tbuckley/cabot-search huggingface dataset:
Lipid-induced changes in intracellular iron homeostasis in vitro and in vivo.
Authors: B J Van Lenten, J Prieve, M Navab, S Hama, A J Lusis, A M Fogelman
Journal: Journal of Clinical Investigation (1995)

Iron promotes cellular damage via its capacity to catalyze hydroxyl radical formation and by peroxidation of unsaturated lipids. The major cellular iron storage depot, ferritin, acts as a critical antioxidant defense by sequestering unbound or "free" iron, limiting its participation in damaging oxidative reactions. In this study, we investigated the relationship between LDL modified by artery wall cells and the regulation of intracellular free iron levels in the mouse model and in a human aortic endothelial and smooth muscle cell coculture system. We found in response to an atherogenic diet, fatty streak-resistant C3H/HeJ mice exhibited higher levels of liver apoferritin and lower intracellular concentrations of free iron than did fatty streak-susceptible C57 BL/6J mice. Also, ferritin repressor protein mRNA was not significantly suppressed after 15 wk on the atherogenic diet in female C57BL/6J mice, which exhibit the most extensive fatty streak formation, but was significantly reduced in C3H/HeJ mice. Iron loading of coculture cells resulted in elevations of cellular free iron and enhanced LDL-induced monocyte transmigration. Pretreatment of cells with apoferritin completely abolished iron-induced LDL modification. Addition of LDL to cocultures resulted in elevations in lipid peroxidation products, intracellular free iron, apoferritin mRNA expression, and apoferritin synthesis, suggesting a possible relationship between the oxidative modification of LDL and iron metabolism.
Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies
Authors: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Krisztian Homicsko, Angelica Fasolo, Gianluca Del Conte, Anna Durigova, Nadia Hayaoui, Sophie Gourgou, Luca Gianni, Caroline Mollevi
Journal: Journal of Clinical Oncology (2015)

We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds.We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013.A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion.This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.
P185 Pulmonary infection in PiZZ antitrypsin individuals is associated with increased oxidative and nitrosative stress
Authors: S Alam, J Parmar, K Santhanakrishnan, R Mahadeva
Journal: Thorax (2013)

<h3></h3> Severe deficiency <i>of</i> the major anti-elastase α<sub>1</sub>-antitrypsin (AT) due to the Z (Glu342Lys) variant is associated with early-onset emphysema which can require lung transplantation. AT is mainly produced by the liver and a lesser proportion (around 10%) is produced in the lung. Therefore individuals with Z-AT post-lung transplantation remain severely deficient in AT. We studied patients with and without AT deficiency with infection (post lung transplantation) to examine the relationship between deficiency of AT and oxidative/nitrosative stress. BALF was obtained at scheduled surveillance, and when clinically indicated to assess for infection, rejection and airway injury. 25 patients post-transplant were evaluated; 12/26 samples from 12 Z-AT patients had infective tracheobronchitis, and 7/29 samples from 13 M(normal)-AT had infective tracheobronchitis. The level of oxidative stress (F<sub>2</sub>-Isoprostane), TNF-α, IL-1β, IFN-γ was quantified using respective ELISA kits and for total glutathione (GSH) and oxidised GSH (GSSG) using OxiSelect™ Total Glutathione (GSSG/GSH) Assay Kit and nitrosative stress using Griess reagent. BALF of Z-AT patients with infection had increased oxidative stress compared to infected M-AT patients; F<sub>2</sub>-Isoprostane, 773SEM ± 79.5 pg/ml vs. 425.8 ± 53.2, P &lt; 0.001 respectively, oxidised glutathione (0.112 ± 0.1μM/ml vs. 0.155 ± 0.1, P = 0.027). However, total glutathione was unchanged (0.885 ± 13 μM/ml vs. 1.17 ± 0.141, P = 0.117). There was increased nitrosative stress in Z-AT vs. M-AT patients (nitrite release as a measure of nitric oxide (NO) production (261 ± 47 pg/ml vs. 117 ± 41.2, P &lt; 0.001), and increased levels of TNF-α (91 ± 16.3 pg/ml vs. 59 ± 10.5, P = 0.002), IL-1β (121.2 ± 17.4 pg/ml vs. 69.6 ± 5.8, P = 0.047) and IFN-γ (481.3 ± 74.8 pg/ml vs. 201.2 ± 28.5, P = 0.025). Infected Z-AT BALF had increased free HLE compared to infected M-AT patients (167 ± 16 ng/ml vs. 42.7 ± 16, P &lt; 0.001). In conclusion, Z-AT lungs had increased oxidative and nitrosative stress, and furthermore had increased levels of cytokines that are associated with induction of the inducible NO synthase (iNOS) gene. This suggests that excess production of iNOS-derived NO is likely to contribute to exaggerated inflammation in the PiZZ individuals lungs during episodes of infection which may contribute to progression of their lung disease.
Endogenous parathyroid hormone is associated with reduced cartilage volume in vivo in a population-based sample of adult women
Authors: Sharon Lee Brennan, Flavia M Cicuttini, Geoff C Nicholson, Julie A Pasco, Mark A Kotowicz, Anita E Wluka
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Animal and in vitro studies suggest that parathyroid hormone (PTH) may affect articular cartilage. However, little is known of the relationship between PTH and human joints in vivo. <h3>Design</h3> Longitudinal. <h3>Setting</h3> Barwon Statistical Division, Victoria, Australia. <h3>Participants</h3> 101 asymptomatic women aged 35–49 years (2007–2009) and without clinical knee osteoarthritis, selected from the population-based Geelong Osteoporosis Study. <h3>Risk factors</h3> Blood samples obtained 10 years before (1994–1997) and stored at −80°C for random batch analyses. Serum intact PTH was quantified by chemiluminescent enzyme assay. Serum 25-hydroxyvitamin D (25(OH)D) was assayed using equilibrium radioimmunoassay. Models were adjusted for age, bone area and body mass index; further adjustment was made for 25(OH)D and calcium supplementation. <h3>Outcome</h3> Knee cartilage volume, measured by MRI. <h3>Results</h3> A higher lnPTH was associated with reduced medial—but not lateral—cartilage volume (regression coefficient±SD, p value: −72.2±33.6 mm<sup>3</sup>, p=0.03) after adjustment for age, body mass index and bone area. Further sinusoidal adjustment (−80.8±34.4 mm<sup>3</sup>, p=0.02) and 25(OH)D with seasonal adjustment (−72.7±35.1 mm<sup>3</sup>, p=0.04), calcium supplementation and prevalent osteophytes did not affect the results. <h3>Conclusions</h3> A higher lnPTH might be detrimental to knee cartilage in vivo. Animal studies suggest that higher PTH concentrations reduce the healing ability of cartilage following minor injury. This may be apparent in the presence of increased loading, which occurs in the medial compartment, placing the medial cartilage at higher risk for injury.
Neuroblastoma mRNAs Predict Outcome in Children With Stage 4 Neuroblastoma: A European HR-NBL1/SIOPEN Study
Authors: Virginie F. Viprey, Walter M. Gregory, Maria V. Corrias, Andrei Tchirkov, Katrien Swerts, Ales Vicha, Sandro Dallorso, Penelope Brock, Roberto Luksch, Dominique Valteau-Couanet, Vassilios Papadakis, Genevieve Laureys, Andrew D. Pearson, Ruth Ladenstein, Susan A. Burchill
Journal: Journal of Clinical Oncology (2014)

To evaluate the hypothesis that detection of neuroblastoma mRNAs by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) in peripheral blood (PB) and bone marrow aspirates (BM) from children with stage 4 neuroblastoma are clinically useful biomarkers of risk.
Celecoxib, a Cyclooxygenase-2 Inhibitor, Reduces Neointimal Hyperplasia Through Inhibition of Akt Signaling
Authors: Han-Mo Yang, Hyo-Soo Kim, Kyung-Woo Park, Hyun-Jeong You, Soo-In Jeon, Seock-Won Youn, Sung-Hwan Kim, Byung-Hee Oh, Myoung-Mook Lee, Young-Bae Park, Kenneth Walsh
Journal: Circulation (2004)

Background— Celecoxib has been shown to have antitumor effects that may be mediated through the cyclooxygenase-independent inhibition of Akt signaling. Here, we examined the effects of celecoxib on neointimal formation after balloon injury and its mechanism of action. Methods and Results— In vitro experiments were performed to evaluate the effects of celecoxib on the Akt/GSK signaling axis and the viability of rat vascular smooth muscle cells (VSMCs). In vivo experiments examined the effects of celecoxib, aspirin, and vehicle on neointimal growth after denudation injury to rat carotid arteries. In vitro, celecoxib suppressed the phosphorylation of Akt and GSK in cultured VSMCs, leading to a reduction in viable cell number, which was reversed by transduction of constitutively active Akt. Such a reduction in cell number was mediated by inhibition of proliferation and induction of apoptosis. In vivo, celecoxib reduced injury-induced phosphorylation of Akt and GSK, reduced VSMC proliferation, and increased caspase-3 activation and VSMC apoptosis at 3 days after injury, whereas aspirin had no effect. At 2 weeks after injury, celecoxib reduced intima-to-media ratio, whereas aspirin had no effect. Adenovirus-mediated delivery of dominant negative Akt was as effective as celecoxib at inhibiting neointimal formation. Conversely, gene delivery of constitutively active Akt significantly reversed the inhibition of intimal hyperplasia by celecoxib, providing causal evidence that the modulation of Akt signaling by celecoxib is a physiologically relevant mechanism. Conclusions— Celecoxib is a potential inhibitor of neointimal formation by blocking injury-induced Akt activation. These findings suggest a potential use for celecoxib in the prevention of restenosis after angioplasty.
MDM2 SNP309 Accelerates Tumor Formation in a Gender-Specific and Hormone-Dependent Manner
Authors: Gareth L. Bond, Kim M. Hirshfield, Tomas Kirchhoff, Gabriella Alexe, Elisabeth E. Bond, Harlan Robins, Frank Bartel, Helge Taubert, Peter Wuerl, William Hait, Deborah Toppmeyer, Kenneth Offit, Arnold J. Levine
Journal: Cancer Research (2006)

Abstract The importance of the p53 stress response pathway in the suppression of tumor formation is well documented. In a previous report, a single nucleotide polymorphism (SNP309 T/G) was found in the promoter of the MDM2 gene resulting in higher levels of MDM2 RNA and protein and, consequently, in the attenuation of the p53 pathway both in vitro and in vivo. As the SNP309 locus is found in a region of the MDM2 promoter, which is regulated by hormonal signaling pathways, and the G-allele of SNP309 increases the affinity of a well-described cotranscriptional activator of nuclear hormone receptors (i.e., Sp1), the hypothesis that the SNP309 locus could alter the effects of hormones on tumorigenesis was tested in vivo in humans. Data obtained from patients with three different sporadic cancers, from four independent case studies, support this hypothesis, providing an example for the genetic basis of gender differences in cancer and showing that the genotype at a specific locus can affect how hormones, like estrogen, affect tumorigenesis in humans. (Cancer Res 2006; 66(10): 5104-10)
Molecular Profiling of Pancreatic Neuroendocrine Tumors in Sporadic and Von Hippel-Lindau Patients
Authors: Daniela Speisky, Aurélie Duces, Ivan Bièche, Vinciane Rebours, Pascal Hammel, Alain Sauvanet, Stéphane Richard, Pierre Bedossa, Michel Vidaud, Arnaud Murat, Patricia Niccoli, Jean-Yves Scoazec, Philippe Ruszniewski, Anne Couvelard
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Von Hippel-Lindau (VHL) disease is an inherited syndrome caused by germline mutations in the VHL tumor suppressor gene, predisposing to a variety of neoplasms including pancreatic neuroendocrine tumors (PanNET). In VHL disease, PanNET probably progress according to a specific pathway of carcinogenesis. Our aim was to characterize by molecular quantitative analysis a panel of molecules implicated in the VHL pathway and in tumor progression in the PanNET of patients with VHL. Experimental Design: The expression of 52 genes was studied by quantitative reverse transcriptase PCR in 18 patients with VHL operated on for PanNET and compared with 16 non-VHL PanNET. The VHL and non-VHL tumors were matched according to their size and cell proliferation. For some genes, we looked for differences in the protein expression in VHL PanNET (n = 31), microadenomas (n = 22), and non-VHL PanNET (n = 16), included in tissue microarray blocks. Results: Nineteen (36%) genes were significantly upregulated and three (6%) downregulated in VHL PanNET. The upregulated genes were related to (i) hypoxia-inducible factor (HIF) molecules (CA9, HIF2A, and GLUT1), (ii) angiogenesis (CDH5, VEGFR1, EDNRA, ANGPT2, CD34, VEGFR2, VEGFA, and ANGPT1), (iii) the processes of epithelial–mesenchymal transition (VIM) and/or metastasis (LAMA4 and CXCR4), (iv) growth factors and receptors (PDGFB, IRS1, and ERBB1), or (v) cell cycle (CCND1 and CDKN2A). The downregulated genes were related to (i) EMT (OCLN) and (ii) signaling pathways (RPS6KB1 and GADD45B). Conclusion: This study shows that the progression of PanNET in patients with VHL tumors follows a specific pathway and supports that targeting molecules specifically involved may be of therapeutic importance. Clin Cancer Res; 18(10); 2838–49. ©2012 AACR.
Prostate-specific antigen doubling time before onset of chemotherapy as a predictor of survival for hormone-refractory prostate cancer patients
Authors: S. Oudard, E. Banu, F. Scotte, A. Banu, J. Medioni, P. Beuzeboc, F. Joly, J.-M. Ferrero, F. Goldwasser, J.-M. Andrieu
Journal: Annals of Oncology (2007)
Circus movement in canine right ventricle.
Authors: J M de Bakker, B Henning, W Merx
Journal: Circulation Research (1979)

The present study reports on the epicardial spread of excitation during premature beats and during the initial stages of ventricular fibrillation, both of which were induced by single-test stimuli during regional ischemia or local hypothermia. Simultaneous recording of the activity at 48 epicardial sites on the right ventricle of dog hearts enabled us in some instances to demonstrate a circus movement.
Shear stress–induced changes in atherosclerotic plaque composition are modulated by chemokines
Authors: Caroline Cheng, Dennie Tempel, Rien van Haperen, Hetty C. de Boer, Dolf Segers, Martin Huisman, Anton Jan van Zonneveld, Pieter J.M. Leenen, Anton van der Steen, Patrick W. Serruys, Rini de Crom, Rob Krams
Journal: Journal of Clinical Investigation (2007)

We previously found that low shear stress (LSS) induces atherosclerotic plaques in mice with increased lipid and matrix metalloproteinase content and decreased vascular smooth muscle and collagen content. Here, we evaluated the role of chemokines in this process, using an extravascular device inducing regions of LSS, high shear stress, and oscillatory shear stress (OSS) in the carotid artery. One week of shear stress alterations induced expression of IFN-gamma-inducible protein-10 (IP-10) exclusively in the LSS region, whereas monocyte chemoattractant protein-1 (MCP-1) and the mouse homolog of growth-regulated oncogene alpha (GRO-alpha) were equally upregulated in both LSS and OSS regions. After 3 weeks, GRO-alpha and IP-10 were specifically upregulated in LSS regions. After 9 weeks, lesions with thinner fibrous caps and larger necrotic cores were found in the LSS region compared with the OSS region. Equal levels of MCP-1 expression were observed in both regions, while expression of fractalkine was found in the LSS region only. Blockage of fractalkine inhibited plaque growth and resulted in striking differences in plaque composition in the LSS region. We conclude that LSS or OSS triggers expression of chemokines involved in atherogenesis. Fractalkine upregulation is critically important for the composition of LSS-induced atherosclerotic lesions.
Detection of Underdiagnosed and Poorly Controlled Asthma in a Hospital-Based Outpatient Pediatric Clinic using a Health Risk Assessment (HRA) System
Authors: B. Nichols, L. Scott, S. Jones, K. Kwong, T. Morphew, L.T. Clement, F. Lifson, C.A. Jones
Journal: Journal of Allergy and Clinical Immunology (2007)
Cholesterol induced lipid accumulation in cardiomyocytes
Authors: M. AVIRAM
Journal: Cardiovascular Research (1993)

Journal Article Cholesterol induced lipid accumulation in cardiomyocytes Get access MICHAEL AVIRAM MICHAEL AVIRAM Lipid Research Laboratory, Rambam Medical Centre, Haifa, Israel Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 27, Issue 3, March 1993, Page 538, https://doi.org/10.1093/cvr/27.3.538 Published: 01 March 1993
Muscle biopsy in polymyositis and dermatomyositis: a clinicopathological study.
Authors: H A Schwarz, G Slavin, P Ward, B M Ansell
Journal: Annals of the Rheumatic Diseases (1980)

The initial muscle biopsies of 30 patients with active polymyositis or dermatomyositis have been assessed histologically and morphometrically. Only 1 patient (3.3%) had a normal biopsy, while 3 had a normal electromyograph and 8 had a normal serum CPK level. No significant morphological differences were found between the various diagnostic subgroups. Sequential biopsies of 11 of these patients treated either with corticosteroids only or with intensive immunosuppression were studied. With response to treatment atrophy factors, variability coefficients, internal nuclei count, and the various histological changes improved in the whole group of patients. However, there was no consistent correlation between any of the morphological features or between these and clinical parameters in individual patients. The percentage of fibres with internal nuclei in the initial biopsy was lower (P &lt; 0.001) in patients responding to up to 60 mg prednisolone per day than in those who eventually required cytotoxic drugs in addition.
Rising Double-Mastectomy Rates Attract Increasing Scrutiny
Authors: J. Susan
Journal: JNCI Journal of the National Cancer Institute (2015)

one high-risk feature. A recent joint analysis of the NSABP B-31 and NCCTG N9831 randomized phase III trials that led to these approvals showed that adjuvant trastuzumab added to chemotherapy increased 10-year overall survival from 75.2% to 84% and 10-year DFS from 62.2% to 73.7%, Salazar said. “So the question becomes, if you add the vaccine to trastuzumab to prevent recurrence, does it improve survival even more? And with this vaccine, it’s limited to those who are HLA-A2+, so that’s a small pool of breast cancer patients.” (About 40%–55% of the population has the HLA-A2 allele.) Mittendorf acknowledged that obstacles to bringing a HER2 vaccine forward exist. “The HER2 space is crowded,” she said. “Trastuzumab is no longer the only player. There is TDM-1 (Kadcyla). There is pertuzumab (Perjeta). These agents are being tested in the neoadjuvant and adjuvant setting. We will need to further investigate and see who really needs what. [HER2-targeted] therapies are expensive regimens” to combine, and they have side effects. The vaccine is nontoxic, is very inexpensive and might stimulate a memory response that would work against HER2 for life.” And that excites researchers. “The logic to test these vaccines is there and the potential is definitely there,” Slamon said. “It’s been known for a long time you that you could get an immune response to what you are immunizing against. But just because you can measure an immune response doesn’t mean it will translate into a clinical response or clinical benefit. You only know that by looking at clinical outcomes and that takes time.” Norwell owns the GP2 vaccine. Mittendorf is the principal investigator on vaccine trials that Galena Biopharma (NeuVax), Antigen Express (AE37), and Norwell sponsored. The M. D. Anderson Cancer Center receives financial support for each study patient enrolled. George E. Peoples Jr., M.D., F.A.C.S., a coauthor of the GP2 study, holds inventor rights to GP2.
Stem Cells for Treating Glioblastoma: How Close to Reality?
Authors: C. D. James, W. K. Cavenee
Journal: Neuro-Oncology (2008)

It is widely acknowledged that the incurable nature of glioblastoma (GBM) is primarily attributable to the infiltrative growth of the cancer.This makes complete surgical resection at best unlikely and necessitates that adjunctive therapies must eradicate all residual tumor cells in the brains of affected patients to prevent tumor recurrence.Moreover, this should ideally be accomplished while causing as little damage to the normal brain as possible.The history of translational research toward this end now spans more than 50 years, with only incremental improvements in extending glioblastoma patients' lives.This slow progress has not been due to a lack of creative approaches for treating GBM.To the contrary, innovative therapeutic approaches have proliferated in recent years.Nonetheless, results from the clinical trials associated with these approaches have proven GBM to be a formidable and therapy-resistant foe.We are currently testing targeted therapies, and it is teaching us about the importance of tailoring therapies to individuals.Perhaps in the not-too-distant future, the ability to obtain comprehensive tumor molecular profiles in a clinically meaningful time frame will coalesce with a sufficiently large body of knowledge regarding the relationships between these molecular characteristics and responses to specific therapeutic regimens.Until, and if, such a time is reached, the search for broadly applicable therapies continues.The newest entrant in the field of promising approaches is the subject of this editorial.
Letter: Acute respiratory failure in Muslim babies.
Authors: E M Carr-Saunders
Journal: BMJ (1974)

work with normal and malignant cells of identical tissue origin has clearly Ehown that thermosensitivity is one of the early charac- teristics of the malignant cell transforma- tion.1 2 A paper, not cited by Mr. Hall and his colleagues, on the relationship of hyper- thermia and radiation in the treatnent of bladder cancer was published by Cockett et al. in 1967.3Though heat alone can cure cancer in a few experimental systems4' many of the 'published papers report investigations into the use of heat as a "sensitizer" to radiation6-8 or chemotherapic agents.9-"Un- published in vitro data of my own show that a temperature of 42'C applied;for two hours enhances the killing effect of several chemo- therapic agents by factors varying fromn 10 to 100.-I am, etc.,