tbuckley/cabot-search huggingface dataset:
Regulation of glomerular TGF-beta expression in the contralateral kidney of two-kidney, one-clip hypertensive rats.
Authors: G Wolf, A Schneider, U Wenzel, U Helmchen, R A Stahl
Journal: Journal of the American Society of Nephrology (1998)

Previous studies have demonstrated that angiotensin II stimulates expression of transforming growth factor-beta (TGF-beta) in cultured renal cells. To investigate whether similar mechanisms are operative in vivo, glomerular TGF-beta mRNA expression was investigated in two-kidney, one-clip (2-K 1-C) hypertensive rats. Glomerular TGF-beta1 transcripts were elevated in the clipped kidney 6 d, but not 3 d, after surgery. Later, during the course of the disease (21 to 35 d), TGF-beta1 mRNA was upregulated in contralateral kidneys compared with sham-operated control kidneys. There was no difference in plasma TGF-beta1 levels between 2-K 1-C rats and controls. Treatment with the AT1 receptor antagonist losartan, as well as with triple therapy (hydralazine, reserpine, and hydrochlorothiazide), started 1 d after clipping, significantly reduced systolic BP in hypertensive rats at day 21 after clipping. Both treatments were equally effective in preventing the increase in glomerular TGF-beta1 mRNA and protein expression in the contralateral kidney at day 21. In a second set of experiments, interventional treatment with losartan or triple therapy, starting 14 d after surgery, was investigated. This treatment for 3 wk significantly reduced the increase in TGF-beta1 expression in the contralateral kidney. At day 35 after clipping, considerable glomerular damage and sclerosis were present, mainly in contralateral kidneys. Interventional treatment with losartan or triple therapy partly prevented this glomerular damage of the contralateral kidney. The data demonstrate that TGF-beta1 expression in the contralateral kidney in 2-K 1-C rats is regulated by the increase in systemic BP rather than by direct effects of angiotensin II.
Influence of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone on serologic parameters and clinical course in lymphoma patients with autoimmune diseases
Authors: S. Wöhrer, M. Troch, J. Zwerina, G. Schett, C. Skrabs, A. Gaiger, U. Jaeger, C.C. Zielinski, M. Raderer
Journal: Annals of Oncology (2007)
Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β<sub>1</sub>signalling
Authors: Gökhan M Mutlu, G R Scott Budinger, Minghua Wu, Anna P Lam, Aaron Zirk, Stephanie Rivera, Daniela Urich, Sergio E Chiarella, Leonard H T Go, Asish K Ghosh, Moises Selman, Annie Pardo, John Varga, David W Kamp, Navdeep S Chandel, Jacob Iasha Sznajder, Manu Jain
Journal: Thorax (2011)

<h3>Background</h3> The development of organ fibrosis after injury requires activation of transforming growth factor β<sub>1</sub> which regulates the transcription of profibrotic genes. The systemic administration of a proteasomal inhibitor has been reported to prevent the development of fibrosis in the liver, kidney and bone marrow. It is hypothesised that proteasomal inhibition would prevent lung and skin fibrosis after injury by inhibiting TGF-β<sub>1</sub>-mediated transcription. <h3>Methods</h3> Bortezomib, a small molecule proteasome inhibitor in widespread clinical use, was administered to mice beginning 7 days after the intratracheal or intradermal administration of bleomycin and lung and skin fibrosis was measured after 21 or 40 days, respectively. To examine the mechanism of this protection, bortezomib was administered to primary normal lung fibroblasts and primary lung and skin fibroblasts obtained from patients with idiopathic pulmonary fibrosis and scleroderma, respectively. <h3>Results</h3> Bortezomib promoted normal repair and prevented lung and skin fibrosis when administered beginning 7 days after the initiation of bleomycin. In primary human lung fibroblasts from normal individuals and patients with idiopathic pulmonary fibrosis and in skin fibroblasts from a patient with scleroderma, bortezomib inhibited TGF-β<sub>1</sub>-mediated target gene expression by inhibiting transcription induced by activated Smads. An increase in the abundance and activity of the nuclear hormone receptor PPARγ, a repressor of Smad-mediated transcription, contributed to this response. <h3>Conclusions</h3> Proteasomal inhibition prevents lung and skin fibrosis after injury in part by increasing the abundance and activity of PPARγ. Proteasomal inhibition may offer a novel therapeutic alternative in patients with dysregulated tissue repair and fibrosis.
NHS Direct could be a useful early warning system for respiratory infections
Authors: Roger Dobson
Journal: BMJ (2007)

More than 600 000 calls about respiratory problems, including influenza and cough, were made over two years to NHS Direct, the NHS's 24 hour telephone helpline.

Almost half of these calls were about fever, says a new study in the Journal of Infection (doi: 10.1016/j.jinf.2007.04.353) that looked at the seasonality of calls concerning respiratory problems that were made to the nurse led service, which has been running for eight years.

Calls concerning cough and difficulty in breathing peaked in late December, and the numbers of calls …
Identification of Epigenetically Silenced Genes in Tumor Endothelial Cells
Authors: Debby M.E.I. Hellebrekers, Veerle Melotte, Emmanuelle Viré, Elise Langenkamp, Grietje Molema, François Fuks, James G. Herman, Wim Van Criekinge, Arjan W. Griffioen, Manon van Engeland
Journal: Cancer Research (2007)

Tumor angiogenesis requires intricate regulation of gene expression in endothelial cells. We recently showed that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors directly repress endothelial cell growth and tumor angiogenesis, suggesting that epigenetic modifications mediated by DNMTs and HDAC are involved in regulation of endothelial cell gene expression during tumor angiogenesis. To understand the mechanisms behind the epigenetic regulation of tumor angiogenesis, we used microarray analysis to perform a comprehensive screen to identify genes down-regulated in tumor-conditioned versus quiescent endothelial cells, and reexpressed by 5-aza-2'-deoxycytidine (DAC) and trichostatin A (TSA). Among the 81 genes identified, 77% harbored a promoter CpG island. Validation of mRNA levels of a subset of genes confirmed significant down-regulation in tumor-conditioned endothelial cells and reactivation by treatment with a combination of DAC and TSA, as well as by both compounds separately. Silencing of these genes in tumor-conditioned endothelial cells correlated with promoter histone H3 deacetylation and loss of H3 lysine 4 methylation, but did not involve DNA methylation of promoter CpG islands. For six genes, down-regulation in microdissected human tumor endothelium was confirmed. Functional validation by RNA interference revealed that clusterin, fibrillin 1, and quiescin Q6 are negative regulators of endothelial cell growth and angiogenesis. In summary, our data identify novel angiogenesis-suppressing genes that become silenced in tumor-conditioned endothelial cells in association with promoter histone modifications and reactivated by DNMT and HDAC inhibitors through reversal of these epigenetic modifications, providing a mechanism for epigenetic regulation of tumor angiogenesis.
<i>HOXB13</i>-to-<i>IL17BR</i> Expression Ratio Is Related With Tumor Aggressiveness and Response to Tamoxifen of Recurrent Breast Cancer: A Retrospective Study
Authors: Maurice P.H.M. Jansen, Anieta M. Sieuwerts, Maxime P. Look, Kirsten Ritstier, Marion E. Meijer-van Gelder, Iris L. van Staveren, Jan G.M. Klijn, John A. Foekens, Els M.J.J. Berns
Journal: Journal of Clinical Oncology (2007)

Purpose A HOXB13-to-IL17BR expression ratio was previously identified to predict clinical outcome of breast cancer patients treated with adjuvant tamoxifen. However, this ratio may predict a tumor's response to tamoxifen, its intrinsic aggressiveness, or both. Patients and Methods We have measured the HOXB13 and IL17BR expression levels by real-time polymerase chain reaction in 1,252 primary breast tumor specimens. Expression levels were normalized to housekeeper gene levels and related to clinicopathologic factors for all patients. The primary objective of this study was to determine the relationship of a HOXB13-to-IL17BR ratio with tumor aggressiveness and/or with response to tamoxifen therapy in estrogen receptor (ER) -positive disease. We selected ER-positive tumors, and clinical end points for the HOXB13-to-IL17BR ratio were disease-free survival (DFS) in patients with primary breast cancer (N = 619) and progression-free survival (PFS) in patients with recurrent breast cancer treated with first-line tamoxifen monotherapy (N = 193). The odds ratio (OR) and hazard ratio (HR) and their 95% CI were calculated, and all P values were two-sided. Results The HOXB13-to-IL17BR ratio was significantly associated with DFS and PFS. In multivariate analysis, HOXB13-to-IL17BR ratio expression levels were associated with a shorter DFS for node-negative patients only. Corrected for traditional predictive factors, the dichotomized HOXB13-to-IL17BR ratio was the strongest predictor in multivariate analysis for a poor response to tamoxifen therapy (OR = 0.16; 95% CI, 0.06 to 0.45; P &lt; .001) and a shorter PFS (HR = 2.97; 95% CI, 1.82 to 4.86; P &lt; .001). Conclusion High HOXB13-to-IL17BR ratio expression levels associate with both tumor aggressiveness and tamoxifen therapy failure.
Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study
Authors: Bernard Fisher, Joseph P. Costantino, D. Lawrence Wickerham, Carol K. Redmond, Maureen Kavanah, Walter M. Cronin, Victor Vogel, André Robidoux, Nikolay Dimitrov, James Atkins, Mary Daly, Samuel Wieand, Elizabeth Tan-Chiu, Leslie Ford, Norman Wolmark
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. Methods: Women (N = 13 388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35–59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n = 6707) or 20 mg/day tamoxifen (n = 6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. Results: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50–59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35–4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. Conclusions: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease. [J Natl Cancer Inst 1998;90:1371–88]
THE RELATION TO THE COURSE OF AVIAN MALARIA OF BIOTIN AND A FAT-SOLUBLE MATERIAL HAVING THE BIOLOGICAL ACTIVITIES OF BIOTIN
Authors: William Trager
Journal: The Journal of Experimental Medicine (1947)

Biotin deficiency produced by a synthetic biotin-deficient diet was as effective in decreasing the resistance of chickens to infection with Plasmodium lophurae as biotin deficiency produced by a diet high in egg white. In moderately biotin-deficient ducks Plasmodium cathemerium at first multiplied more slowly than in adequately fed controls. The parasitemia in the deficient animals later overtook that in the controls and attained higher peak parasite numbers. The multiplication of P. cathemerium was notably inhibited in ducks inoculated when they were approaching death from biotin deficiency. The total and differential leucocyte count of biotin-deficient chickens did not differ significantly from that of adequately fed controls. During infection of chickens with P. lophurae and ducks with either P. lophurae or P. cathemerium significant changes occur in the concentration in the plasma of free biotin and of a material which on hydrolysis yields a fat-soluble substance (FSF) having the biological activities of biotin but differing chemically from it. In ducks which survived infections with P. cathemerium or P. lophurae the biotin concentration rose very early in the course of the infection, before there was any anemia. It fell slightly, rose to a peak at about the time of the peak parasite number, and then returned to normal. The concentration of bound FSF, which was determined in terms of its biotin activity, increased at first, then decreased, then rose and continued at a high level throughout the period of decline in parasitemia. In most of the animals which died of either infection the free biotin, instead of returning to normal, rose to very high values Just before death, while the bound FSF, instead of remaining at a high value, fell to very low values, reaching zero in several animals. Greater resistance seemed to be associated with a greater excess of bound FSF over free biotin. In animals about to die the free biotin exceeded the bound FSF. The biotin content of the liver of ducks and chickens fed an adequate diet and killed just after having undergone an infection with either P. lophurae or P. cathemerium was much less than that of control uninfected animals. When P. lophurae was cultured in vitro in suspensions of duck erythrocytes a very wide range in biotin concentration in the culture fluid did not affect its rate of multiplication. Plasma protein fractions relatively rich in FSF at a concentration of 0.75 per cent inhibited multiplication, while comparable concentrations of plasma fractions poor in FSF did not. The results obtained fit the assumption that the substance in plasma which yields FSF is directly concerned in resistance to avian malaria.
Complexity and Redundancy in the Pathogenesis of Asthma: Reassessing the Roles of Mast Cells and T Cells
Authors: Stephen J. Galli
Journal: The Journal of Experimental Medicine (1997)

Asthma affects millions of people worldwide, and its reported incidence is increasing dramatically in many developed nations; the human and economic costs of this disorder, in morbidity, health care expenses, lost productivity, and, most tragically, even mortality, are staggering (([1][1]), ([2][2
Quantifying resilience: Theoretical or pragmatic for translational research?
Authors: Gleb P. Shumyatsky, Tanja Jovanovic, Talma Handler
Journal: Behavioral and Brain Sciences (2015)

Abstract Quantifying resilience allows for several testable hypotheses, such as that resilience is equal to the number of mental health problems given a known quantity of stressor load. The proposed model lends itself well to prospective studies with data collection pre- and post-adversity; however, prestressor assessments are not always available. Challenges remain for adapting quantifying resilience to animal research, even if the idea of its translation value is significant.
Crosstalk Between BCR/ABL Oncoprotein and CXCR4 Signaling through a Src Family Kinase in Human Leukemia Cells
Authors: Andrzej Ptasznik, Elzbieta Urbanowska, Suneetha Chinta, Melinda A. Costa, Benjamin A. Katz, Marisha A. Stanislaus, Gokhan Demir, Diana Linnekin, Zhixing K. Pan, Alan M. Gewirtz
Journal: The Journal of Experimental Medicine (2002)

Stromal-derived factor (SDF)-1 and its G protein–coupled receptor, CXCR4, regulate stem/progenitor cell migration and retention in the marrow and are required for hematopoiesis. We show here an interaction between CXCR4 and the Src-related kinase, Lyn, in normal progenitors. We demonstrate that CXCR4-dependent stimulation of Lyn is associated with the activation of phosphatidylinositol 3-kinase (PI3-kinase). This chemokine signaling, which involves a Src-related kinase and PI3-kinase, appears to be a target for BCR/ABL, a fusion oncoprotein expressed only in leukemia cells. We show that the binding of phosphorylated BCR/ABL to Lyn results in the constitutive activation of Lyn and PI3-kinase, along with a total loss of responsiveness of these kinases to SDF-1 stimulation. Inhibition of BCR/ABL tyrosine kinase with STI571 restores Lyn responsiveness to SDF-1 signaling. Thus, BCR/ABL perturbs Lyn function through a tyrosine kinase-dependent mechanism. Accordingly, the blockade of Lyn tyrosine kinase inhibits both BCR/ABL-dependent and CXCR4-dependent cell movements. Our results demonstrate, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. These results define a Src tyrosine kinases-dependent mechanism whereby BCR/ABL (and potentially other oncoproteins) dysregulates G protein–coupled receptor signaling and function of mammalian precursors.
The Lymphocyte Function–associated Antigen 1 I Domain Is a Transient Binding Module for Intercellular Adhesion Molecule (ICAM)-1 and ICAM-3 in Hydrodynamic Flow
Authors: Ruth Knorr, Michael L. Dustin
Journal: The Journal of Experimental Medicine (1997)

The I domain of lymphocyte function–associated antigen (LFA)-1 contains an intercellular adhesion molecule (ICAM)-1 and ICAM-3 binding site, but the relationship of this site to regulated adhesion is unknown. To study the adhesive properties of the LFA-1 I domain, we stably expressed a GPI-anchored form of this I domain (I-GPI) on the surface of baby hamster kidney cells. I-GPI cells bound soluble ICAM-1 (sICAM-1) with a low avidity and affinity. Flow cell experiments demonstrated a specific rolling interaction of I-GPI cells on bilayers containing purified full length ICAM-1 or ICAM-3. The LFA-1 activating antibody MEM-83, or its Fab fragment, decreased the rolling velocity of I-GPI cells on ICAM-1–containing membranes. In contrast, the interaction of I-GPI cells with ICAM-3 was blocked by MEM-83. Rolling of I-GPI cells was dependent on the presence of Mg2+. Mn2+ only partially substituted for Mg2+, giving rise to a small fraction of rolling cells and increased rolling velocity. This suggests that the I domain acts as a transient, Mg2+-dependent binding module that cooperates with another Mn2+-stimulated site in LFA-1 to give rise to the stable interaction of intact LFA-1 with ICAM-1.
Response to Bell: Industry Perspective
Authors: Alain D. Baron
Journal: Diabetes Care (2001)

David S.H. Bell’s letter in the March issue of Diabetes Care (1) raises important and timely concerns about the ethics of conducting placebo controlled trials for regulatory approval of compounds for the treatment of type 2 diabetes. Standard pivotal trial design involves withdrawal of patients from current therapy and comparison of the investigational drug with an inactive placebo rather than with current therapy (active placebo) to evaluate efficacy. Bell argues that the use of inactive placebo for 6-month regulatory trials is unethical because of the inherent, potentially detrimental exposure to exaggerated hyperglycemia in placebo-treated patients.

Two competing concerns are at play. The valid concern over the ethics of this traditional, placebo-controlled trial approach is counterbalanced by the equally worrisome potential of missing the actual therapeutic potential of a drug candidate by comparing it with active placebo rather than placebo. At least two general trial designs come to mind for active placebo: The investigational drug could either be added to or substituted for current therapy. In the former situation, the investigational drug would be deemed effective only if effects beyond those achieved with current therapy alone were observed. However, even if no added benefit were observed, the compound might still be effective as monotherapy. For example, there may be no beneficial effect …
Evidence for the Reaffirmation of the U.S. Preventive Services Task Force Recommendation on Screening for High Blood Pressure
Authors: Tracy Wolff, Therese Miller
Journal: Annals of Internal Medicine (2007)

Background: High blood pressure is common, and screening is a well-established evidence-based standard of current medical practice. Purpose: To perform a literature search for new, substantial evidence on screening for high blood pressure that would inform the reaffirmation of the U.S. Preventive Services Task Force recommendation on screening for high blood pressure. Data Sources: The PubMed and Cochrane databases were searched. The searches were limited to English-language articles on studies of adult humans (age >18 years) that were published between 1 October 2001 and 31 March 2006 in core clinical journals. Study Selection: For the literature on benefits, meta-analyses; systematic reviews; and randomized, controlled trials were included. For harms, meta-analyses; systematic reviews; randomized, controlled trials; cohort studies; case–control studies; and case series of large, multisite databases were included. Two reviewers independently reviewed titles, abstracts, and full articles for inclusion. Data Extraction: No new evidence was found on benefits or harms of screening. Two reviewers extracted data from studies on the harms of early treatment, including adverse effects of drug therapy and adverse quality-of-life outcomes. Data Synthesis: No new evidence was found for the benefits of screening for high blood pressure. New evidence on the harms of treatment of early hypertension shows that pharmacologic therapy is associated with common side effects; serious adverse events are uncommon. Limitations: The nonsystematic search may have missed some smaller studies on the benefits and harms of screening and treatment for high blood pressure. Conclusion: No new evidence was found on the benefits of screening. Pharmacotherapy for early hypertension is associated with common side effects.