tbuckley/cabot-search huggingface dataset:
Antielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema.
Authors: J E Gadek, G A Fells, R L Zimmerman, S I Rennard, R G Crystal
Journal: Journal of Clinical Investigation (1981)

The current concepts of the pathogenesis of emphysema hold that progressive, chronic destruction of the alveolar structures occurs because there was in imbalance between the proteases and antiproteases in the lower respiratory tract. In this context, proteases, particularly neutrophil elastase, work unimpeded to destroy the alveolar structures. This concept has evolved from consideration of patients with alpha 1-antitrypsin deficiency, who have decreased levels of serum alpha 1-antitrypsin and who have progressive panacinar emphysema. To directly assess the antiprotease side of this equation, the lower respiratory tract of non-smoking individuals with normal serum antiproteases and individuals with PiZ homozygous alpha 1-antitrypsin deficiency underwent bronchoalveolar lavage to evaluate the antiprotease screen of their lower respiratory tract. These studies demonstrated that: (a) alpha 1-antitrypsin is the major antielastase of the normal human lower respiratory tract; (b) alpha 2-macroglobulin, a large serum antielastase, and the bronchial mucous inhibitor, an antielastase of the central airways, do not contribute to the antielastase protection of the human alveolar structures; (c) individuals with PiZ alpha 1-antitrypsin deficiency have little or no alpha 1-antitrypsin in their lower respiratory tract and have no alternative antiprotease protection against neutrophil elastase; and (d) the lack of antiprotease protection of the lower respiratory tract of PiZ individuals is a chronic process, suggesting their vulnerability to neutrophil elastase is always present.
In Vivo Evidence for a Role of Toll-Like Receptor 4 in the Development of Intimal Lesions
Authors: Aryan Vink, Arjan H. Schoneveld, Jelger J. van der Meer, Ben J. van Middelaar, Joost P.G. Sluijter, Mirjam B. Smeets, Paul H.A. Quax, Sai Kiang Lim, Cornelius Borst, Gerard Pasterkamp, Dominique P.V. de Kleijn
Journal: Circulation (2002)

Inflammation plays an important role in atherogenesis. The toll-like receptor 4 (TLR4) is the receptor for bacterial lipopolysaccharides and also recognizes cellular fibronectin and heat shock protein 60, endogenous peptides that are produced in response to tissue injury. To explore a possible role for this receptor in arterial obstructive disease, we determined the expression of TLR4 in the atherosclerotic arterial wall, including adventitia, and studied the effect of adventitial TLR4 activation on neointima formation in a mouse model.Localization of TLR4 was studied in human atherosclerotic coronary arteries by immunohistochemistry and detected in plaque and adventitia. In the adventitia, not all TLR4-positive cells colocalized with macrophages. In primary human adventitial fibroblasts, expression of TLR4 was demonstrated by immunofluorescence, Western blot, and reverse transcriptase-polymerase chain reaction. Adding lipopolysaccharide to these fibroblasts induced activation of NF-kappaB and an increase of mRNAs of various cytokines. The effect of adventitial stimulation of TLR4 was studied in a mouse model. A peri-adventitial cuff was placed around the femoral artery. Application of lipopolysaccharide between cuff and artery augmented neointima formation induced by the cuff (intimal area+/-SEM, 9134+/-1714 versus 2353+/-1076 microm(2), P<0.01). In TLR4-defective mice, application of cuff and lipopolysaccharide resulted in a smaller neointima than in wild-type mice (intimal area, 3859+/-904 microm(2), P=0.02 versus wild type).A functional TLR4 is expressed in human adventitial fibroblasts and macrophages. Adventitial TLR4 activation augmented neointima formation in a mouse model. These results provide evidence for a link between the immune receptor TLR4 and intimal lesion formation.
Financial burden for tuberculosis patients in low- and middle-income countries: a systematic review
Authors: Tadayuki Tanimura, Ernesto Jaramillo, Diana Weil, Mario Raviglione, Knut Lönnroth
Journal: European Respiratory Journal (2014)

In order to inform the development of appropriate strategies to improve financial risk protection, we conducted a systematic literature review of the financial burden of tuberculosis (TB) faced by patients and affected families. The mean total costs ranged from $55 to $8198, with an unweighted average of $847. On average, 20% (range 0-62%) of the total cost was due to direct medical costs, 20% (0-84%) to direct non-medical costs, and 60% (16-94%) to income loss. Half of the total cost was incurred before TB treatment. On average, the total cost was equivalent to 58% (range 5-306%) of reported annual individual and 39% (4-148%) of reported household income. Cost as percentage of income was particularly high among poor people and those with multidrug-resistant TB. Commonly reported coping mechanisms included taking a loan and selling household items. The total cost of TB for patients can be catastrophic. Income loss often constitutes the largest financial risk for patients. Apart from ensuring that healthcare services are fairly financed and delivered in a way that minimises direct and indirect costs, there is a need to ensure that TB patients and affected families receive appropriate income replacement and other social protection interventions.
The Epidermal Growth Factor Receptor: A Role in Repair of Radiation-Induced DNA Damage
Authors: David J. Chen, Chaitanya S. Nirodi
Journal: Clinical Cancer Research (2007)

Abstract The epidermal growth factor receptor (EGFR), which is frequently expressed in tumors of epithelial origin, is an important determinant of tumor responses to ionizing radiation. Elevated EGFR expression and activity frequently correlate with tumor resistance to radiotherapy in patients. EGFR is thought to confer tumor resistance to radiation through the activation of survival and cell proliferation pathways. Recent discoveries have identified a novel radioprotective function of EGFR which involves the radiation-induced nuclear translocation of the receptor and its interactions with the DNA-dependent protein kinase, a key component of the nonhomologous end-joining DNA repair pathway. Targeting the DNA repair function of EGFR may serve as a therapeutic model for sensitizing tumors to radiotherapy in patients.
Multisite Validation Study to Determine Performance Characteristics of a 92-Gene Molecular Cancer Classifier
Authors: Sarah E. Kerr, Catherine A. Schnabel, Peggy S. Sullivan, Yi Zhang, Veena Singh, Brittany Carey, Mark G. Erlander, W. Edward Highsmith, Sarah M. Dry, Elena F. Brachtel
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Accurate tumor classification is essential for cancer management as patient outcomes improve with use of site- and subtype-specific therapies. Current clinicopathologic evaluation is varied in approach, yet standardized diagnoses are critical for determining therapy. While gene expression–based cancer classifiers may potentially meet this need, imperative to determining their application to patient care is validation in rigorously designed studies. Here, we examined the performance of a 92-gene molecular classifier in a large multi-institution cohort. Experimental Design: Case selection incorporated specimens from more than 50 subtypes, including a range of tumor grades, metastatic and primary tumors, and limited tissue samples. Formalin-fixed, paraffin-embedded tumors passed pathologist-adjudicated review between three institutions. Tumor classification using a 92-gene quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay was conducted on blinded tumor sections from 790 cases and compared with adjudicated diagnoses. Results: The 92-gene assay showed overall sensitivities of 87% for tumor type [95% confidence interval (CI), 84–89] and 82% for subtype (95% CI, 79–85). Analyses of metastatic tumors, high-grade tumors, or cases with limited tissue showed no decrease in comparative performance (P = 0.16, 0.58, and 0.16). High specificity (96%–100%) was showed for ruling in a primary tumor in organs commonly harboring metastases. The assay incorrectly excluded the adjudicated diagnosis in 5% of cases. Conclusions: The 92-gene assay showed strong performance for accurate molecular classification of a diverse set of tumor histologies. Results support potential use of the assay as a standardized molecular adjunct to routine clinicopathologic evaluation for tumor classification and primary site diagnosis. Clin Cancer Res; 18(14); 3952–60. ©2012 AACR.
Text-Book of the Embryology of Invertebrates.
Authors: E. Korschelt, Matilda. Bernard, K. Heider, E. L. Mark, Martin Fountain Woodward, William McMichael Woodworth
Journal: JAMA (1900)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Does Induction Chemotherapy Have a Role in the Management of Locoregionally Advanced Squamous Cell Head and Neck Cancer?
Authors: David J. Adelstein, Michael LeBlanc
Journal: Journal of Clinical Oncology (2006)

The use of systemic chemotherapy before definitive locoregional management, or induction chemotherapy, has been a theoretically attractive and well-studied approach in the management of squamous cell head and neck cancer. Although a decrease in distant metastases has frequently been observed, an improvement in survival from induction has been difficult to demonstrate. When chemotherapy and radiation are used concomitantly, however, an improvement in both survival and locoregional control can be identified, and this has led to the adoption of concurrent chemoradiotherapy as a standard of care for these patients. With this improvement in locoregional control, distant metastases have become a more frequently recognized cause of treatment failure, suggesting that an intervention, such as induction chemotherapy, directed at improving distant control might now be of some importance in improving overall treatment success. The recent development of taxane-containing, three-drug induction regimens that are capable of producing significantly better response rates than the older cisplatin and fluorouracil combination has also raised the possibility of a new and more important role for induction. The results of phase II investigations using this kind of a sequential schedule of induction chemotherapy followed by concurrent chemoradiotherapy have been encouraging, and phase III trials are now underway. This treatment approach remains investigational however, and these phase III studies are critical. The current randomized trials are reviewed and discussed.
Phosphoproteomic Profiling Reveals Vasopressin-Regulated Phosphorylation Sites in Collecting Duct
Authors: Amar D. Bansal, Jason D. Hoffert, Trairak Pisitkun, Shelly Hwang, Chung-Lin Chou, Emily S. Boja, Guanghui Wang, Mark A. Knepper
Journal: Journal of the American Society of Nephrology (2010)

Protein phosphorylation is an important component of vasopressin signaling in the renal collecting duct, but the database of known phosphoproteins is incomplete. We used tandem mass spectrometry to identify vasopressin-regulated phosphorylation events in isolated rat inner medullary collecting duct (IMCD) suspensions. Using multiple search algorithms to identify the phosphopeptides from spectral data, we expanded the size of the existing collecting duct phosphoproteome database from 367 to 1187 entries. Label-free quantification in vasopressin- and vehicle-treated samples detected a significant change in the phosphorylation of 29 of 530 quantified phosphopeptides. The targets include important structural, regulatory, and transporter proteins. The vasopressin-regulated sites included two known sites (Ser-486 and Ser-499) present in the urea channel UT-A1 and one previously unknown site (Ser-84) on vasopressin-sensitive urea channels UT-A1 and UT-A3. In vitro assays using synthetic peptides showed that purified protein kinase A (PKA) could phosphorylate all three sites, and immunoblotting confirmed the PKA dependence of Ser-84 and Ser-486 phosphorylation. These results expand the known list of collecting duct phosphoproteins and highlight the utility of targeted phosphoproteomic approaches.
Dose-Escalating and Pharmacological Study of Oxaliplatin in Adult Cancer Patients With Impaired Renal Function: A National Cancer Institute Organ Dysfunction Working Group Study
Authors: Chris H. Takimoto, Scot C. Remick, Sunil Sharma, Sridhar Mani, Ramesh K. Ramanathan, James Doroshow, Anne Hamilton, Daniel Mulkerin, Martin Graham, Graham F. Lockwood, Percy Ivy, Merrill Egorin, Barbara Schuler, Denis Greenslade, Andrew Goetz, Ronald Knight, Rebecca Thomas, Brian P. Monahan, William Dahut, Jean L. Grem
Journal: Journal of Clinical Oncology (2003)

This study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m2 every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL > or =60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCL 20 to 39 mL/min), and group D (severe dysfunction, CrCL <20 mL/min). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations.No dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m2 was well tolerated in all patient groups with a CrCL > or =20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCL had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r2 = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance.Oxaliplatin at 130 mg/m2 every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.
The UK accelerated immunisation programme and sudden unexpected death in infancy: case-control study
Authors: P. J Fleming
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objectives:</b> To investigate whether the accelerated immunisation programme in the United Kingdom is associated, after adjustment for potential confounding, with the sudden infant death syndrome. <b>Design:</b> Population based case-control study, February 1993 to March 1996. Parental interviews were conducted for each death and for four controls matched for age, locality, and time of sleep. Immunisation status was taken from records held by the parents. <b>Setting:</b> Five regions in England with a combined population of over 17 million. <b>Subjects:</b> Immunisation details were available for 93% (303/325) of infants whose deaths were attributed to the sudden infant death syndrome (SIDS); 90% (65/72) of infants with explained sudden deaths; and 95% (1515/1588) of controls. <b>Results:</b> After all potential confounding factors were controlled for, immunisation uptake was strongly associated with a lower risk of SIDS (odds ratio 0.45 (95% confidence interval 0.24 to 0.85)). This difference became non-significant (0.67 (0.31 to 1.43)) after further adjustment for other factors specific to the infant9s sleeping environment. Similar proportions of SIDS deaths and reference sleeps (corresponding to the time of day during which the index baby had died) among the controls occurred within 48 hours of the last vaccination (5% (7/149) <i>v</i> 5% (41/822)) and within two weeks (21% (31/149) <i>v</i> 27% (224/822)). No longer term temporal association with immunisation was found (P=0.78). Of the SIDS infants who died within two weeks of vaccination, 16% (5/31) had signs and symptoms of illness that suggested that medical contact was required, compared with 26% (16/61) of the non-immunised SIDS infants of similar age. The findings for the infants who died suddenly and unexpectedly but of explained causes mirrored those for SIDS infants. <b>Conclusions:</b> Immunisation does not lead to sudden unexpected death in infancy, and the direction of the relation is towards protection rather than risk. <h3>What is already known on this topic</h3> Some studies have suggested a link between the sudden infant death syndrome and primary immunisation, but most have failed to show a link Potential bias in the studies includes lack of a comparative control group with similar low immunisation uptake and misclassification of cause of death <h3>What this study adds</h3> This study investigated explained sudden infant deaths as well as the sudden infant death syndrome and took into account potential bias After confounding was controlled for, immunisation uptake was lowest among the infants who died, with no temporal relation or correlation with signs and symptoms of illness
What's all the fuss about?
Authors: Jan Wilkinson
Journal: BMJ (2006)

Risks of opting outWith the opt-out approach, patient demographics and medical record numbers would be stored in the regional database without patients' approval.Historical records could be used to populate the regional index rapidly.However, if the regional index is compromised, information on all institutions would be leaked.This could cause much anxiety for patients if they had not consented to that information being shared or been properly informed about the regional index.With an opt-out approach, patients have only one choice during a clinical visit-either consent to enable a clinician to query records at all sites or deny consent.Telling a clinician, "I consent to you retrieving my Beth Israel records but not my McLean or Fenway records" is disclosing, so patients with concerns are more likely to withhold consent in the opt-out model.If a patient arrives unconscious, the clinician can over-ride the opt-out consent and look up the entire patient record.Although this may benefit the patient, it may lead to unwanted privacy breaches.This may affect patient confidence in the system.In conclusion, we have only one opportunity to build a healthcare information superhighway that patients and providers can trust.We should let the patients decide if they want to drive on it.
Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease
Authors: Lemin Zheng, Benedicta Nukuna, Marie-Luise Brennan, Mingjiang Sun, Marlene Goormastic, Megan Settle, Dave Schmitt, Xiaoming Fu, Leonor Thomson, Paul L. Fox, Harry Ischiropoulos, Jonathan D. Smith, Michael Kinter, Stanley L. Hazen
Journal: Journal of Clinical Investigation (2004)

In recent studies we demonstrated that systemic levels of protein-bound nitrotyrosine (NO2Tyr) and myeloperoxidase (MPO), a protein that catalyzes generation of nitrating oxidants, serve as independent predictors of atherosclerotic risk, burden, and incident cardiac events. We now show both that apolipoprotein A-I (apoA-I), the primary protein constituent of HDL, is a selective target for MPO-catalyzed nitration and chlorination in vivo and that MPO-catalyzed oxidation of HDL and apoA-I results in selective inhibition in ABCA1-dependent cholesterol efflux from macrophages. Dramatic selective enrichment in NO2Tyr and chlorotyrosine (ClTyr) content within apoA-I recovered from serum and human atherosclerotic lesions is noted, and analysis of serum from sequential subjects demonstrates that the NO2Tyr and ClTyr contents of apoA-I are markedly higher in individuals with cardiovascular disease (CVD). Analysis of circulating HDL further reveals that higher NO2Tyr and ClTyr contents of the lipoprotein are each significantly associated with diminished ABCA1-dependent cholesterol efflux capacity of the lipoprotein. MPO as a likely mechanism for oxidative modification of apoA-I in vivo is apparently facilitated by MPO binding to apoA-I, as revealed by cross-immunoprecipitation studies in plasma, recovery of MPO within HDL-like particles isolated from human atheroma, and identification of a probable contact site between the apoA-I moiety of HDL and MPO. To our knowledge, the present results provide the first direct evidence for apoA-I as a selective target for MPO-catalyzed oxidative modification in human atheroma. They also suggest a potential mechanism for MPO-dependent generation of a proatherogenic dysfunctional form of HDL in vivo.
A Predictive Model of Human Myelotoxicity Using Five Camptothecin Derivatives and the <b> <i>In vitro</i> </b> Colony-Forming Unit Granulocyte/Macrophage Assay
Authors: Noriko Masubuchi, Richard D. May, Ryo Atsumi
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Many promising anticancer drugs are limited by myelosuppression. It is difficult to evaluate human myelotoxicity before a Phase I study because of the susceptibility of humans and animals to hematotoxicity. The purpose of this study was to establish a reliable method to predict the human maximum tolerated dose (MTD) of five camptothecin derivatives: SN-38, DX-8951f, topotecan, 9-aminocamptothecin, and camptothecin. Experimental Design: The myelotoxicity of SN-38 and DX-8951f were evaluated on bone marrow from mice, dogs, and humans using a 14-day colony-forming unit, granulocyte-macrophage (CFU-GM) assay to determine the 50%, 75%, and 90% inhibitory concentration values (IC50, IC75, and IC90, respectively). Results: Species differences in myelotoxicity were observed for SN-38 and DX-8951f. Using human and murine IC90s for myelotoxicity of these compounds and other camptothecin compounds (topotecan, 9-aminocamptothecin, and camptothecin), in vivo toxicological data, and pharmacokinetic parameters (data referred to in the literature), human MTDs were predicted retrospectively. The mechanism-based prediction model that is proposed uses the in vitro camptothecin assay and in vivo parameters on the basis of free fraction of area under the concentration-curve at the MTD (r2 = 0.887) and suggests that the human MTDs were well predicted for the five camptothecin derivatives by this model rather than by other models. Conclusion: The human MTDs of the camptothecin drugs were successfully predicted using the mechanism-based prediction model. The application of this model for in vitro hematotoxicology could play an important role for the development of new anticancer agents.