tbuckley/cabot-search huggingface dataset:
Cetuximab and Irinotecan Interact Synergistically to Inhibit the Growth of Orthotopic Anaplastic Thyroid Carcinoma Xenografts in Nude Mice
Authors: Seungwon Kim, Christopher N. Prichard, Maher N. Younes, Yasemin D. Yazici, Samar A. Jasser, B. Nebiyou Bekele, Jeffrey N. Myers
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Anaplastic thyroid carcinoma (ATC) remains one of the most lethal known human cancers. Targeted molecular therapy with cetuximab, a monoclonal antibody against epidermal growth factor receptor, offers new treatment potentials for patient with ATC. Cetuximab has also been reported to have synergistic effects when combined with irinotecan, a topoisomerase inhibitor. Therefore, we hypothesized that cetuximab and irinotecan would be effective in inhibiting the growth and progression of ATC in a murine orthotopic model. Experimental Design: The in vitro antiproliferative effects of cetuximab and irinotecan on ATC cell line ARO were examined. We also studied the in vivo effects of cetuximab and irinotecan on the growth, invasion, and metastasis of orthotopic ATC tumors in nude mice. The in vivo antitumor efficacy of cetuximab/irinotecan combination was also compared with that of doxorubicin. Results: Cetuximab alone did not show any antiproliferative or proapoptotic effect on this cell line. However, when combined with irinotecan, cetuximab potentiated the in vitro antiproliferative and proapoptotic effect of irinotecan. Cetuximab, irinotecan, and cetuximab/irinotecan combination resulted in 77%, 79%, and 93% in vivo inhibition of tumor growth, respectively. Incidences of lymph node metastasis, laryngeal invasion, and tumor microvessel density were also significantly decreased in these treatment groups. Furthermore, the cetuximab/irinotecan combination was significantly more effective than doxorubicin in inhibiting the growth of orthotopic ATC xenografts. Conclusions: Combination therapy with cetuximab/irinotecan inhibits the growth and progression of orthotopic ATC xenografts in nude mice. Given the lack of curative options for patients with ATC, combination therapy with cetuximab and irinotecan treatment warrants further study.
Training in dogs with normal coronary arteries: lack of effect on collateral development
Authors: M. V Cohen
Journal: Cardiovascular Research (1990)

Journal Article Training in dogs with normal coronary arteries: lack of effect on collateral development Get access Michael V Cohen Michael V Cohen Division of Cardiology and Department of Medicine, Montefiore Medical Center and the Albert Einstein College of Medicine, 111 East 210 Street, Bronx, NY 10467, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 24, Issue 2, February 1990, Pages 121–128, https://doi.org/10.1093/cvr/24.2.121 Published: 01 February 1990 Article history Received: 10 May 1989 Accepted: 06 October 1989 Published: 01 February 1990
Ultralarge von Willebrand Factor Fibers Mediate Luminal <i>Staphylococcus aureus</i> Adhesion to an Intact Endothelial Cell Layer Under Shear Stress
Authors: Karin I. Pappelbaum, Christian Gorzelanny, Sandra Grässle, Jan Suckau, Matthias W. Laschke, Markus Bischoff, Corinne Bauer, Marina Schorpp-Kistner, Christopher Weidenmaier, Reinhard Schneppenheim, Tobias Obser, Bhanu Sinha, Stefan W. Schneider
Journal: Circulation (2013)

During pathogenesis of infective endocarditis, Staphylococcus aureus adherence often occurs without identifiable preexisting heart disease. However, molecular mechanisms mediating initial bacterial adhesion to morphologically intact endocardium are largely unknown.Perfusion of activated human endothelial cells with fluorescent bacteria under high-shear-rate conditions revealed 95% attachment of the S aureus by ultralarge von Willebrand factor (ULVWF). Flow experiments with VWF deletion mutants and heparin indicate a contribution of the A-type domains of VWF to bacterial binding. In this context, analyses of different bacterial deletion mutants suggest the involvement of wall teichoic acid but not of staphylococcal protein A. The presence of inactivated platelets and serum increased significantly ULVWF-mediated bacterial adherence. ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) caused a dose-dependent reduction of bacterial binding and a reduced length of ULVWF, but single cocci were still tethered by ULVWF at physiological levels of ADAMTS13. To further prove the role of VWF in vivo, we compared wild-type mice with VWF knockout mice. Binding of fluorescent bacteria was followed in tumor necrosis factor-α-stimulated tissue by intravital microscopy applying the dorsal skinfold chamber model. Compared with wild-type mice (n=6), we found less bacteria in postcapillary (60±6 versus 32±5 bacteria) and collecting venules (48±5 versus 18±4 bacteria; P<0.05) of VWF knockout mice (n=5).Our data provide the first evidence that ULVWF contributes to the initial pathogenic step of S aureus-induced endocarditis in patients with an apparently intact endothelium. An intervention reducing the ULVWF formation with heparin or ADAMTS13 suggests novel therapeutic options to prevent infective endocarditis.
Increased circulating endothelial progenitor cells in patients with bacterial pneumonia: evidence that bone marrow derived cells contribute to lung repair
Authors: M Yamada
Journal: Thorax (2005)

<b>Background:</b> Tissue repair often occurs in organs damaged by various inflammatory diseases including pneumonia. Inflammatory stimuli induce a rapid and massive release of inflammatory cells from the bone marrow. Recent studies have suggested that bone marrow cells have the potential to differentiate into a variety of cell types. It has been shown that administration of lipopolysaccharide (LPS) to murine lungs induces a rapid release of endothelial progenitor cells (EPCs) into the circulation, and that bone marrow derived progenitor cells including EPCs contribute to lung repair after lung injury in mice. This study was undertaken to investigate the mobilisation of EPCs in humans following acute pneumonia. <b>Methods:</b> Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood taken from 23 patients with pneumonia during both the acute and convalescent phase. 1×10<sup>6</sup> PBMCs were plated on fibronectin coated culture slides and cultured in culture medium for endothelium. The numbers of EPCs were counted 8 days after plating. <b>Results:</b> The number of circulating EPCs significantly increased in patients with pneumonia (p&lt;0.0001). Patients with low EPC counts tended to have persistent fibrotic changes in their lungs even after their recovery from pneumonia. <b>Conclusions:</b> Inflammatory stimuli induce a rapid release of EPCs into the circulation in humans. A sufficient number of EPCs is necessary for proper lung repair following bacterial pneumonia.
The death of a footballer, equality, and medicine
Authors: S. Davies
Journal: BMJ (1998)

Doctors deal with death and inequality every day, yet attitudes persist within the medical profession that may contribute to both of these.

The death of the football player, Justin Fashanu, was reported in an uncharacteristically dignified way. We were offered the portrait of a gifted striker whose career was ruined because he was gay, his life ending in sordid shame. We seem comfortable with the notion of homosexuality as a tragic, often fatal flaw, shared by a long list of admired figures including Oscar Wilde, Rock Hudson, Gianni Versace, and George Michael.

Fashanu's obituaries should have given an account of a courageous man who fought to overcome many adversities–abandonment by his parents to the orphanage, racial prejudice, and homophobia. Rather than allow whispers about his sexuality, he “came out” in 1990, braving further rejection, by his younger brother, his team mates, his manager, and the press with speculation of scandals with MPs. Despite all of this he was determined to continue with football. He …
Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling
Authors: Vivek Rai, Fatouma Touré, Seth Chitayat, Renjun Pei, Fei Song, Qing Li, Jinghua Zhang, Rosa Rosario, Ravichandran Ramasamy, Walter J. Chazin, Ann Marie Schmidt
Journal: The Journal of Experimental Medicine (2012)

The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA–RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.
Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis
Authors: Z. K. Pinnix, L. D. Miller, W. Wang, R. D'Agostino, T. Kute, M. C. Willingham, H. Hatcher, L. Tesfay, G. Sui, X. Di, S. V. Torti, F. M. Torti
Journal: Science Translational Medicine (2010)

Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. Ferroportin is the only known mechanism for export of intracellular non–heme-associated iron; its stability is regulated by the hormone hepcidin. Although ferroportin profoundly affects concentrations of intracellular iron in tissues important for systemic iron absorption and trafficking, ferroportin concentrations in breast cancer and their influence on growth and prognosis have not been examined. We demonstrate here that both ferroportin and hepcidin are expressed in cultured human breast epithelial cells and that hepcidin regulates ferroportin in these cells. Further, ferroportin protein is substantially reduced in breast cancer cells compared to nonmalignant breast epithelial cells; ferroportin protein abundance correlates with metabolically available iron. Ferroportin protein is also present in normal human mammary tissue and markedly decreased in breast cancer tissue, with the highest degree of anaplasia associated with lowest ferroportin expression. Transfection of breast cancer cells with ferroportin significantly reduces their growth after orthotopic implantation in the mouse mammary fat pad. Gene expression profiles in breast cancers from >800 women reveal that decreased ferroportin gene expression is associated with a significant reduction in metastasis-free and disease-specific survival that is independent of other breast cancer risk factors. High ferroportin and low hepcidin gene expression identifies an extremely favorable cohort of breast cancer patients who have a 10-year survival of >90%. Ferroportin is a pivotal protein in breast biology and a strong and independent predictor of prognosis in breast cancer.
Adult immunization. Summary of the National Vaccine Advisory Committee Report
Authors: D S Fedson
Journal: JAMA (1994)

In January 1994 the National Vaccine Advisory Committee adopted a report that reviewed the status of adult immunization in the United States. Vaccine-preventable infections of adults represent a continuing cause of morbidity and mortality. Their major impact is among older persons. Effective and safe vaccines against these diseases are available, but they are poorly used. Several reasons account for low immunization levels among adults, including inadequate awareness by health care providers and the public of the importance and benefits of vaccination. Health care providers often fail to take advantage of opportunities to immunize adults during office, clinic, and hospital contacts and fail to organize programs in medical settings that ensure adults are offered the vaccines they need. Inadequate reimbursement for adult immunization by public and private health insurers and a lack of federal programs to support vaccine delivery are also major problems. The National Vaccine Advisory Committee's report includes five goals and 18 recommendations for improving adult immunization. To reach the Public Health Service adult immunization goals for the year 2000, the Committee recommends (1) improvements in public and provider education; (2) major changes in clinical practice; (3) increased financial support by public and private health insurers; (4) improved surveillance of vaccine-preventable diseases and vaccine production and delivery; and (5) support for research on vaccine-preventable diseases, new and improved vaccines, immunization practices, and international programs for adult immunization.
Characterising cortical density in the mid-tibia: intra-individual variation in adolescent girls and boys
Authors: D M L Cooper, Y Ahamed, H M Macdonald, H A McKay
Journal: British Journal of Sports Medicine (2008)

Background: Inter-individual differences in cortical bone volumetric density (CoD), such as those related to sex, are a product of differences in remodelling rates. While cortical bone is often treated as a uniform tissue, remodelling rates also vary within individual bones. This level of adaptation has largely been overlooked in analyses of peripheral quantitative computed tomography (pQCT) images. Further, such variation in CoD has never been assessed in growing bones. We hypothesised that CoD varied significantly within the same cross-section of the mid-tibia of adolescents. We further hypothesised that due to the profound impact of oestrogen on remodelling, this variation would be different between sexes. Methods: Subjects were 183 adolescents (99 girls and 84 boys) in grade 6 and 7 with a mean age of 12.1 years. We used age at peak height velocity to adjust for maturational differences between sexes. Image data from a mid-tibia pQCT scan of each subject were assessed regionally within eight sectors distributed about the cortex and aligned by the anterior tibial crest. We used a repeated measures general linear model to assess intra-individual variation in CoD while controlling for differences in ethnicity, maturity, height, weight, physical activity level and total cross-sectional bone area (ToA). Results: Sector based variation in CoD was significant (p&lt;0.001), with the anterior cortex having lower density than the posterior cortex. The largest percentage difference (anterior vs posteromedial sectors) was 12.2%. A significant sector*sex interaction (p = 0.018) was detected; however, its impact was relatively small with girls having 1.1–3.6% denser bones than boys depending on the sector (2.7% average difference). Conclusions: The magnitude of the variation in CoD across sectors within individuals of both sex was far greater than the mean differences between the sexes. This finding indicates that the microstructural variation within the mid-tibia is detectable by pQCT and its magnitude suggests an important level of adaptation to loading.
The CXCR5 Chemokine Receptor Is Expressed by Carcinoma Cells and Promotes Growth of Colon Carcinoma in the Liver
Authors: Joost Meijer, Ingrid S. Zeelenberg, Bence Sipos, Ed Roos
Journal: Cancer Research (2006)

Abstract The chemokine receptor CXCR5 is expressed by B cells and certain T cells and controls their migration into and within lymph nodes. Its ligand BCA-1/CXCL13 is present in lymph nodes and spleen and also in the liver. Surprisingly, we detected CXCR5 in several mouse and human carcinoma cell lines. CXCR5 was particularly prominent in pancreatic carcinoma cell lines and was also detected by immunohistochemistry in 7 of 18 human pancreatic carcinoma tissues. Expression in CT26 colon carcinoma was low in vitro, up-regulated in vivo, and rapidly lost when cells were explanted in vitro. CXCL13 strongly promoted proliferation of CXCR5-transfected CT26 cells in vitro. In the liver, after intrasplenic injection, these CXCR5 transfectants initially grew faster than controls, but the growth rate of control tumors accelerated later to become similar to the transfectants, likely due to the up-regulation of CXCR5. Inhibition of CXCR5 function, by trapping CXCR5 in the endoplasmic reticulum using a CXCL13-KDEL “intrakine,” had no effect on initial growth of liver foci but later caused a prolonged growth arrest. In contrast, s.c. and lung tumors of CXCR5- and intrakine-transfected cells grew at similar rates as controls. We conclude that expression of CXCR5 on tumor cells promotes the growth of tumor cells in the liver and, at least for CT26 cells, seems to be required for outgrowth to large liver tumors. Given the limited expression on normal cells, CXCR5 may constitute an attractive target for therapy, particularly for pancreatic carcinoma. (Cancer Res 2006; 66(19): 9576-82)
The propositional nature of human associative learning
Authors: Chris J. Mitchell, Jan De Houwer, Peter F. Lovibond
Journal: Behavioral and Brain Sciences (2009)

The past 50 years have seen an accumulation of evidence suggesting that associative learning depends on high-level cognitive processes that give rise to propositional knowledge. Yet, many learning theorists maintain a belief in a learning mechanism in which links between mental representations are formed automatically. We characterize and highlight the differences between the propositional and link approaches, and review the relevant empirical evidence. We conclude that learning is the consequence of propositional reasoning processes that cooperate with the unconscious processes involved in memory retrieval and perception. We argue that this new conceptual framework allows many of the important recent advances in associative learning research to be retained, but recast in a model that provides a firmer foundation for both immediate application and future research.
Some principles and practices of genetic biobanking studies
Authors: A. K. MacLeod, D. C. M. Liewald, M. M. McGilchrist, A. D. Morris, S. M. Kerr, D. J. Porteous
Journal: European Respiratory Journal (2009)

Genetic biobanking studies are becoming increasingly common as researchers recognise the need for large samples to identify the genetic basis of susceptibility to complex disease. In the present review, the authors give a brief overview of some of the issues that should be considered when implementing such a large-scale project, from study design to sample management, data coding and storage to the statistical analysis and engagement with the public. Specific solutions to these issues are presented, as implemented in the Generation Scotland projects, but the general principles outlined are relevant to any biobanking study.
Arrhythmias and conduction disturbances in obstructive sleep apnoea: the heart of the problem?
Authors: Frédéric Roche
Journal: European Respiratory Journal (2013)

Heart rhythm disorders temporally associated with obstructive apnoeic events have been highlighted for more than 30 years. An ECG from polysomnographic recordings enables both sleep medicine specialists and cardiologists to address occasional very impressive paroxysmal atrioventricular conduction blocks or sinus pauses (of up to 10 s during rapid eye movement (REM) sleep) [1]. The pathophysiology of these disorders induced by respiratory events is obviously complex and represents an exciting challenge in the context of integrative human physiology. The role of acute and chronic imbalances in the autonomic nervous system (ANS) associated with obstructive sleep apnoeas or hypopnoeas (OSA) has been clearly demonstrated in many cellular mechanisms of myocardial adaptation to such repeated stresses [2–4]. In addition, these autonomic disorders are now recognised as independent risk factors or triggers of sudden cardiac death not only in heart failure patients [5] but also in people with preserved systolic/diastolic left ventricular function [6, 7]. Although sleep is normally a time when the parasympathetic modulation of the heart predominates and myocardial electrical stability is enhanced, OSA disturbs this quiescence, creating an autonomic profile in which both profound vagal activity leading to bradycardia and sympathetic overactivity favouring ventricular ectopy are commonly observed [8].

The authors of a review paper published in the current issue of the European Respiratory Journal [9] must be congratulated for successfully detailing of the mechanisms present during apnoea/hypopnoea that can lead to heart rhythm disturbances. This paper is, for me, a remarkable teaching tool that I will use again in the future due to its clarity and its “updated” literature review.

In a second part …
Curability of Advanced Indolent or Low-Grade Follicular Lymphomas: Time for a New Paradigm?
Authors: Fernando Cabanillas
Journal: Journal of Clinical Oncology (2012)

As oncologists, we have for decades accepted two major paradigms that have shaped our management of non-Hodgkin lymphomas (NHLs): the current incurability of advanced indolent or low-grade NHL and the potential curability of most types of histologically aggressive NHL.Essentially all working oncologists have been raised under these precepts to the point that they have become our operational doctrine and sometimes our practicing dogma.After so many years, it is fitting to examine the basis for these two paradigms.The first paradigm in essence tells us that advanced low-grade NHLs are incurable disorders marked by multiple relapses in which the average patient survives for 6 to 9 years.With the advent of rituximab, their average survival has been lengthened to Ն 10 years.This paradigm is the basis for the watch-and-wait approach first promulgated by the Stanford group, 1,2 the origins of which stem from the fact that if the disease behaves indolently and is incurable, why treat it?Indeed, a few randomized trials that have attempted to look at early intervention have failed to prove superiority in survival over watch and wait. 3,4he second paradigm states that aggressive NHLs are potentially curable, and if a patient survives disease free beyond 2 years, he or she can be considered cured.The source of this practice standard can be traced back to a report by De Vita et al, 5 entitled "Diffuse Histiocytic Lymphoma, a Potentially Curable Disease," published in Lancet in 1974.It described a total of 27 patients with what used to be called diffuse histiocytic lymphoma, which is now designated diffuse largecell lymphoma (DLCL).Of these 27 patients, 10 achieved complete remission, and of these 10, only one experienced relapse.On the basis of these nine so-called cured patients, they concluded that "survival free of disease beyond two years from the end of treatment may be considered tantamount to cure." 5(p248) Having summarized the basis and origins of these two paradigms, it is now appropriate to examine their legitimacy.Because these paradigms have shaped our thinking throughout decades, these issues are not of merely academic significance.If we accept that indolent NHLs are indeed incurable, then the research questions that we will ask, as well as the therapeutic goals that we will set, can be fogged by this concept of incurability.The primary goals of phase II trials can then become response rate and progressionfree survival; cure can turn into a nonissue, thus leading to discovery of multiple new active agents but not to the development of an integrated curative strategy.