tbuckley/cabot-search huggingface dataset:
Leuprorelin Acetate Every-3-Months Depot Versus Cyclophosphamide, Methotrexate, and Fluorouracil As Adjuvant Treatment in Premenopausal Patients With Node-Positive Breast Cancer: The TABLE Study
Authors: Peter Schmid, Michael Untch, Valentin Kossé, Grigorij Bondar, Leonid Vassiljev, Valerie Tarutinov, Ute Lehmann, Lutz Maubach, Juergen Meurer, Diethelm Wallwiener, Kurt Possinger
Journal: Journal of Clinical Oncology (2007)

Ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists is an effective adjuvant treatment for premenopausal women with estrogen receptor (ER) -positive breast cancer. Whereas monthly LHRH agonist therapy has been well established, the value of every-3-months (3-monthly) formulations is unclear.This randomized phase III trial was performed to compare the 3-monthly depot LHRH agonist leuprorelin acetate (LAD-3M; n = 299) and chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF; n = 300) in pre- or perimenopausal patients with ER-positive, node-positive breast cancer.With a median follow-up of 5.8 years, recurrence-free survival was similar for patients treated with LAD-3M or CMF (hazard ratio [HR], 1.19; 95% CI, 0.94 to 1.51; P = .15). There was no substantial heterogeneity in the relative treatment effect among subgroups defined by age, progesterone receptor (PR) status, nodal status, hormone levels, or menstrual recovery after treatment. Exploratory overall survival analysis favored LAD-3M (HR, 1.50; 95% CI, 1.13 to 1.99; P = .005). Chemotherapy-related adverse effects such as nausea, vomiting, and alopecia were more common with CMF, whereas symptoms of estrogen suppression such as hot flushes and sweating were initially more pronounced with LAD-3M.The 3-monthly depot LHRH-agonist leuprorelin acetate is an effective adjuvant treatment in premenopausal patients with hormone receptor-positive, node-positive breast cancer that is not inferior to CMF.
Effects of aging on mechanics and composition of cerebral arterioles in rats.
Authors: M A Hajdu, D D Heistad, J E Siems, G L Baumbach
Journal: Circulation Research (1990)

The purpose of this study was to examine effects of aging on the mechanics and composition of cerebral arterioles. We measured pressure (servo-null) and diameter in pial arterioles in anesthetized adult (9-12 months old) and aged (24-27 months old) Fischer 344 rats. After deactivation of smooth muscle with EDTA, diameter of pial arterioles at 70 mm Hg pial arteriolar pressure was less in aged than in adult rats (67 +/- 4 vs. 81 +/- 4 microns [mean +/- SEM], p less than 0.05). The stress-strain relation and the slope of tangential elastic modulus versus stress (6.8 +/- 0.6 vs. 5.3 +/- 0.3, p less than 0.05) indicated that distensibility of pial arterioles was reduced in aged rats. Cross-sectional area of the vessel wall, measured histologically, was less in aged than adult rats (1,239 +/- 91 vs. 1,832 +/- 180 microns2, p less than 0.05). Point counting stereology was used to quantitate smooth muscle, elastin, collagen, and basement membrane in the arteriolar wall. Cross-sectional areas of smooth muscle and elastin were significantly less in aged than adult rats (744 +/- 57 vs. 1,291 +/- 119 microns2 for smooth muscle, 52 +/- 6 vs. 113 +/- 15 microns2 for elastin; p less than 0.05), whereas cross-sectional areas of collagen and basement membrane were not significantly different in aged and adult rats (4 +/- 1 vs. 3 +/- 1 microns2 for collagen, 236 +/- 17 vs. 258 +/- 31 microns2 for basement membrane). The ratio of nondistensible (collagen and basement membrane) to distensible (smooth muscle and elastin) components was greater in aged than adult rats (0.30 +/- 0.01 vs. 0.18 +/- 0.01, p less than 0.05). Thus, we conclude that, during aging, cerebral arterioles undergo atrophy, distensibility of cerebral arterioles is reduced, and the relative proportion of distensible elements, elastin and smooth muscle, is reduced in the arteriolar wall.
Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: S. Novello, F. Barlesi, R. Califano, T. Cufer, S. Ekman, M. Giaj Levra, K. Kerr, S. Popat, M. Reck, S. Senan, G.V. Simo, J. Vansteenkiste, S. Peters
Journal: Annals of Oncology (2016)
In Vivo Detection of Dendritic Cell Antigen Presentation to CD4+ T Cells
Authors: Elizabeth Ingulli, Anna Mondino, Alexander Khoruts, Marc K. Jenkins
Journal: The Journal of Experimental Medicine (1997)

Although lymphoid dendritic cells (DC) are thought to play an essential role in T cell activation, the initial physical interaction between antigen-bearing DC and antigen-specific T cells has never been directly observed in vivo under conditions where the specificity of the responding T cells for the relevant antigen could be unambiguously assessed. We used confocal microscopy to track the in vivo location of fluorescent dye-labeled DC and naive TCR transgenic CD4+ T cells specific for an OVA peptide–I-Ad complex after adoptive transfer into syngeneic recipients. DC that were not exposed to the OVA peptide, homed to the paracortical regions of the lymph nodes but did not interact with the OVA peptide-specific T cells. In contrast, the OVA peptide-specific T cells formed large clusters around paracortical DC that were pulsed in vitro with the OVA peptide before injection. Interactions were also observed between paracortical DC of the recipient and OVA peptide-specific T cells after administration of intact OVA. Injection of OVA peptide-pulsed DC caused the specific T cells to produce IL-2 in vivo, proliferate, and differentiate into effector cells capable of causing a delayed-type hypersensitivity reaction. Surprisingly, by 48 h after injection, OVA peptide-pulsed, but not unpulsed DC disappeared from the lymph nodes of mice that contained the transferred TCR transgenic population. These results demonstrate that antigen-bearing DC directly interact with naive antigen-specific T cells within the T cell–rich regions of lymph nodes. This interaction results in T cell activation and disappearance of the DC.
Local Expression of C-Type Natriuretic Peptide Suppresses Inflammation, Eliminates Shear Stress–Induced Thrombosis, and Prevents Neointima Formation Through Enhanced Nitric Oxide Production in Rabbit Injured Carotid Arteries
Authors: Jian-Yong Qian, Akihiro Haruno, Yujiro Asada, Takahiro Nishida, Yasushi Saito, Takehisa Matsuda, Hikaru Ueno
Journal: Circulation Research (2002)

We previously observed that adenovirus-mediated expression of C-type natriuretic peptide (CNP) markedly inhibits neointima formation after balloon injury in rat carotid arteries, suggesting that CNP has multiple effects over its modest inhibitory effect on cellular proliferation. We hypothesized that local expression of CNP might have antithrombotic and antiinflammatory effects. Balloon-injured rabbit carotid arteries were infected with an adenovirus expressing human CNP (AdCNP), human tissue factor pathway inhibitor (AdTFPI), or bacterial β-galactosidase (AdLacZ) or infused with saline. Seven days later, shear stress–induced thrombosis was evaluated by cyclic flow variation (CFV), reflecting recurrent cycles of thrombus formation and dislodgment. CFV was observed in all AdLacZ-infected and saline-infused arteries but not in arteries infected with AdCNP or AdTFPI even in the presence of epinephrine. Injury increased the expressions of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and infiltration of macrophages. However, these effects were markedly reduced in AdCNP-treated arteries but not in AdTFPI-infected ones. In AdCNP-infected arteries, injury-induced expression of inducible NO synthase (iNOS) was enhanced, leading to increased NO generation. Interestingly, when the enhanced NO production was inhibited, neither inhibitory effect was observed, and suppression of neointima formation by CNP was canceled. Our study demonstrates that overexpression of CNP shows antithrombotic and antiinflammatory effects and reduces neointima formation mainly through enhanced NO production.
Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling
Authors: S S Ferguson
Journal: Pharmacological Reviews (2001)

G protein-coupled receptors (GPCRs) are seven transmembrane proteins that form the largest single family of integral membrane receptors. GPCRs transduce information provided by extracellular stimuli into intracellular second messengers via their coupling to heterotrimeric G proteins and the subsequent regulation of a diverse variety of effector systems. Agonist activation of GPCRs also initiates processes that are involved in the feedback desensitization of GPCR responsiveness, the internalization of GPCRs, and the coupling of GPCRs to heterotrimeric G protein-independent signal transduction pathways. GPCR desensitization occurs as a consequence of G protein uncoupling in response to phosphorylation by both second messenger-dependent protein kinases and G protein-coupled receptor kinases (GRKs). GRK-mediated receptor phosphorylation promotes the binding of beta-arrestins, which not only uncouple receptors from heterotrimeric G proteins but also target many GPCRs for internalization in clathrin-coated vesicles. beta-Arrestin-dependent endocytosis of GPCRs involves the direct interaction of the carboxyl-terminal tail domain of beta-arrestins with both beta-adaptin and clathrin. The focus of this review is the current and evolving understanding of the contribution of GRKs, beta-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitization. In addition to their role as GPCR-specific endocytic adaptor proteins, beta-arrestins also serve as molecular scaffolds that foster the formation of alternative, heterotrimeric G protein-independent signal transduction complexes. Similar to what is observed for GPCR desensitization and resensitization, beta-arrestin-dependent GPCR internalization is involved in the intracellular compartmentalization of these protein complexes.
Low back pain investigations and prognosis: a review
Authors: K M Refshauge, C G Maher
Journal: British Journal of Sports Medicine (2006)

Low back pain is reviewed in terms of when investigations are useful and its clinical course. Despite the extensive evaluation of the accuracy of investigations such as radiography, magnetic resonance imaging, and myelography, there is a surprising dearth of research to inform their use in primary care. There is no clear evidence on which to base judgments for selection of appropriate tests to confirm or exclude low back pain pathology. It appears that investigations are rarely necessary for low back pain. Specific investigations should be ordered to identify a particular pathology but should not be ordered routinely for general screening. In the absence of pathology, low back pain and its associated disability improve rapidly in the first weeks after onset, but, in contradiction to all guidelines, both commonly persist and the best evidence suggests that recurrences are common.
Incidence and mortality rates of biopsy-proven giant cell arteritis in southern Sweden
Authors: Aladdin J Mohammad, Jan-Åke Nilsson, Lennart TH Jacobsson, Peter A Merkel, Carl Turesson
Journal: Annals of the Rheumatic Diseases (2014)

Objectives To study the epidemiology and mortality in patients with biopsy-proven giant cell arteritis (GCA) in southern Sweden. Methods The study area was the County of Skåne. Patients with a positive temporal artery biopsy between 1997 and 2010 were identified using a regional register and a structured review of all histopathology reports. Standardised mortality ratios (SMR) were calculated using data for the Swedish population as the reference. Results There were 840 patients with biopsy-proven GCA (626 women). The annual incidence rate per 100 000 inhabitants aged ≥50 years was 14.1 (95% CI 13.1 to 15.0); 7.7 (6.7 to 8.7) for men and 19.6 (18.1 to 21.1) for women, without seasonal variations. The incidence increased with age, with estimates of 2.0, 11.8, and 31.3 per 100 000 in the age groups 50–60, 61–70, 71–80 years, respectively (p&lt;0.001). The age-standardised and sex-standardised incidence rate decreased from 15.9/100 000 in 1997–2001 to 13.3/100 000 in 2007–2010 (p=0.026). Two hundred and seventy-nine patients (207 women) died during the observation period. Mortality was significantly increased over the first 2 years after GCA diagnosis (SMR 1.52 (95% CI 1.20 to 1.85)), but not with longer follow-up. The estimated excess mortality was greater in women and in patients aged ≤70 years at diagnosis. Conclusions In this large population-based study of biopsy-proven GCA from southern Sweden, the incidence of GCA may have decreased over time. Short-term mortality was increased, in particular among those diagnosed at ≤70 years of age, but long-term survival was not impaired.
Patient-Controlled Methylphenidate for Cancer Fatigue: A Double-Blind, Randomized, Placebo-Controlled Trial
Authors: Eduardo Bruera, Vicente Valero, Larry Driver, Loren Shen, Jie Willey, Tao Zhang, J. Lynn Palmer
Journal: Journal of Clinical Oncology (2006)

Purpose To evaluate the effectiveness of patient-controlled methylphenidate as compared with placebo in cancer patients with fatigue, as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). Patients and Methods Patients with a fatigue score of at least 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) and hemoglobin level of at least 10 g/dL were included. Patients were randomly assigned to receive 5 mg methylphenidate or placebo every 2 hours as needed (maximum of four capsules a day), for 7 days. Patients completed a daily diary including study drug record and fatigue intensity. A research nurse telephoned patients daily to assess toxicity and fatigue level. All patients were offered open-label methylphenidate for 4 weeks. FACIT-F and the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 15, and 36. The FACIT-F fatigue subscore on day 8 was considered the primary end point. Results Of 112 patients randomly assigned, 52 patients in the methylphenidate and 53 in the placebo group were assessable for analysis. Fatigue intensity improved significantly on day 8 in both the methylphenidate and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .31) or ESAS (P = .14) between groups. In open-label phase, fatigue intensity maintained low as compared with baseline. No significant toxicities were observed. Conclusion Both methylphenidate and placebo resulted in significant symptom improvement. Methylphenidate was not significantly superior to placebo after 1 week of treatment. Longer study duration is justified. The role of daily telephone calls from a research nurse should be explored as a palliative care intervention.
Massive modularity is consistent with most forms of neural reuse
Authors: J. Brendan Ritchie, Peter Carruthers
Journal: Behavioral and Brain Sciences (2010)

Abstract Anderson claims that the hypothesis of massive neural reuse is inconsistent with massive mental modularity. But much depends upon how each thesis is understood. We suggest that the thesis of massive modularity presented in Carruthers (2006) is consistent with the forms of neural reuse that are actually supported by the data cited, while being inconsistent with a stronger version of reuse that Anderson seems to support.
Retinoic Acid Increases the Expression of p53 and Proapoptotic Caspases and Sensitizes Keratinocytes to Apoptosis
Authors: Paul Mrass, Michael Rendl, Michael Mildner, Florian Gruber, Barbara Lengauer, Claudia Ballaun, Leopold Eckhart, Erwin Tschachler
Journal: Cancer Research (2004)

Retinoids influence growth and differentiation of keratinocytes (KCs) and are widely used for the management of skin diseases and for prevention of nonmelanoma skin cancer (NMSC) in predisposed patients. Here we investigated the effect of all-trans-retinoic acid (ATRA) on KC apoptosis. When KCs were cultured in confluent monolayers for several days, they acquired resistance against UVB-induced apoptosis. In contrast, when the cells were treated with 1 micromol/L ATRA for 6 days and subsequently irradiated with different doses of UVB, they underwent massive apoptosis as assessed by morphology, expression of activated caspase-3, and DNA fragmentation. The same effect was observed when doxorubicin was used instead of UVB. Analysis by real-time PCR and Western blot revealed that ATRA treatment strongly increased the mRNA and protein expression of p53 and caspase-3, -6, -7, and -9, which are key regulators of apoptosis. UVB irradiation of ATRA-treated cells but not of control cells led to the accumulation of p53 protein and of its target gene Noxa. Inhibition of p53 and caspases with alpha-pifithrin and z-Val-Ala-Asp-fluoromethyl ketone, respectively, blocked UVB- and doxorubicin-induced apoptosis in ATRA-treated KCs. Analogous to the observed ATRA effects in monolayer cultures, in vitro-generated organotypic skin cultures reacted with up-regulation of p53 and proapoptotic caspases and displayed increased sensitivity to UVB-induced apoptosis. The ability of retinoic acid to regulate the expression of proapoptotic genes and to sensitize KCs to apoptosis may play a role in their prevention of NMSC in transplant patients and patients with DNA-repair deficiencies.
Distinct Mutations in <i>IRAK-4</i> Confer Hyporesponsiveness to Lipopolysaccharide and Interleukin-1 in a Patient with Recurrent Bacterial Infections
Authors: Andrei E. Medvedev, Arnd Lentschat, Douglas B. Kuhns, Jorge C.G. Blanco, Cindy Salkowski, Shuling Zhang, Moshe Arditi, John I. Gallin, Stefanie N. Vogel
Journal: The Journal of Experimental Medicine (2003)

We identified previously a patient with recurrent bacterial infections who failed to respond to gram-negative LPS in vivo, and whose leukocytes were profoundly hyporesponsive to LPS and IL-1 in vitro. We now demonstrate that this patient also exhibits deficient responses in a skin blister model of aseptic inflammation. A lack of IL-18 responsiveness, coupled with diminished LPS and/or IL-1–induced nuclear factor–κB and activator protein-1 translocation, p38 phosphorylation, gene expression, and dysregulated IL-1R–associated kinase (IRAK)–1 activity in vitro support the hypothesis that the defect lies within the signaling pathway common to toll-like receptor 4, IL-1R, and IL-18R. This patient expresses a “compound heterozygous” genotype, with a point mutation (C877T in cDNA) and a two-nucleotide, AC deletion (620–621del in cDNA) encoded by distinct alleles of the IRAK-4 gene (GenBank/EMBL/DDBJ accession nos. AF445802 and AY186092). Both mutations encode proteins with an intact death domain, but a truncated kinase domain, thereby precluding expression of full-length IRAK-4 (i.e., a recessive phenotype). When overexpressed in HEK293T cells, neither truncated form augmented endogenous IRAK-1 kinase activity, and both inhibited endogenous IRAK-1 activity modestly. Thus, IRAK-4 is pivotal in the development of a normal inflammatory response initiated by bacterial or nonbacterial insults.
Introductory Address Delivered at St. Thomas's Hospital, London
Authors: F. l. G. Clark
Journal: BMJ (1871)

MR. TREASURER,-It is now many years-I do not care to say how many-since I exchanged my school-days for an articled student's life within the walls of our venerable Hospital.I may, even then, have in- dulged in the fond anticipation that, at some long distant future, I might realise the promotion which every hospital-apprentice of my time hoped for, but few attained.Yet I knew that unremitting exertion was needed in this competitive race, and I sought with others the mental re- laxation and physical bracing which exercise on our river afforded.We used to come to Stangate; and many a time have I tripped, in the lightness of heart which the young and unwarped spirit alone knows, over the long shelving shore at low water to launch my boat.Even the
When Heparins Promote Thrombosis
Authors: Ik-Kyung Jang, Marcie J. Hursting
Journal: Circulation (2005)

H eparin-induced thrombocytopenia (HIT; sometimes known as HIT type II) is a serious, immune systemmediated complication of heparin therapy often resulting in devastating thromboembolic outcomes.Although nomenclature distinctions have been made historically between this condition and the non-immune system-mediated, asymptomatic transient drop in platelet count in some patients receiving heparin (sometimes known as HIT type I), the term "HIT" is now preferably reserved for the immune system-mediated condition. 1An estimated 1 in 100 patients who receive unfractionated heparin for at least 5 days will develop HIT-associated thrombosis. 2 The pervasive use of heparins makes HIT one of the most important adverse drug reactions confronting physicians.Heparin is routinely used for thromboprophylaxis or treatment in many clinical settings, including cardiovascular surgery and interventional procedures, acute coronary syndromes, venous thromboembolism, atrial fibrillation, peripheral occlusive disease, dialysis, and extracorporeal circulation.It is among the most frequently prescribed medications in the United States, with Ͼ1 trillion units used 3 and 12 million patients treated 4 annually.Because thrombocytopenia is common in hospitalized patients, occurring in up to 58% of critically ill patients, and can be caused by a variety of factors, 5 HIT unfortunately often remains unrecognized.However, consistent with standard clinical practice for life-threatening conditions, HIT should be suspected in a heparin-treated patient who has thrombocytopenia with or without thrombosis.Increased awareness and a high degree of suspicion for HIT are critical to ensure its prompt recognition, diagnosis, and treatment.Advances in understanding the pathophysiology of HIT and its natural history have led to current treatment recommendations-specifically, that heparin must be discontinued immediately and alternative anticoagulation must be initiated. 6erein we review the pathogenesis, frequency, natural history, diagnosis, and treatment of HIT.
Stable bone mineral density in lumbar spine and hip in contrast to bone loss in the hands during long-term treatment with infliximab in patients with rheumatoid arthritis
Authors: D. A. Eekman, M. Vis, I. E. M. Bultink, D. J. Kuik, A. E. Voskuyl, B. A. C. Dijkmans, W. F. Lems
Journal: Annals of the Rheumatic Diseases (2010)

Osteoporosis is a well-known complication of rheumatoid arthritis (RA), related to disease activity, steroid use and immobility.1,–,6

In a 1-year observational study it has been suggested that infliximab can have a positive effect on bone mineral density (BMD) in patients with RA.6 In the present study, patients with RA who had been treated with infliximab for 2 years and more in the Slotervaart Hospital or the VU University Medical Center were included if BMD measurements at baseline and at 2-year intervals had been performed. Patients fulfilled the American College of Rheumatology 1987 criteria and had a disease activity score in 28 joints greater than 3.2 at baseline. Infliximab (3 mg/kg) was given at 0, 2, 6 and 14 weeks and thereafter every 8 weeks.

BMD measurements of the spine (L1–L4) …