were found to be present in native endothelial cells, localized to endothelial cell membrane projections proximal to vascular smooth muscle cells. AITC-induced dilation was insensitive to nitric oxide synthase or cyclooxygenase inhibition but was blocked by luminal administration of the small and intermediate conductance Ca(2+)-activated K(+) channel blockers apamin and TRAM34. BaCl(2), a blocker of inwardly rectifying K(+) channels, also inhibited AITC-induced dilation. AITC-induced smooth muscle cell hyperpolarization was blocked by apamin and TRAM34. We conclude that Ca(2+) influx via endothelial TRPA1 channels elicits vasodilation of cerebral arteries by a mechanism involving endothelial cell Ca(2+)-activated K(+) channels and inwardly rectifying K(+) channels in arterial myocytes.