tbuckley/cabot-search huggingface dataset:
Letrozole after Tamoxifen for Breast Cancer — What Is the Price of Success?
Authors: John Bryant, Norman Wolmark
Journal: New England Journal of Medicine (2003)

In this issue of the Journal, Goss et al.1 report results from a trial that will have a considerable effect on the treatment of early-stage breast cancer. The study was led by the National Cancer Institute of Canada Clinical Trials Group and was a joint effort of the North American Intergroup and the Breast International Group. These organizations are to be commended for a well-conceived and well-conducted clinical trial. Their work is an excellent example of the way in which clinical-trial organizations can work together efficiently and expeditiously to investigate clinical questions of common interest.Previous trials have shown that . . .
Increased absence due to sickness among employees with fibromyalgia
Authors: M Kivimaki, P Leino-Arjas, L Kaila-Kangas, M Virtanen, M Elovainio, S Puttonen, L Keltikangas-Jarvinen, J Pentti, J Vahtera
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> Little is known about the effect of fibromyalgia on absence due to sickness in working populations. <b>Objective:</b> To examine the risk of absence due to sickness among employees with fibromyalgia. <b>Methods:</b> A prospective cohort study with 1-year follow-up of recorded and certified absence due to sickness after a survey of chronic diseases among 34 100 Finnish public sector employees (27 360 women and 6740 men) aged 17–65 years at baseline in 2000–2. <b>Results:</b> 20 224 days of absence due to sickness for the 644 employees with fibromyalgia and 454 816 days for others were documented. Of those with fibromyalgia, 67% had co-occurring chronic conditions such as osteoarthritis, rheumatoid arthritis, depression or other psychiatric disorders. Compared with employees with none of these chronic conditions, the hazard ratio (HR) adjusted for age, sex and occupational status was 1.85-fold (95% confidence interval (CI) 1.53 to 2.18) for people with fibromyalgia alone and 2.63-fold (95% CI 2.34 to 2.96) for employees with fibromyalgia with coexisting conditions. The excess rate of absence due to sickness was 61 episodes/100 person-years among people with fibromyalgia alone. Among employees with musculoskeletal and psychiatric disorders, secondary fibromyalgia was associated with a 1.4–1.5-fold increase in risk of absence. <b>Conclusion:</b> Fibromyalgia is associated with a substantially increased risk of medically certified absence due to sickness that is not accounted for by coexisting osteoarthritis, rheumatoid arthritis or psychiatric disorders.
Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance
Authors: Miguel López, Luis Varela, María J Vázquez, Sergio Rodríguez-Cuenca, Carmen R González, Vidya R Velagapudi, Donald A Morgan, Erik Schoenmakers, Khristofor Agassandian, Ricardo Lage, Pablo Blanco Martínez de Morentin, Sulay Tovar, Rubén Nogueiras, David Carling, Christopher Lelliott, Rosalía Gallego, Matej Orešič, Krishna Chatterjee, Asish K Saha, Kamal Rahmouni, Carlos Diéguez, Antonio Vidal-Puig
Journal: Nature Medicine (2010)
Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes
Authors: R L Young, K Sutherland, N Pezos, S M Brierley, M Horowitz, C K Rayner, L A Blackshaw
Journal: Gut (2008)

<h3>Objective:</h3> Nutrient feedback from the small intestine modulates upper gastrointestinal function and energy intake; however, the molecular mechanism of nutrient detection is unknown. In the tongue, sugars are detected via taste T1R2 and T1R3 receptors and signalled via the taste G-protein α-gustducin (Gα<sub>gust</sub>) and the transient receptor potential ion channel, TRPM5. These taste molecules are also present in the rodent small intestine, and may regulate gastrointestinal function. <h3>Subjects and methods:</h3> Absolute transcript levels for T1R2, T1R3, Gα<sub>gust</sub> and TRPM5 were quantified in gastrointestinal mucosal biopsies from subjects with and without type 2 diabetes; immunohistochemistry was used to locate Gα<sub>gust</sub>. Effects of luminal glucose on jejunal expression of taste molecules were also quantified in mice. <h3>Results:</h3> T1R2, T1R3, Gα<sub>gust</sub> and TRPM5 were preferentially expressed in the proximal small intestine in humans, with immunolabelling for Gα<sub>gust</sub> localised to solitary cells dispersed throughout the duodenal villous epithelium. Expression of T1R2, T1R3, TRPM5 (all p&lt;0.05) and Gα<sub>gust</sub> (p&lt;0.001) inversely correlated with blood glucose concentration in type 2 diabetes subjects but, as a group, did not differ from control subjects. Transcript levels of T1R2 were reduced by 84% following jejunal glucose perfusion in mice (p&lt;0.05). <h3>Conclusions:</h3> Taste molecules are expressed in nutrient detection regions of the proximal small intestine in humans, consistent with a role in "tasting". This taste molecule expression is decreased in diabetic subjects with elevated blood glucose concentration, and decreased by luminal glucose in mice, indicating that intestinal "taste" signalling is under dynamic metabolic and luminal control.
Cytokine Response Modifier A (CrmA) Inhibits Ceramide Formation in Response to Tumor Necrosis Factor (TNF)-α: CrmA and Bcl-2 Target Distinct Components in the Apoptotic Pathway
Authors: Ghassan S. Dbaibo, David K. Perry, Chris J. Gamard, Rheanna Platt, Guy G. Poirier, Lina M. Obeid, Yusuf A. Hannun
Journal: The Journal of Experimental Medicine (1997)

Proteases are now firmly established as major regulators of the “execution” phase of apoptosis. Here, we examine the role of proteases and their relationship to ceramide, a proposed mediator of apoptosis, in the tumor necrosis factor-α (TNF-α)–induced pathway of cell death. Ceramide induced activation of prICE, the protease that cleaves the death substrate poly(ADP-ribose) polymerase. Bcl-2 inhibited ceramide-induced death, but not ceramide generation. In contrast, Cytokine response modifier A (CrmA), a potent inhibitor of Interleukin-1β converting enzyme and related proteases, inhibited ceramide generation and prevented TNF-α–induced death. Exogenous ceramide could overcome the CrmA block to cell death, but not the Bcl-2 block. CrmA, however, did not inhibit the activation of nuclear factor (NF)-κB by TNF-α, demonstrating that other signaling functions of TNF-α remain intact and that ceramide does not play a role in the activation of NF-κB. These studies support a distinct role for proteases in the signaling/activation phase of apoptosis acting upstream of ceramide formation.
Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus
Authors: Makiko Kido-Nakahara, Jörg Buddenkotte, Cordula Kempkes, Akihiko Ikoma, Ferda Cevikbas, Tasuku Akiyama, Frank Nunes, Stephan Seeliger, Burcu Hasdemir, Christian Mess, Timo Buhl, Mathias Sulk, Frank-Ulrich Müller, Dieter Metze, Nigel W. Bunnett, Aditi Bhargava, Earl Carstens, Masutaka Furue, Martin Steinhoff
Journal: Journal of Clinical Investigation (2014)

In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein–coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin–converting enzyme 1 (ECE-1) as a key regulator of ET-1–induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1–containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1–induced activation of ERK1/2, but not p38. In a murine itch model, ET-1–induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1–induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.
The Chemokine Receptor CXCR7 Is Highly Expressed in Human Glioma Cells and Mediates Antiapoptotic Effects
Authors: Kirsten Hattermann, Janka Held-Feindt, Ralph Lucius, Susanne Sebens Müerköster, Mark E.T. Penfold, Thomas J. Schall, Rolf Mentlein
Journal: Cancer Research (2010)

Abstract The chemokine CXCL12/stromal cell–derived factor-1 and its receptor CXCR4 play a major role in tumor invasion, proliferation, and metastasis. Recently, CXCR7 was identified as a novel, alternate receptor for CXCL12 and CXCL11/I-TAC. Because both chemokines are expressed abundantly in human astrocytomas and glioblastomas, we investigated the occurrence and function of both receptors in astroglial tumors. In situ, CXCR7 is highly expressed on tumor endothelial, microglial, and glioma cells whereas CXCR4 has a much more restricted localization; CXCL12 is often colocalized with CXCR7. CXCR7 transcription in tumor homogenates increased with malignancy. In vitro, CXCR7 was highly expressed in all glioma cell lines investigated whereas CXCR4 was only scarcely transcribed on one of eight lines. In contrast, a tumor stem-like cell line preferentially expressed CXCR4 which diminished upon differentiation, whereas CXCR7 increased drastically. Stimulation of CXCR7-positive glioma cells (CXCR4- and CXCR3-negative) by CXCL12 induced transient phosphorylation of extracellular signal-regulated kinases Erk1/2, indicating that the receptor is functionally active. The phosphoinositide-specific phospholipase C inhibitor U73122 effectively inhibited Erk activation and suggests that the mitogen-activated protein kinase pathway is activated indirectly. Whereas proliferation and migration were little influenced, chemokine stimulation prevented camptothecin- and temozolomide-induced apoptosis. The selective CXCR7 antagonist CCX733 reduced the antiapoptotic effects of CXCL12 as shown by nuclear (Nicoletti) staining, caspase-3/7 activity assays, and cleavage of poly(ADP-ribose) polymerase-1. Thus, CXCR7 is a functional receptor for CXCL12 in astrocytomas/glioblastomas and mediates resistance to drug-induced apoptosis. Whereas CXCR7 is found on “differentiated” glioma cells, the alternate receptor CXCR4 is also localized on glioma stem-like cells. Cancer Res; 70(8); 3299–308. ©2010 AACR.
Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells
Authors: Wing-hong Kwan, William van der Touw, Estela Paz-Artal, Ming O. Li, Peter S. Heeger
Journal: The Journal of Experimental Medicine (2013)

Thymus-derived (natural) CD4+ FoxP3+ regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell–expressed C5a receptor (C5aR) and C3a receptor (C3aR) to activation, differentiation, and expansion of conventional CD4+CD25− T cells (T conv cells), raised the possibility that C3aR/C5aR signaling on nT reg cells could physiologically modulate nT reg cell function and thereby further impact the induced strength of T cell immune responses. In this study, we demonstrate that nT reg cells express C3aR and C5aR, and that signaling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function via controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses.
Mechanism of basic calcium phosphate crystal-stimulated matrix metalloproteinase-13 expression by osteoarthritic synovial fibroblasts: inhibition by prostaglandin E2
Authors: E S Molloy, M P Morgan, G A Doherty, B McDonnell, J O'Byrne, D J Fitzgerald, G M McCarthy
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To determine the mechanism of matrix metalloproteinase (MMP)-13 upregulation in osteoarthritic synovial fibroblasts (OASF) in response to stimulation with basic calcium phosphate (BCP) crystals and to investigate the effect of prostaglandin (PG)E<sub>2</sub> on BCP crystal-stimulated MMP expression. <h3>Methods:</h3> Primary OASF were stimulated with BCP crystals; mRNA expression was measured by real-time reverse transcription–polymerase chain reaction and protein levels were assessed by Western blotting. <h3>Results:</h3> BCP crystals upregulated MMP-13 mRNA expression over 20-fold and increased MMP-13 protein production in OASF. BCP crystal-stimulated MMP-13 mRNA expression was blocked by inhibition of the extracellular regulated kinase (ERK1/2) and p38 mitogen activated protein kinase (MAPK) pathways and inhibition of the activation of nuclear factor κB. Addition of exogenous PGE<sub>2</sub> downregulated BCP crystal-stimulated MMP-13 expression. In contrast, PGE<sub>2</sub> upregulated, and had no effect, on BCP crystal stimulated MMP-3 and MMP-1 mRNA expression, respectively. These effects of PGE<sub>2</sub> were diminished by L-161,982, a selective EP4 receptor antagonist, and mimicked by CAY10399, a selective EP2 receptor agonist, and forskolin, an adenylate cyclase activator. <h3>Conclusions:</h3> These data suggest that BCP crystal induction of MMP-13 expression may involve the ERK1/2 and p38 MAPK pathways and activation of nuclear factor κB; this upregulation of MMP-13 may contribute to the accelerated cartilage breakdown in BCP crystal-associated osteoarthritis. PGE<sub>2</sub> had contrasting effects on BCP crystal-stimulated MMP-3 and MMP-13 mRNA expression, mediated in an EP2/EP4/cAMP-dependent manner, suggesting that PGE<sub>2</sub> may have beneficial as well as deleterious effects in BCP crystal-associated osteoarthritis.
Retinol-binding protein: the transport protein for vitamin A in human plasma
Authors: Masamitsu Kanai, Amiram Raz, DeWitt S. Goodman
Journal: Journal of Clinical Investigation (1968)

Vitamin A circulates in human plasma as retinol bound to a specific transport protein. This protein differs from the known low and high density plasma lipoproteins and has a hydrated density greater than 1.21. In order to study this protein, volunteers were injected intravenously with retinol-15-(14)C. Plasma was collected 1-3 days later, and the purification of retinol-binding protein (RBP) was monitored by assaying for (14)C and also by following the fluorescence of the protein-bound retinol. Purification of RBP was effected by the sequence: Cohn fractionation, chromatography on columns of Sephadex G-200 and diethylaminoethyl (DEAE)-Sephadex, preparative polyacrylamide gel electrophoresis, and finally chromatography on Sephadex G-100. These procedures resulted in a preparation of RBP which was at least 98% pure and which had been purified more than 1500-fold. Purified RBP has alpha(1) mobility on electrophoresis and has a molecular weight of approximately 21,000-22,000. There appears to be one binding site for retinol per molecule of RBP. Solutions of RBP are fluorescent (characteristic of retinol) and have ultraviolet absorption spectra with peaks at 330 mmu (resulting from the bound retinol) and at 280 mmu. There are no fatty acid or fatty acyl chains present in purified RBP. The usual concentration of RBP in plasma is of the order of 3-4 mg/100 ml. In plasma, RBP apparently circulates as a complex, together with another, larger protein with prealbumin mobility on electrophoresis. The RBP-prealbumin complex remains intact during Cohn fractionation and during chromatography on Sephadex and on DEAE-Sephadex columns. The complex dissociates during gel electrophoresis, permitting the isolation and subsequent purification of each of the components. The complex is again formed by mixing together solutions of the separated RBP and of prealbumin. Retinol transport in plasma thus appears to involve both a lipid-protein (retinol-RBP) interaction and a protein-protein (RBP-prealbumin) interaction.
Aging Leads to Disturbed Homeostasis of Memory Phenotype CD8+ Cells
Authors: Xiaohong Zhang, Hideki Fujii, Hidehiro Kishimoto, Eric LeRoy, Charles D. Surh, Jonathan Sprent
Journal: The Journal of Experimental Medicine (2002)

Examining the rate of in vivo T cell turnover (proliferation) in aged mice revealed a marked reduction in turnover at the level of memory-phenotype CD44hi CD8+ cells relative to young mice. Based on adoptive transfer experiments, the reduced turnover of aged CD44hi CD8+ cells reflected an inhibitory influence of the aged host environment. Aged CD44hi CD8+ cells also showed poor in vivo responses to IL-15 and IL-15–inducing agents, but responded well to IL-15 in vitro. Two mechanisms could account for the reduced turnover of aged CD44hi CD8+ cells in vivo. First, aging was associated with a prominent and selective increase in Bcl-2 expression in CD44hi CD8+ cells. Hence, the reduced turnover of aged CD44hi CD8+ cells may in part reflect the antiproliferative effect of enhanced Bcl-2 expression. Second, the impaired in vivo response of aged CD44hi CD8+ cells to IL-15 correlated with increased serum levels of type I interferons (IFN-I) and was largely reversed by injection of anti–IFN-I antibody. Hence the selective reduction in the turnover of aged CD44hi CD8+ cells in vivo may reflect the combined inhibitory effects of enhanced Bcl-2 expression and high IFN-I levels.
Screening in the Dark: Ethical Considerations of Providing Screening Tests to Individuals When Evidence is Insufficient to Support Screening Populations
Authors: Ingrid M. Burger, Nancy E. Kass
Journal: The American Journal of Bioethics (2009)

During the past decade, screening tests using computed tomography (CT) have disseminated into practice and been marketed to patients despite neither conclusive evidence nor professional agreement about their efficacy and cost-effectiveness at the population level. This phenomenon raises questions about physicians' professional roles and responsibilities within the setting of medical innovation, as well as the appropriate scope of patient autonomy and access to unproven screening technology. This article explores how physicians ought to respond when new screening examinations that lack conclusive evidence of overall population benefit emerge in the marketplace and are requested by individual patients. To this end, the article considers the nature of evidence and how it influences decision-making for screening at both the public policy and individual patient levels. We distinguish medical and ethical differences between screening recommended for a population and screening considered on an individual patient basis. Finally, we discuss specific cases to explore how evidence, patient risk factors and preferences, and physician judgment ought to balance when making individual patient screening decisions.
A Phase I and Pharmacokinetic Study of Exisulind and Docetaxel in Patients with Advanced Solid Tumors
Authors: Samir E. Witta, Daniel L. Gustafson, A. Scott Pierson, Alexander Menter, Scott N. Holden, Michele Basche, Martha Persky, Cindy L. O’Bryant, Chan Zeng, Anna Baron, Michael E. Long, Amy Gibbs, Karen Kelly, Paul A. Bunn, Daniel C. Chan, Patrick Pallansch, S. Gail Eckhardt
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non–small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of combining exisulind (150–250 mg) given orally twice daily and docetaxel (30–36 mg/m2) administered intravenously on days 1, 8, and 15 of a 4-week cycle. Results: Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35–77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m2. Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed. Conclusions: The combination of docetaxel (36 mg/m2, weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non–small-cell lung cancer.
Autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for the treatment of persistent active EBV infection
Authors: Barbara Savoldo, M. Helen Huls, Zhensheng Liu, Takayuki Okamura, Hans-Dieter Volk, Petra Reinke, Robert Sabat, Nina Babel, James F. Jones, Jennifer Webster-Cyriaque, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney
Journal: Blood (2002)
Immunoglobulin G Levels before and after Lung Transplantation
Authors: Natalie H. Yip, David J. Lederer, Steven M. Kawut, Jessie S. Wilt, Frank D'Ovidio, Yuanjia Wang, Edward Dwyer, Joshua R. Sonett, Selim M. Arcasoy
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

The determinants of immunoglobulin G (IgG) level and the risk of hypogammaglobulinemia (HGG) in patients with severe lung disease before and after lung transplantation are unknown.
VEGFR-2, CXCR-2 and PAR-1 germline polymorphisms as predictors of survival in pancreatic carcinoma
Authors: F.G. Uzunoglu, J. Kolbe, H. Wikman, C. Güngör, B.A. Bohn, M.F. Nentwich, M. Reeh, A.M. König, M. Bockhorn, A. Kutup, O. Mann, J.R. Izbicki, Y.K. Vashist
Journal: Annals of Oncology (2013)