tbuckley/cabot-search huggingface dataset:
Lasofoxifene in Postmenopausal Women with Osteoporosis
Authors: Steven R. Cummings, Kristine Ensrud, Pierre D. Delmas, Andrea Z. LaCroix, Slobodan Vukicevic, David M. Reid, Steven Goldstein, Usha Sriram, Andy Lee, John Thompson, Roisin A. Armstrong, David D. Thompson, Trevor Powles, Jose Zanchetta, David Kendler, Patrick Neven, Richard Eastell
Journal: New England Journal of Medicine (2010)

The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)
Correlates of Insulin Injection Omission
Authors: Mark Peyrot, Richard R. Rubin, Davida F. Kruger, Luther B. Travis
Journal: Diabetes Care (2010)

The purpose of this study was to assess factors associated with patient frequency of intentionally skipping insulin injections.Data were obtained through an Internet survey of 502 U.S. adults self-identified as taking insulin by injection to treat type 1 or type 2 diabetes. Multiple regression analysis assessed independent associations of various demographic, disease, and injection-specific factors with insulin omission.Intentional insulin omission was reported by more than half of respondents; regular omission was reported by 20%. Significant independent risk factors for insulin omission were younger age, lower income and higher education, type 2 diabetes, not following a healthy diet, taking more daily injections, interference of injections with daily activities, and injection pain and embarrassment. Risk factors differed between type 1 and type 2 diabetic patients, with diet nonadherence more prominent in type 1 diabetes and age, education, income, pain, and embarrassment more prominent in type 2 diabetes.Whereas most patients did not report regular intentional omission of insulin injections, a substantial number did. Our findings suggest that it is important to identify patients who intentionally omit insulin and be aware of the potential risk factors identified here. For patients who report injection-related problems (interference with daily activities, injection pain, and embarrassment), providers should consider recommending strategies and tools for addressing these problems to increase adherence to prescribed insulin regimens. This could improve clinical outcomes.
Metabolomics Strategy Reveals Subpopulation of Liposarcomas Sensitive to Gemcitabine Treatment
Authors: Daniel Braas, Ethan Ahler, Brenna Tam, David Nathanson, Mirielle Riedinger, Matthias R. Benz, Kathleen B. Smith, Fritz C. Eilber, Owen N. Witte, William D. Tap, Hong Wu, Heather R. Christofk
Journal: Cancer Discovery (2012)

Unlike many cancers that exhibit glycolytic metabolism, high-grade liposarcomas often exhibit low 2[18F]fluoro-2-deoxy-D-glucose uptake by positron emission tomography (PET), despite rapid tumor growth. Here, we used liquid chromatography tandem mass spectrometry to identify carbon sources taken up by liposarcoma cell lines derived from xenograft tumors in patients. Interestingly, we found that liposarcoma cell lines consume nucleosides from culture media, suggesting nucleoside salvage pathway activity. The nucleoside salvage pathway is dependent on deoxycytidine kinase (dCK) and can be imaged in vivo by PET with 1-(2'-deoxy-2'-[18F]fluoroarabinofuranosyl) cytosine (FAC). We found that liposarcoma cell lines and xenograft tumors exhibit dCK activity and dCK-dependent FAC uptake in vitro and in vivo. In addition, liposarcoma cell lines and xenograft tumors are sensitive to treatment with the nucleoside analogue prodrug gemcitabine, and gemcitabine sensitivity is dependent on dCK expression. Elevated dCK activity is evident in 7 of 68 clinical liposarcoma samples analyzed. These data suggest that a subpopulation of liposarcoma patients have tumors with nucleoside salvage pathway activity that can be identified noninvasively using [18F]-FAC-PET and targeted using gemcitabine.Patients with high-grade liposarcoma have poor prognoses and often fail to respond to chemotherapy. This report identifies elevated nucleoside salvage activity in a subset of liposarcomas that are identifiable using noninvasive PET imaging with FAC and that are sensitive to gemcitabine. Thus, we suggest a new treatment paradigm for liposarcoma patients that uses [18F]-FAC-PET in the clinic to delineate gemcitabine responders from nonresponders.
Fluorescence <i>In situ</i> Hybridization Analysis of Circulating Tumor Cells in Metastatic Prostate Cancer
Authors: Margaret A. Leversha, Jialian Han, Zahra Asgari, Daniel C. Danila, Oscar Lin, Rita Gonzalez-Espinoza, Aseem Anand, Hans Lilja, Glenn Heller, Martin Fleisher, Howard I. Scher
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To assess the feasibility of characterizing gene copy number alteration by fluorescence in situ hybridization (FISH) of circulating tumor cells (CTC) isolated using the CellSearch system in patients with progressive castration-resistant metastatic prostate cancer. Experimental Design: We used probe combinations that included the androgen receptor (AR) and MYC genes for FISH analysis of CTC samples collected from 77 men with castration-resistant metastatic prostate cancer. Results: High-level chromosomal amplification of AR was detected in 38% and relative gain of MYC in 56% of samples analyzed. No such abnormalities were detected in samples with CTC counts of &amp;lt;10, reflecting ascertainment difficulty in these lower count samples. Conclusion: The CTC isolated from our patient cohort present a very similar molecular cytogenetic profile to that reported for late-stage tumors and show that FISH analysis of CTC can be a valuable, noninvasive surrogate for routine tumor profiling. That as many as 50% of these patients have substantial amplification of the AR locus indicates that androgen signaling continues to play an important role in late-stage prostate cancer.
Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy
Authors: Stefano Cassanelli, Elisa Pignatti, Giuliana Montosi, Cinzia Garuti, Maria Mariano, Daniele Campioli, Anna Carbonieri, Erasmo Baldini, Antonello Pietrangelo
Journal: Journal of Hepatology (2001)
Interleukin-5 inhibits glucocorticoid-mediated apoptosis in human eosinophils
Authors: S. Brode, N. Farahi, A. S. Cowburn, J. K. Juss, A. M. Condliffe, E. R. Chilvers
Journal: Thorax (2010)

Glucocorticoids (GCs) represent one of the most effective treatments for eosinophil-mediated inflammatory diseases such as asthma. GCs act through the GC receptor, leading to proinflammatory cytokine suppression and a reduction in the number of inflammatory cells including eosinophils and T cells.1 However, the benefits of GCs have been limited by their side effects and the presence of GC resistance. This led to the development of more selective GCs such as fluticasone propionate (FP) and fluticasone furoate (FF).2

Increased eosinophil survival has been proposed as a mechanism underlying tissue eosinophilia, and part of the anti-inflammatory effects of GCs has been attributed to their ability to promote eosinophil apoptosis. Interleukin 5 (IL-5) enhances eosinophil survival by inhibiting apoptosis, and increased IL-5 expression is reported in eosinophilic inflammation.3 We sought to address the ability of the ‘enhanced-affinity’ FF, alongside dexamethasone (DEX) and FP, to modulate eosinophil apoptosis and their potential to …
Thiopurinemethyltransferase (TPMT) genotype and TPMT activity in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: relation to azathioprine maintenance treatment and adverse effects
Authors: P M Stassen, R P H Derks, C G M Kallenberg, C A Stegeman
Journal: Annals of the Rheumatic Diseases (2009)

Azathioprine is used in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) to maintain remission. Azathioprine is inactivated and converted into hepatotoxic metabolites by the enzyme thiopurine methyltransferase (TPMT). Polymorphisms in the gene encoding TPMT lead to differences in activity of the enzyme. In our patients with AAV, we determined the prevalence of variant TPMT genotypes and abnormal TPMT activity, and investigated the relationship between TPMT and the efficacy and toxicity of azathioprine.

Patients newly diagnosed with AAV between 1995 and 2006, who were initially treated with cyclophosphamide and corticosteroids followed by azathioprine, were included and followed for 47 months. All patients were treated without knowledge of their TPMT status. Data were retrospectively retrieved …
Genetic Polymorphisms of Selected DNA Repair Genes, Estrogen and Progesterone Receptor Status, and Breast Cancer Risk
Authors: Kyoung-Mu Lee, Ji-Yeob Choi, Changwon Kang, Changsoo Paul Kang, Sue Kyung Park, Hyunmi Cho, Dae-Yeon Cho, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Chung-Gyu Park, Qingyi Wei, Daehee Kang
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Genetic polymorphisms of DNA repair genes seem to determine the DNA repair capacity, which in turn may affect the risk of breast cancer. To evaluate the role of genetic polymorphisms of DNA repair genes in breast cancer, we conducted a hospital-based case-control study of Korean women. Experimental Design: We included 872 incident breast cancer cases and 671 controls recruited from several teaching hospitals in Seoul from 1995 to 2002. Twelve loci of selected DNA repair genes were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (XRCC2 Arg188His, XRCC4 921G &amp;gt; T, XRCC6 1796G &amp;gt; T, LIG4 1977T/C, RAD51 135G &amp;gt; C, 172G &amp;gt; T, RAD52 2259C &amp;gt; T, LIG1 551A &amp;gt; C, ERCC1 8092A &amp;gt; C, 354C &amp;gt; T, hMLH1 −93G &amp;gt; A, and Ile219Val). Results: We found that the RAD52 2259 CT or TT, hMLH1 −93 GG, and ERCC1 8092 AA genotypes were associated with breast cancer risk after adjustment for known risk factors [odds ratio (OR), 1.33; 95% confidence interval (95% CI), 1.02-1.75; OR, 1.31; 95% CI, 0.99-1.74; and OR, 0.58; 95% CI, 0.38-0.89, respectively]. When Bonferroni's method was used to correct for multiple comparisons for nine polymorphisms with P = 0.005, all of these associations were not significant. However, the effects of RAD52 2259 CT or TT and ERCC1 354 CT or TT genotypes were more evident for the estrogen/progesterone receptor–negative cases (OR, 2.03; 95% CI, 1.24-3.34 and OR, 1.99; 95% CI, 1.35-2.94, respectively). Conclusion: Our findings suggest that genetic polymorphisms of RAD52, ERCC1, and hMLH1 may be associated with breast cancer risk in Korean women.
Multicenter Validation of a 1,550-Gene Expression Profile for Identification of Tumor Tissue of Origin
Authors: Federico A. Monzon, Maureen Lyons-Weiler, Ljubomir J. Buturovic, C. Ted Rigl, W. David Henner, Christin Sciulli, Catherine I. Dumur, Fabiola Medeiros, Glenda G. Anderson
Journal: Journal of Clinical Oncology (2009)

Malignancies found in unexpected locations or with poorly differentiated morphologies can pose a significant challenge for tissue of origin determination. Current histologic and imaging techniques fail to yield definitive identification of the tissue of origin in a significant number of cases. The aim of this study was to validate a predefined 1,550-gene expression profile for this purpose.Four institutions processed 547 frozen specimens representing 15 tissues of origin using oligonucleotide microarrays. Half of the specimens were metastatic tumors, with the remainder being poorly differentiated and undifferentiated primary cancers chosen to resemble those that present as a clinical challenge.In this blinded multicenter validation study the 1,550-gene expression profile was highly informative in tissue determination. The study found overall sensitivity (positive percent agreement with reference diagnosis) of 87.8% (95% CI, 84.7% to 90.4%) and overall specificity (negative percent agreement with reference diagnosis) of 99.4% (95% CI, 98.3% to 99.9%). Performance within the subgroup of metastatic tumors (n = 258) was found to be slightly lower than that of the poorly differentiated and undifferentiated primary tumor subgroup, 84.5% and 90.7%, respectively (P = .04). Differences between individual laboratories were not statistically significant.This study represents the first adequately sized, multicenter validation of a gene-expression profile for tissue of origin determination restricted to poorly differentiated and undifferentiated primary cancers and metastatic tumors. These results indicate that this profile should be a valuable addition or alternative to currently available diagnostic methods for the evaluation of uncertain primary cancers.
Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor
Authors: Gregorio D. Chazenbalk, Pavel Pichurin, Chun-Rong Chen, Francesco Latrofa, Alan P. Johnstone, Sandra M. McLachlan, Basil Rapoport
Journal: Journal of Clinical Investigation (2002)

Graves disease is directly caused by thyroid-stimulating autoantibodies (TSAb's) that activate the thyrotropin receptor (TSHR). We observed upon flow cytometry using intact cells that a mouse mAb (3BD10) recognized the TSHR ectodomain with a glycosidylphosphatidylinositol (ECD-GPI) anchor approximately tenfold better than the same ectodomain on the wild-type TSHR, despite the far higher level of expression of the latter. The 3BD10 epitope contains the N-terminal cysteine cluster critical for TSAb action. Consequently, we hypothesized and confirmed that TSAb (but not thyrotropin-blocking autoantibodies [TBAb's]) also poorly recognize the wild-type TSHR relative to the ECD-GPI. Despite poor recognition by TSAb of the holoreceptor, soluble TSHR A subunits (known to be shed from surface TSHR) fully neutralized autoantibody-binding activity. These data indicate that the epitope(s) for TSAb's, but not for TBAb's, are partially sterically hindered on the holoreceptor by the plasma membrane, the serpentine region of the TSHR, or by TSHR dimerization. However, the TSAb epitope on the soluble A subunit is freely accessible. This observation, as well as other evidence, supports the concept that A subunit shedding either initiates or amplifies the autoimmune response to the TSHR, thereby causing Graves disease in genetically susceptible individuals.
Child-bearing and Tuberculosis
Authors: R. C. Cohen
Journal: BMJ (1947)

the regular weekly hour advocated by your correspondent.Incidentally I have yet to meet a psychiatrist who did not prescribe phenobarbitone in some form for his cases.Needless to say the more severe forms of functional disability should be referred to an expert, though in many industrial areas psychiatrists are in very short supply.One can only hope that more psychiatric clinics will be set up in the near future.All this and more will no doubt be provided in Mr. Bevan's nationalized Utopia, which we are assured is just around the corner.
Capacity of genetically different T lymphocytes to induce lethal graft-versus-host disease correlates with their capacity to generate suppression but not with their capacity to generate anti-F1 killer cells. A non-H-2 locus determines the inability to induce lethal graft-versus-host disease.
Authors: E H Van Elven, A G Rolink, F V Veen, E Gleichmann
Journal: The Journal of Experimental Medicine (1981)

When comparing, in a murine model, the kind of graft-versus-host (GVH) disease (GVHD) induced by the donor strain DBA/2 on the one hand and several H-2-congenic resistant B10 donor strains on the other, we found that strain DBA/2 was a universal nonkilling GVH donor for H-2-incompatible nonirradiated F1 hybrid recipients. In this respect, DBA/2 T cells differed from those of the H-2-identical donor strain B10.D2 as well as those of other b10 donor strains. The inability of strain DBA/2 to kill by GVH reaction was not limited to certain H-2 incompatibilities in the F1 recipients, but was nonspecific. The inability to kill is determined by a dominant locus not linked to H-2. DBA/2 T cells were also incapable of inducing the severe suppression of hematocrit values, bone marrow erythropoiesis, thymic cell proliferation, and splenic IgG production in the F1 recipients that was observed after the injection of T cell from the B10 strains. However, DBA/2 T cells, in contrast with those of the B10 donor strains, were vigorous stimulators of IgG production in H-2-incompatible F1 hybrid recipients. Surprisingly, strain DBA/2 as well as the B10 donor strains had good capacity to generate anti-F1 TK cells. Taken together, these findings raise the possibility that lethal GVHD disease is not caused, or not caused exclusively, by donor killer T cells, but by those donor T cells that directly or indirectly induce a suppression of cell proliferation in certain vital organs of the recipient.
End-of-Life Practices in the Netherlands under the Euthanasia Act
Authors: Agnes van der Heide, Bregje D. Onwuteaka-Philipsen, Mette L. Rurup, Hilde M. Buiting, Johannes J.M. van Delden, Johanna E. Hanssen-de Wolf, Anke G.J.M. Janssen, H. Roeline W. Pasman, Judith A.C. Rietjens, Cornelis J.M. Prins, Ingeborg M. Deerenberg, Joseph K.M. Gevers, Paul J. van der Maas, Gerrit van der Wal
Journal: New England Journal of Medicine (2007)

In 2002, an act regulating the ending of life by a physician at the request of a patient with unbearable suffering came into effect in the Netherlands. In 2005, we performed a follow-up study of euthanasia, physician-assisted suicide, and other end-of-life practices.We mailed questionnaires to physicians attending 6860 deaths that were identified from death certificates. The response rate was 77.8%.In 2005, of all deaths in the Netherlands, 1.7% were the result of euthanasia and 0.1% were the result of physician-assisted suicide. These percentages were significantly lower than those in 2001, when 2.6% of all deaths resulted from euthanasia and 0.2% from assisted suicide. Of all deaths, 0.4% were the result of the ending of life without an explicit request by the patient. Continuous deep sedation was used in conjunction with possible hastening of death in 7.1% of all deaths in 2005, significantly increased from 5.6% in 2001. In 73.9% of all cases of euthanasia or assisted suicide in 2005, life was ended with the use of neuromuscular relaxants or barbiturates; opioids were used in 16.2% of cases. In 2005, 80.2% of all cases of euthanasia or assisted suicide were reported. Physicians were most likely to report their end-of-life practices if they considered them to be an act of euthanasia or assisted suicide, which was rarely true when opioids were used.The Dutch Euthanasia Act was followed by a modest decrease in the rates of euthanasia and physician-assisted suicide. The decrease may have resulted from the increased application of other end-of-life care interventions, such as palliative sedation.
THE RELATION BETWEEN HEMOLYTIC AND NON-HEMOLYTIC STREPTOCOCCI, AND ITS POSSIBLE SIGNIFICANCE
Authors: Ralph A. Kinsella
Journal: The Journal of Experimental Medicine (1918)

1. The relation between hemolytic and non-hemolytic streptococci is orderly and arises from the fact that the former variety is unique while the latter is heterogeneous. 2. Analogous considerations of the classification, distribution, and pathogenicity of the streptococcus group and the pneumococcus and colon-typhoid groups show a definite parallelism. 3. These considerations suggest that unique varieties of bacteria associated with man are the more highly invasive, while the heterogeneous varieties are more saprophytic.
Direct Vascular Effects of Protease-Activated Receptor Type 1 Agonism In Vivo in Humans
Authors: Ingibjörg J. Gudmundsdóttir, Ian L. Megson, Jillian S. Kell, Christopher A. Ludlam, Keith A.A. Fox, David J. Webb, David E. Newby
Journal: Circulation (2006)

Protease-activated receptor type 1 (PAR-1) has been proposed as the principal thrombin receptor in humans, although its actions in vivo have not been defined. The aim of the present study was to determine the direct vascular actions of PAR-1 agonism in humans.Dorsal hand vein diameter was measured by the Aellig technique in 14 healthy volunteers during local intravenous SFLLRN (PAR-1 agonist; 0.05 to 15 nmol/min) and SLIGKV (PAR-2 agonist; 1.6 to 160 nmol/min) infusions. The venous effects of SFLLRN were further assessed in the presence or absence of norepinephrine or the glycoprotein IIb/IIIa antagonist tirofiban. Forearm blood flow was measured by venous occlusion plethysmography in 16 volunteers during infusion of SFLLRN (1 to 50 nmol/min), SLIGKV (160 to 800 nmol/min), and the endothelium-dependent vasodilator bradykinin (100 to 1000 pmol/min). Platelet-monocyte binding (a sensitive measure of platelet activation) and plasma tissue plasminogen activator (tPA), plasminogen-activator inhibitor 1, and von Willebrand factor concentrations were measured at intervals throughout the study. SFLLRN caused dose-dependent venoconstriction (P<0.001) that was unaffected by norepinephrine or tirofiban co-infusion. In forearm resistance vessels, SFLLRN increased forearm blood flow (P<0.001), tPA release (P<0.001), and platelet-monocyte binding (P<0.0001) without affecting plasma plasminogen-activator inhibitor 1 or von Willebrand factor concentrations. SLIGKV caused venous (P<0.001) and arterial (P<0.01) dilatation without tPA release.We have demonstrated that PAR-1 agonism causes platelet activation, venous constriction, arterial dilatation, and tPA release in vivo in humans. These unique and contrasting effects provide important insights into the physiological and pathophysiological role of thrombin in the human venous and arterial circulations.