tbuckley/cabot-search huggingface dataset:
Systemic Iron Homeostasis and the Iron-Responsive Element/Iron-Regulatory Protein (IRE/IRP) Regulatory Network
Authors: Martina U. Muckenthaler, Bruno Galy, Matthias W. Hentze
Journal: Annual Review of Nutrition (2008)

The regulation and maintenance of systemic iron homeostasis is critical to human health. Iron overload and deficiency diseases belong to the most common nutrition-related pathologies across the globe. It is now well appreciated that the hormonal hepcidin/ferroportin system plays an important regulatory role for systemic iron metabolism. We review recent data that uncover the importance of the cellular iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network in systemic iron homeostasis. We also discuss how the IRE/IRP regulatory system communicates with the hepcidin/ferroportin system to connect the control networks for systemic and cellular iron balance.
Regulation of Peripheral Inflammation by Spinal p38 MAP Kinase in Rats
Authors: David L Boyle, Toni L Jones, Deepa Hammaker, Camille I Svensson, Sanna Rosengren, Salvatore Albani, Linda Sorkin, Gary S Firestein
Journal: PLoS Medicine (2006)

Background Somatic afferent input to the spinal cord from a peripheral inflammatory site can modulate the peripheral response. However, the intracellular signaling mechanisms in the spinal cord that regulate this linkage have not been defined. Previous studies suggest spinal cord p38 mitogen-activated protein (MAP) kinase and cytokines participate in nociceptive behavior. We therefore determined whether these pathways also regulate peripheral inflammation in rat adjuvant arthritis, which is a model of rheumatoid arthritis. Methods and Findings Selective blockade of spinal cord p38 MAP kinase by administering the p38 inhibitor SB203580 via intrathecal (IT) catheters in rats with adjuvant arthritis markedly suppressed paw swelling, inhibited synovial inflammation, and decreased radiographic evidence of joint destruction. The same dose of SB203580 delivered systemically had no effect, indicating that the effect was mediated by local concentrations in the neural compartment. Evaluation of articular gene expression by quantitative real-time PCR showed that spinal p38 inhibition markedly decreased synovial interleukin-1 and −6 and matrix metalloproteinase (MMP3) gene expression. Activation of p38 required tumor necrosis factor α (TNFα) in the nervous system because IT etanercept (a TNF inhibitor) given during adjuvant arthritis blocked spinal p38 phosphorylation and reduced clinical signs of adjuvant arthritis. Conclusions These data suggest that peripheral inflammation is sensed by the central nervous system (CNS), which subsequently activates stress-induced kinases in the spinal cord via a TNFα-dependent mechanism. Intracellular p38 MAP kinase signaling processes this information and profoundly modulates somatic inflammatory responses. Characterization of this mechanism could have clinical and basic research implications by supporting development of new treatments for arthritis and clarifying how the CNS regulates peripheral immune responses.
Regulation of the Inflammatory Response in Cardiac Repair
Authors: Nikolaos G. Frangogiannis
Journal: Circulation Research (2012)

Myocardial necrosis triggers an inflammatory reaction that clears the wound from dead cells and matrix debris, while activating reparative pathways necessary for scar formation. A growing body of evidence suggests that accentuation, prolongation, or expansion of the postinfarction inflammatory response results in worse remodeling and dysfunction following myocardial infarction. This review manuscript discusses the cellular effectors and endogenous molecular signals implicated in suppression and containment of the inflammatory response in the infarcted heart. Clearance of apoptotic neutrophils, recruitment of inhibitory monocyte subsets and regulatory T cells, macrophage differentiation and pericyte/endothelial interactions may play an active role in restraining postinfarction inflammation. Multiple molecular signals may be involved in suppressing the inflammatory cascade. Negative regulation of toll-like receptor signaling, downmodulation of cytokine responses, and termination of chemokine signals may be mediated through the concerted action of multiple suppressive pathways that prevent extension of injury and protect from adverse remodeling. Expression of soluble endogenous antagonists, decoy receptors, and posttranslational processing of bioactive molecules may limit cytokine and chemokine actions. Interleukin-10, members of the transforming growth factor-β family, and proresolving lipid mediators (such as lipoxins, resolvins, and protectins) may suppress proinflammatory signaling. In human patients with myocardial infarction, defective suppression, and impaired resolution of inflammation may be important mechanisms in the pathogenesis of remodeling and in progression to heart failure. Understanding of inhibitory and proresolving signals in the infarcted heart and identification of patients with uncontrolled postinfarction inflammation and defective cardiac repair is needed to design novel therapeutic strategies.
One Hundred and Twenty-Seven Cultured Human Tumor Cell Lines Producing Tumors in Nude Mice23
Authors: Jørgen Fogh, Jens M. Fogh, Thomas Orfeo
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article One Hundred and Twenty-Seven Cultured Human Tumor Cell Lines Producing Tumors in Nude Mice Get access Jørgen Fogh, Jørgen Fogh Search for other works by this author on: Oxford Academic PubMed Google Scholar Jens M. Fogh, Jens M. Fogh Search for other works by this author on: Oxford Academic PubMed Google Scholar Thomas Orfeo Thomas Orfeo Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 59, Issue 1, July 1977, Pages 221–226, https://doi.org/10.1093/jnci/59.1.221 Published: 01 July 1977 Article history Received: 08 November 1976 Accepted: 25 January 1977 Published: 01 July 1977
Different Splenic Uptake of Tc-99m Sulfur Colloid and Tc-99m Heat-Denatured Red Blood Cells in an Infant With Complete Situs Inversus
Authors: Riemer H.J.A. Slart, T T. Ha Phan, Melle D. Talsma, Peter L. Jager
Journal: Clinical Nuclear Medicine (2004)

A 5-week-old male infant with complete situs inversus and suspected asplenia underwent Tc-99m sulfur colloid and Tc-99m heat-denatured red blood cell (RBC) imaging to evaluate possible spleen function. The heat-denatured Tc-99m-labeled RBC scan revealed intense uptake in the normal-shaped right-side spleen, whereas the Tc-99m sulfur colloid scan showed only slight uptake in the reticuloendothelial system (RES). Therefore, the patient received antipneumococcal vaccination and antibiotic prophylaxis to prevent infections in the future.
Transport of macrophage Fc receptors and Fc receptor-bound ligands to lysosomes.
Authors: P Ukkonen, V Lewis, M Marsh, A Helenius, I Mellman
Journal: The Journal of Experimental Medicine (1986)

Mouse macrophage Fc receptors specific for IgG1/IgG2b mediate the binding and pinocytic uptake of soluble IgG-containing antibody-antigen complexes. Internalization of these multivalent IgG complexes is accompanied not only by the intracellular degradation of the ligand, but also by a net decrease in the number of plasma membrane Fc receptors and an accelerated rate of receptor turnover. In contrast, internalized receptors bound to a monovalent ligand, the high affinity Fab fragment of the antireceptor mAb 2.4G2, escape degradation by rapidly recycling to the cell surface. In this paper, we have characterized the intracellular pathway involved in the endocytosis and transport of Fc receptors in the J774 macrophage cell line. The results show that the uptake of multivalent ligands follows the normal pathway of receptor-mediated endocytosis: internalization in clathrin-coated pits and coated vesicles, delivery to endosomes, and finally to acid hydrolase-rich lysosomes. Immunoprecipitation of radiolabeled receptor from Percoll density gradients showed that endocytosis of the IgG complexes also results in the concomitant transport of the receptor to lysosomes. Although uptake of the monovalent Fab fragment had no detectable effect on intracellular receptor distribution, preparations of 2.4G2 Fab rendered multivalent by adsorption to colloidal gold were as effective as the IgG complexes at causing lysosomal accumulation of internalized receptors. Thus, it is likely that the down-regulation and degradation of Fc receptors which occurs during the endocytosis of antibody-antigen complexes is due to the transport of internalized receptors to lysosomes. Moreover, the ability of certain Fc receptor-bound ligands to interfere with receptor recycling and trigger lysosomal transport seems to depend on ligand valency rather than on the presence or absence of Fc domains on intact IgG molecules.
What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker?
Authors: Lars Gullestad, John Wikstrand, Prakash Deedwania, Åke Hjalmarson, Kenneth Egstrup, Uri Elkayam, Stephen Gottlieb, Andrew Rashkow, Hans Wedel, Georgina Bermann, John Kjekshus
Journal: Journal of the American College of Cardiology (2005)
Treatment of age-related macular degeneration
Authors: A. C Browning, W. M Amoaku, H. S Dua
Journal: Journal of the Royal Society of Medicine (2004)

Age-related macular degeneration (ARMD) is the most common cause of irreversible central visual loss in the elderly populations of the industrialized world,1-3 and will place increasing demands on health services as people live longer. For many years, the only treatment proven to be effective in arresting the progression of the wet form of ARMD was laser photocoagulation.4 Even then, only a small proportion of patients within a specific disease subgroup have been shown to benefit from this treatment, and the rate of disease recurrence (paradoxically often under the fovea) is high.5 Lately, researchers have developed novel strategies based on improved understanding of the pathophysiology, and this article summarizes recent advances in treatment.
Repeat treatment with icatibant for multiple hereditary angioedema attacks: FAST-2 open-label study
Authors: M. Baş, J. Greve, T. K. Hoffmann, A. Reshef, W. Aberer, M. Maurer, S. Kivity, H. Farkas, B. Floccard, F. Arcoleo, L. Martin, B. Sitkauskiene, L. Bouillet, P. Schmid-Grendelmeier, H. Li, A. Zanichelli
Journal: Allergy (2013)

Background The For Angioedema Subcutaneous Treatment (FAST)-2, a phase III, double-blind, randomized, multicenter, placebo-controlled study (ClinicalTrials.gov identifier: NCT00500656), established the efficacy and safety of single injections of icatibant, a bradykinin B2 receptor antagonist, in the treatment of hereditary angioedema (HAE) attacks. Here, we evaluate the efficacy and safety of repeated treatment with icatibant in adult patients experiencing HAE attacks during the FAST-2 open-label extension (OLE) phase. Methods Patients completing the controlled phase were eligible to participate in the OLE phase and receive open-label icatibant (30 mg subcutaneously) for the treatment of cutaneous, abdominal, and/or laryngeal HAE attack(s) severe enough to warrant treatment. Time to onset of symptom relief was calculated for each attack. Descriptive analyses (median, 95% CIs) were performed for all attacks; post hoc analyses were conducted in patients with at least five icatibant-treated attacks throughout the FAST-2 OLE phase. Safety was also monitored. Results Fifty-four patients received icatibant for 374 attacks (176 cutaneous, 168 abdominal, and 30 laryngeal). For cutaneous and/or abdominal attacks (attacks 2–5), the median times to onset of symptom relief ranged between 2.0 and 2.5 h. For all laryngeal attacks, the median times to regression (start of improvement) of symptoms ranged between 0.3 and 4.0 h. Post hoc analyses showed that the overall median time to onset of symptom relief was 2.0 h. Overall, 89.8% of attacks resolved with a single icatibant injection. No drug-related serious adverse events were reported. Conclusions These findings have demonstrated the efficacy and safety of repeated icatibant treatment for HAE attacks.
Reproducible and Sustained Efficacy of Targeted Therapy With Vemurafenib in Patients With <i>BRAF<sup>V600E</sup></i>-Mutated Erdheim-Chester Disease
Authors: Julien Haroche, Fleur Cohen-Aubart, Jean-François Emile, Philippe Maksud, Aurélie Drier, Dan Tolédano, Stéphane Barete, Frédéric Charlotte, Philippe Cluzel, Jean Donadieu, Neïla Benameur, Philippe A. Grenier, Sophie Besnard, Jean-Paul Ory, François Lifermann, Ahmed Idbaih, Brigitte Granel, Bruno Graffin, Baptiste Hervier, Laurent Arnaud, Zahir Amoura
Journal: Journal of Clinical Oncology (2014)

Purpose Histiocytoses are rare disorders with heterogeneous prognosis. BRAF V600E mutations have been observed in half of patients with Langerhans cell histiocytosis (LCH) and in 50% to 100% of patients with Erdheim-Chester disease (ECD) patients. We recently reported short-term efficacy of a BRAF inhibitor (vemurafenib) in three patients with multisystemic ECD. Patients and Methods Vemurafenib was given to eight patients with multisystemic ECD with CNS and/or cardiac involvement. All patients were refractory to first-line treatment and harbored a BRAF V600E mutation. Four patients also had LCH lesions. Positron emission tomography (PET) scan response at month 6 was used as the main evaluation criterion. Secondary evaluation criteria were comparison at baseline and at last visit of PET and of cardiovascular and cerebral infiltrations (computed tomography scan and magnetic resonance imaging [MRI]). Results All patients were partial metabolic responders at 6 months of vemurafenib, and the median reduction in maximum standardized uptake value was 63.5% (range, 41.3% to 86.9%). Evaluation of cardiac and aortic infiltrations showed that seven patients had a partial response and one patient had stable disease according to surface measurements derived from RECIST criteria. The four patients with infratentorial CNS infiltration had an objective decrease of the lesions on MRI. All patients had an improvement of general symptoms and a persistent response to vemurafenib, with a median follow-up time of 10.5 months (range, 6 to 16 months). Skin adverse effects were frequent and severe. Conclusion Vemurafenib has an objective and sustained efficacy in BRAF V600E -mutated ECD as second-line therapy. In contrast to melanoma, no resistance has emerged to date after 6 to 16 months.
Monophasic Curve Analysis and the Ventricular Gradient in the Electrogram of Strips of Turtle Ventricle
Authors: MANUEL GARDBERG, IRVING L. ROSEN
Journal: Circulation Research (1959)

Experiments were performed to test the validity of representing the bipolar electrogram as the algebraic sum of two monophasic curves and the validity of Wilson's concept of the significance of the area, AQRS plus AT. An electronic integrator was employed to measure the areas of bipolar leads recorded from a strip of turtle ventricle which could be stimulated at either end. The close correspondence of the experimental findings with the predictions derived from the representation of the bipolar curve as the algebraic sum of two theoretical monophasic curves supports the validity of the concept tested.
Diseases associated with dermatitis herpetiformis
Authors: T. REUNALA, P. COLLIN
Journal: British Journal of Dermatology (1997)

We have studied the occurrence of associated diseases in a cohort of 305 patients with dermatitis herpetiformis (DH) followed up for a mean of 10 years. The results were compared with those from 383 patients with coeliac disease (CD). Twenty-nine (9.5%) patients with DH and 73 (19.1%) with CD had concomitant endocrine or connective tissue disorders. The following associations were found: auto-immune thyroid disease (4.3% of DH patients and 6.0% of CD patients), insulin dependent diabetes (1.0% DH and 5.5% CD), lupus erythematosus (1.3% DH and 0.3% CD), Sjögren's syndrome (1.0% DH and 2.9% CD), sarcoidosis (1.3% DH and 1.8% CD), and vitiligo or alopecia areata (1.6% DH and 0% CD). We have shown that patients with DH are similar to those with CD in that many have associated endocrine or connective tissue disorders. Most of these diseases began before DH had been diagnosed suggesting that those on a gluten-free diet are not at special risk of contracting them.
Effect of community based management in failure to thrive: randomised controlled trial
Authors: C. M Wright, J. Callum, E. Birks, S. Jarvis
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objective</b> : To evaluate the effectiveness of a health visitor led intervention for failure to thrive in children under 2 years old. <b>Design</b> : Controlled trial, randomised by primary care practice. <b>Setting</b> : Newcastle upon Tyne health district. <b>Intervention</b> : Structured health visitor management, with dietetic, paediatric, and social work input as required. <b>Subjects</b> : 229 children (120 in intervention practices and 109 in control practices) were identified as failing to thrive by population screening during the first 2 years of life. Follow up was by home visit of a research nurse and review of the childrens9 records at age 3 years. <b>Main outcome measures</b> : Follow up weight and height and number of routinely collected weights. <b>Results</b> : 95 of the 97 families offered intervention completed at least the initial assessment. At follow up, 187 (82%) records were reviewed, and these suggested that 15 (16%) controls were lost to follow up immediately after the screening weight was taken compared with only one child in the intervention group. In the 134 (58%) families who consented to home visits, children in the intervention group were significantly heavier and taller and were reported to have better appetites than childen in the control group, although both groups were equally satisfied by the services they had received. When the children were last weighed, 91 (76%) in the intervention group had recovered from their failure to thrive compared with 60 (55%) in the control group (P&lt;0.001). <b>Conclusion</b> : In failure to thrive, health visitor intervention, with limited specialist support, can significantly improve growth compared with conventional management.
Prognostic Factors for Survival in Previously Treated Patients With Metastatic Renal Cell Carcinoma
Authors: Robert J. Motzer, Jennifer Bacik, Lawrence H. Schwartz, Victor Reuter, Paul Russo, Stephanie Marion, Madhu Mazumdar
Journal: Journal of Clinical Oncology (2004)

To describe survival in previously treated patients with metastatic renal cell carcinoma (RCC) who are candidates for clinical trials of new agents as second-line therapy.The relationship between pretreatment clinical features and survival was studied in 251 patients with advanced RCC treated during 29 consecutive clinical trials between 1975 and 2002. Clinical features were first examined in univariate analyses, and then a stepwise modeling approach based on Cox regression was used to form a multivariate model.Median survival for the 251 patients was 10.2 months and differed according to year of treatment, with patients treated after 1990 showing longer survival. In this group, the median overall survival time was 12.7 months. Because the purpose of this analysis was to establish prognostic factors for present-day clinical trial design, prognostic factor analysis was performed on these patients. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status, low hemoglobin level, and high corrected serum calcium. These were used as risk factors to categorize patients into three different groups. The median time to death in patients with zero risk factors was 22 months. The median survival in patients with one of these prognostic factors was 11.9 months. Patients with two or three risk factors had a median survival of 5.4 months.Treatment with novel agents during a clinical trial is indicated for patients with metastatic RCC after progression to cytokine treatment. Three prognostic factors for predicting survival were used to categorize patients into risk groups. These risk categories can be used in clinical trial design and interpretation.
Nox Enzymes and New Thinking on Reactive Oxygen: A Double-Edged Sword Revisited
Authors: J. David Lambeth, Andrew S. Neish
Journal: Annual Review of Pathology Mechanisms of Disease (2013)

Reactive oxygen species (ROS) are a chemical class of molecules that have generally been conceptualized as deleterious entities, albeit ones whose destructive properties could be harnessed as antimicrobial effector functions to benefit the whole organism. This appealingly simplistic notion has been turned on its head in recent years with the discovery of the NADPH oxidases, or Noxes, a family of enzymes dedicated to the production of ROS in a variety of cells and tissues. The Nox-dependent, physiological generation of ROS is highly conserved across virtually all multicellular life, often as a generalized response to microbes and/or other exogenous stressors. This review discusses the current knowledge of the role of physiologically generated ROS and the enzymes that form them in both normal biology and disease.
Hyperventilation-induced asthma: evidence for two mechanisms.
Authors: N M Wilson, P J Barnes, H Vickers, M Silverman
Journal: Thorax (1982)

The mechanism by which airway cooling induces airflow obstruction in asthmatic subjects has not yet been established. Using a pair of isocapnic hyperventilation challenges, with a 40-minute interval, we looked for the presence of a refractory period in 19 asthmatic patients (aged 9-18 years). The subjects fell into two groups. The eight in the "non-refractory" group showed less than a 25% reduction in response to the second challenge, but the 11 in the "refractory" group showed at least a 35% reduction. Twelve subjects also performed a hyperventilation challenge after cholinergic blockade with inhaled ipratropium bromide. In five, in whom no refractoriness after hyperventilation was seen, there was a significant protection from cholinergic blockade (p less than 0.05). In these a vagal (cholinergic) reflex seems likely. The remaining seven, who had a refractory period, received no significant protection from cholinergic blockade and therefore no evidence for the presence of any cholinergic mechanism. We conclude that two mechanisms are responsible for hyperventilation-induced asthma, one of which is a vagal reflex while mediator release may be the other.
Molecular Selection of Patients for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer With Epidermal Growth Factor Inhibitors: Not Quite Ready for Prime Time
Authors: Frances A. Shepherd
Journal: Journal of Clinical Oncology (2008)

Blockade of the epidermal growth factor (EGF) pathway through inhibition of EGF receptor (EGFR) is now well established in the treatment of non–small-cell lung cancer (NSCLC). 1 However, considerable debate remains regarding when to initiate EGFR inhibitor therapy, how best to select patients for treatment, and how EGFR markers should be incorporated into clinical decision making. With respect to this last issue, EGFR protein expression determined by immunohistochemistry (IHC),EGFR gene copy number determined by fluorescent in situ hybridization (FISH), and EGFR mutation status determined by gene sequencing or other more sensitive techniques may each contribute important information regarding which patients are likely to benefit from treatment. In NSCLC, small molecule inhibition of the EGFR tyrosine kinase pathway has been the most successful strategy to date, and two oral tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, have received approval for treatment in the second- and third-line setting. 2,3 In contrast, the addition of these agents to systemic chemotherapy in the first-line